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Ventilatory control and oxygen uptake during exercise
Ventilatory Control and Oxygen Uptake during bxerczse Children and Adolescents
REGINALD
1. WASHINGTON
Division of Pediatric Cardiology University of Colorado School of Medicine Denver, Colorado
VENTILATORY CONTROL Precise control of ventilation is required during rest and exercise to maintain normal arterial oxygen content and acid-base balance. Although control of breathing in adults has been extensively investigated, few studies are available to define differences in children. However, mechanisms of control probably are the same in children and adults. Normal ventilation is accomplished by inspiration and expiration produced by alternate contraction and relaxation of the diaphragm with quiet breathing. During exercise, accessory muscles are used in varying degrees depending upon the intensity of activity. The movement of these muscle groups is regulated by somatic motor neurons in the spinal cord under the control of respiratory centers located in the medulla oblongata and the pons in the brain stem. The respiratory center is influenced by both neural and humoral receptors. Respiratory
Control
Center
The stimulus for inspiration and expiration comes from neurons within the respiratory control center, acting in a reciprocal way to produce a rhythmic pattern of breathing.l At rest, the cycle of voluntary inspiration and passive expiration is intrinsic Address correspondence to Reginald L. Washington, M.D., Presbyterian/St. Luke’s Medical Center, 1601 E. 19th Avenue, Suite 5600, Denver, CO 80218.
to the neural activity of the medulla. Two additional areas in the pons- the apneustic area and the pneumotaxic area-contribute to respiratory controL2 The apneustic area communicates directly with neurons in the rhythmicity center to stop transmission, functioning as an inspiratory cutoff switch. Respiratory neurons in the pneumotaxic area function to fine tune the activity of the apneustic center, and the two centers function together to regulate the depth of breathing.3 Humoral
Chemoreceptors
Chemoreceptors are specialized neurons that respond to changes in the internal environment; they are described according to their location as central or peripheral. Central chemoreceptors located in the medulla are effected by changes in carbon dioxide tension and hydrogen ion concentration of the cerebrospinal fluid. An increase in either one results in central chemoreceptor stimulation of afferent transmission to the respiratory center to increase ventilation. Peripheral chemoreceptors located in the aortic arch (aortic bodies) and at the bifurcation of the common carotid artery (carotid bodies) respond to increases in arterial carbon dioxide tension and hydrogen ion concentrations. The carotid bodies are sensitive to decreases fn arterial oxygen tension and are more prominent.4 There is evidence that in certain animals, including humans, specialized chemoreceptors in the lungs respond to Prog Pediatr Cardiol 1993: 2(2):24-30 Copyright 0 1993 by Andover Medical
Ventilation and Oxygen Uptake
venous carbon dioxide tensions to change ventilation5 In healthy individuals breathing at sea level, changes in arterial oxygen tensions exert little effect on the control of ventilation.6 However, in environments with barometric pressures below sea level, reduced arterial oxygen tensions stimulate the carotid bodies, signaling the respiratory center to increase ventilation. In humans, aortic and central chemoreceptors do not respond to changes in oxygen tension.
25
both neural and humoral input to the respiratory center is most likely. It seems that neural mechanisms produce the primary drive to breathe during exercise, while humoral chemoreceptors provide a means for precise matching of ventilation with the amount of carbon dioxide produced from muscle metabolism. Because determinants of ventilation change with both the duration and intensity of exercise, it is useful to consider three phases of exercise ventilation: (1) an early dynamic phase, (2) a late dynamic phase, and (3) a steady-state phase.9
Neural Input to the Respiratory Control Center
Neural transmission to the respiratory center passes through both efferent and afferent pathways. During exercise, afferent input originates from one of several peripheral receptors, including muscle spindles and joint pressure receptors2 Moreover, it is possible that special muscle chemoreceptors respond to changes in potassium or hydrogen ion concentrations by sending afferent information to the respiratory center. Recent evidence also suggests that receptors in the right ventricle of the heart send afferent information to the respiratory control center in response to exercise-induced increases in cardiac output .7 Temperature
Increases in body temperature directly stimulate neurons in the respiratory center and probably exert some control over ventilation during prolonged exercise. At the beginning and end of exercise, however, changes in ventilation occur too rapidly to be accounted for by changes in core temperature.8
PULMONARY
GAS EXCHANGE
Muscular exercise imposes a potent and sustained stress on pulmonary gas exchange. The regulation of ventilation is responsible for the transfer of oxygen from the alveoli to the blood at speeds to match utilization rates in muscles. In addition, ventilation is responsible for rapid clearance of carbon dioxide from the body to maintain normal acid-base blood concentrations. There is no agreement on the primary mechanism controlling exercise ventilation. Some studies suggest neural mechanisms are responsible2 and others indicate humoral controls, particularly with carbon dioxide-sensitive receptors. A combination of
Early Dynamic Phase I
The rapid increase in ventilation with exercise has been considered neurogenic, originating in working muscles. However, the magnitude of this initial hyperpnea is nearly constant over a wide range of progressively increasing workloads, indicating that the change in ventilation is not simply proportional to the number of motor units recruited. Gogh and LindhardlO were the first to document systematically that ventilation increases in virtual synchrony with the onset of dynamic muscular exercise. They reasoned that this might be associated with an increase in pulmonary blood flow because oxygen consumption also rose rapidly before muscle metabolites could influence mixed venous blood gas tensions. Subsequently, others showed that pulmonary blood flow and ventilation increase rapidly in an almost precise proportion at the onset of exercise.9 Further evidence of the proportionality between initial ventilation and pulmonary blood flow is found when an increment in work rate is imposed on a background of light exercise, i.e., with limbs already moving. In this condition the rapid component of hyperpnea is limited, despite additional motor unit recruitment.ll This response, although inconclusive, suggests a triggering link between the cardiovascular changes and the hyperpnea, mediated by mechanisms originating in the right ventricle. Evidence suggests a parallel activation of cardiovascular and neurogenic mechanisms that results in the early hyperpnea of exercise during phase I. Later Dynamic Phase 11
During exercise, alterations in mixed venous gas tensions from increased muscle metabolic activity lead to a second response of ventilation and gas
Progress in Pediatric Cardiology
26
exchange that has been termed phase II.9 This slower, delayed hyperpnea is thought to involve humoral mediation, because it begins with a time delay consistent with the limb-to-lung transient delay. Important features of the relationship between ventilation and pulmonary gas exchange emerge from phase II response profiles. The dynamic response of ventilation is highly correlated with carbon dioxide exchange in the lung and probably is not influenced by oxygen exchange in the lung or by the rate of tissue carbon dioxide production.12 It has been shown that for steady-state work, ventilation changes are more linearly related to carbon dioxide production than to oxygen consumption. The distribution of ventilation response to carbon dioxide production is narrow, compared to the wider range observed when ventilation is related to oxygen consumption.” The closeness with which ventilation changes in relationship to carbon dioxide production appears to depend on controls mediated by the carotid body. In humans, peripheral chemoreceptor gain is increased by hypoxia or metabolic acidemia during moderate exercise, resulting in a faster ventilatory response, both in absolute terms and in relationship to carbon dioxide production.’ When peripheral chemosensitivity is reduced by hyperoxia or metabolic alkalemia, the kinetics of the ventilatory response to exercise are slowed. This is especially obvious if the carotid bodies have been removed.9 These receptors, therefore, are probably most important in modulating the dynamics of ventilation in response to changes in carbon dioxide production, effecting the tightness with which arterial carbon dioxide tension is regulated throughout the nonsteady-state phase of muscular exercise. Steady-State
during this phase. Proposed mechanisms have included chemoreceptors that respond to (1)mixed venous carbon dioxide content; (2) carbon dioxide flux across the lung from the pulmonary arteriole to the alveolar gas phase; and (3) carbon dioxide flux across the lung from pulmonary arteries to pulmonary veins.9 Above the threshold for oxygen consumption at which sustained lactic acidemia develops, the dynamic characteristics of ventilatory response to exercise become more complex and steady states are highly nonlinear and often unattainable. During such high-intensity exercise, metabolic lactic acidemia leads to an additional ventilatory drive that provides respiratory compensation of the acidemia. In patients who have had both carotid bodies resected, the increase in ventilatory drive at these work rates is significantly reduced.13 Lactic acidemia is not, however, the exclusive mediator for the additional ventilatory drive above lactate thresholds. Circulating catecholamines, high body temperature, and increased blood osmolarity also may operate at these high work rates. Furthermore, patients with McArdle’s syndrome, who are unable to produce lactic acid because of an enzyme deficiency, hyperventilate and develop respiratory alkalemia at low absolute work rates.14 Integrated
Regulation
The control of breathing during exercise is not the result of a single factor but the combined and probably simultaneous effect of several stimuli. A complex system is responsible for the coordination and synchronization of respiration with tissue metabolic requirements, allowing for appropriate tissue supply of oxygen and elimination of carbon dioxide.
Phase Ill
During moderate exercise the steady-state ventilatory response is a summation of mechanisms operating in phase I and of those superimposed during phase II, resulting in maintenance of arterial carbon dioxide tensions close to resting levels. In analyzing these responses, the hyperventilation that occurs in some resting patients when they begin to breathe through a mouthpiece and valve should be considered, particularly when studying children. Evidence of regulation of arterial carbon dioxide tensions during moderate exercise has prompted the search for a mechanism for humoral control
Studies
in Children
Few studies have evaluated ventilatory control in children. During moderate exercise, children exhibit faster responses than adults for both minute ventilation and carbon dioxide excretion. The kinetics of adjustment for oxygen consumption, however, are the same for children and adults, despite slower kinetics for heart rate in children.15 Thus, in spite of age differences in the control of ventilation and production of carbon dioxide, the regulation of intracellular oxidative metabolism is independent of age.
Ventilation and Oxygen Uptake
The relative contribution of peripheral chemoreceptors to the total ventilatory drive of exercise appears greater in children than in adults, according to studies in 6- to lo-year-olds.16 Additional investigation in children is necessary to identify other possible maturational differences of respiratory control.
OXYGEN UPTAKE The previous section reviewed the control of ventilation and how it changes during exercise to maintain the homeostasis that ensures the transfer of oxygen from the atmosphere to metabolizing cells and the elimination of carbon dioxide into the atmosphere. This interchange of respiratory gases between the atmosphere, alveoli, and pulmonary capillaries has been termed external respiration. Internal respiration is the interchange or diffusion of these gases between systemic capillaries and metabolizing cells. Integration of external and internal respiration requires synchronization of the ventilatory and cardiovascular systems. This section will review oxygen utilization and how oxygen uptake is increased during exercise. Oxygen Utilization The principal source of intracellular energy is from the oxidation of carbohydrates, fats, and proteins. Mammals are obligate aerobic organisms, requiring a match of oxygen demands and supply to the tissue. Anaerobic sources of energy are inadequate and inefficient, especially during conditions of stress such as exercise, fever, anemia, or elevated ambient temperature. Proteins, fats, and carbohydrates are oxidized to form chemical energy through a series of complex, enzymatically controlled intracellular biochemical reactions involving adenosine triphosphate. However, maximal exercise, solely dependent on intracellular stores of adenosine triphosphate, can be performed only for a few seconds. Once adenosine triphosphate has been hydrolyzed to form adenosine diphosphate, it must be resynthesized. This process requires oxygen that must be readily available for exercise to continue. Muscular work places large demands on energy stores, and the intensity and duration of exercise determine the amount of energy transferred from potential stores and whether aerobic metabolism can sustain the energy requirements.17
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Oxygen consumption varies widely in different body organs. These variations often differ dramatically from the relative amounts of blood flow to these organs.is For example, little oxygen is used by the kidney to filter blood, excrete urea, and regulate blood pressure, but the kidney receives at least 20 % of the total cardiac output. On the other hand, the heart has a high demand for oxygen and receives only 3% of the total cardiac output. Each tissue meets its need for oxygen by extracting variable amounts from the blood it receives. Body tissue extracts 25% of the oxygen presented and the difference in oxygen content between arterial and mixed venous blood is 4 ml/d1 to 5 ml/dl. If necessary, each organ can extract 80% to 90% of the arterial oxygen content. Once oxygen extraction has reached its physiologic limit, any additional need must be met solely by increased blood flow.17 During physical activity, oxygen consumption in muscles can become enormous and muscles can require a large part of the total cardiac output to function normally. The mechanisms used for transporting oxygen through the blood have been extensively reviewed and will not be presented here.2,8,9J9 Muscular work increases the total oxygen demand of the body and, in particular, the oxygen consumption of working muscles. To sustain aerobic metabolism, minute ventilation and oxygen delivery must increase at proportional rates to meet the level of oxygen demand. With strenuous work, minute ventilation is 8 to 10 times its resting value. In healthy individuals, ventilation rarely limits aerobic work performance .*7,20During progressive exercise the rate and extent of increase in cardiac output are much less than the increase in minute ventilation. In untrained children, cardiac output often increases only 3 to 5 times resting values.21,22 Unlike the lung, the heart has a limited capacity to perform maximal aerobic work, and enhanced oxygen extraction and circulatory autoregulation play important roles to ensure that oxygen is available during exercise and physical activity.15 The physiologic limits of cardiac output and tissue oxygen extraction determine the aerobic capacity of untrained patients. Beyond these limits, additional increments in work are not accompanied by elevations in oxygen utilization. Accordingly, a plateau in oxygen consumption is obtained during vigorous incremental exercise that is termed the
28
Progress in Pediatric Cardiology
maximal oxygen uptake. This plateau is rarely observed in children.= In physically fit athletes, higher levels of maximal oxygen uptake are found in association with greater cardiac reserves and enhanced oxidative metabolism in trained musclesz4 Carbon dioxide is a product of oxidative metabolism. Any elevation in carbon dioxide creates respiratory acidemia with a decrease in pH that must be buffered to prevent serious intracellular damage. As reviewed in the previous section, carbon dioxide is a major respiratory stimulant. During prolonged muscular work, oxygen consumption may increase too quickly for cardiovascular accommodations and anaerobic skeletal muscle metabolism will be less efficient in producing energy. This anaerobic metabolism produces lactate that is quickly buffered by bicarbonate and transformed to carbon dioxide, which further stimulates respiration. The corresponding level of work and oxygen uptake at which anaerobic metabolism predominates is termed the anaerobic threshold.15r23f25 ~e~o~~nu~ic Alteration and Oxygen Consumption During isotonic-dynamic exercise, oxygen consumption is increased in exercising muscles but not in resting muscles. However, isotonic exercise produces a blood volume challenge to the heart in which its pumping function must increase to handle the increase in venous return and to meet increased peripheral oxygen demands.19 On the other hand, isometric-static exercise is associated mainly with a pressure challenge to the left ventricle. Blood flow to isometrically contracting muscles is markedly decreased because systemic vascular resistance does not fall in those muscles. Isometric exercise results in an increase of heart rate, systolic pressure, and diastolic pressure. However, these changes do not effectively increase the oxygen supply to working muscles, because systemic blood flow is not delivered to working muscles, and the cardiovascular responses are thereby wasted. During isometric exercise, oxygen consumption does not increase to the levels obtained with isotonic exercise.17 When exercise is initiated from rest, at least two phases of oxygen demand are observed. The initial component, lasting 15 to 20 seconds, has been attributed to abrupt augmentation of venous return and cardiac output. l1 This occurs also during Phase
I of ventilation. The increase in oxygen consumption with the beginning of exercise may be related to an increase in pulmonary blood flow. This abrupt increase during the first several seconds of exercise is not observed when exercise is initiated from a background of light exercise or in conditions associated with a decreased systemic venous return such as lying supine.]’
OXYGEN DELIVERY Ventilation In healthy adults, arterial concentrations of oxygen and carbon dioxide are maintained at normal levels throughout progressive exercise, as reviewed above, and peak ventilation does not tax the maximal ventilatory capacity. Limited studies suggest that these concepts apply to children as we11.26.27 In children and adults, values for maximal ventilation with exercise parallel those for absolute maximal oxygen uptake. Maximal ventilation progressively increases in males until 20 to 25 years of age.i9 In females the peak occurs around puberty.” These changes with age are related to body weight and parallel changes of indexed maximal oxygen uptake. Normal values for maximal ventilation range between 1.6 L/kg and 2.0 L/kg. Ventilatory oxygen equivalent is the ratio of the number of liters of air needed to ventilate the lungs to supply 1 L of oxygen consumption, In children, a high value is evidence of less efficient ventilation and it occurs with both maximal and submaximal exercise.26 From childhood to young adult years, there is a trend for a decrease in ventilatory oxygen equivalent, suggesting that maturational factors influence breathing economy during exercise. Ventilation appears adequate for maximal exercise in healthy children, but the added energy requirements created by a greater ventilatory equivalent and higher breathing rates could potentially limit their endurance capacity as compared to adults.19 Oxygen Up take The most commonly used index of maximal aerobic power is the measurement of maximal oxygen uptake, defined as the highest volume of oxygen that can be consumed by the body per unit of time. This value reflects the highest metabolic rate available from aerobic energy turnover.22 As stated above,
Ventilation and Oxygen Uptake
adults have a plateau of oxygen consumption during maximal exercise, which is rarely observed in children. There is an increase in maximal oxygen uptake with growth.= Until 12 years of age, values increase at the same rate in boys and girls, although boys have higher values as early as 5 years of age. As with ventilation, maximal oxygen uptake in boys continues to increase at least until 18 years of age, while in girls it usually plateaus by 14 years. Maximal aerobic power is strongly related to lean body mass. When maximal oxygen uptake is plotted against lean leg volume, the regression line is almost identical for both genders.28 It is desirable to express maximal aerobic power in relative, not absolute, terms. The most useful term for maximal oxygen uptake is milliliters per kilogram,22,23 because there are no appreciable differences with age. Although maximal oxygen consumption indexed for weight does not increase during childhood, the maximal ability to deliver oxygen to exercising muscle, expressed as a multiple of resting oxygen consumption, does increase progressively.26 This rise in the ratio of maximal-to-resting oxygen consumption occurs because maximal uptake remains unchanged with growth during a decline of resting metabolic rate indexed for body mass.27f28The increase in this value during growth may indicate an improvement in tissue oxygen delivery beyond that accounted for by organ growth alone.26
CONCLUSIONS The control of ventilation is vital in maintaining homeostasis during vigorous exercise. Oxygen must be provided to exercise tissues for appropriate metabolic processes to occur; this produces carbon dioxide that must be eliminated rapidly to prevent the development of respiratory acidemia. The mechanisms used to control ventilation have been reviewed here. The study of exercise ventilation in children is limited, and much of the research noted has been done in adults. The data collected so far, however, suggest that the mechanisms are identical in children and adults. Oxygen is vital for the production of energy required for exercise, and mechanisms of oxygen utilization during exercise appear to be the same in children and adults.
29
REFERENCES 1. Ricter D. Generation and maintenance of respiratory rhythm. 1 Exp Biol. 1982;100:93-107. 2. Powers SK, Howley ET. Exercise Physiology: Theory and Application to Fitness and Performance. Dubuque, Iowa: WC Brown; 1990. 3. Levitzky M. Pulmonary Physiology. New York: McGraw-Hill; 1987. 4. Dempsey J, Mitchell G, Smith C. Exercise and chemoreception. Am Rev Respir Dis. 1984;129:31-32. 5. Sheldon M, Green J. Evidence for pulmonary Co2 sensitivity on ventilation. 1 Appl Physiol. 1982;52: 1192-1197. 6. Bennett F. A role for neural pathways in exercise hyperpnea. 1 Appl Physiol. 1984;56:1559-1564. 7. Weissman ML, Jones PW, Oren A, Lamarra N, Whipp BJ, Wasserman K. Cardiac output increase and gas exchange at the start of exercise. J Appl Physiol. 1982;52:236-244. 8. McArdle WD, Katch FL, KatchVL. Exercise Physiology: Energy Nutrition and Human Performance. Philadelphia, PA: Lea and Febiger; 1991. 9. Whipp BJ, Ward SA. Coupling of ventilation to pulmonary gas exchange during exercise. In: Whipp BJ, Wasserman K, eds. Exercise: Pulmonary Physiology and Pathophysiology. New York: Marcel Dekker; 1991: 271-307. 10. Krough A, Lindhard J. The regulation of respiration and circulation during the initial stages of muscular work. ] Physiol. 1913:47:112-136. 11. Whipp B J, Ward SA, Lamarra N, Davis JA, Wasserman K. Parameters of ventilatory and gas exchange dynamics during exercise. 1 Appl Physiol. 1982;52: 1506-1513. 12. Wasserman K, Van Kessel AL, Burton GG: Interaction of physiologic mechanisms during exercise. 1 Appl Physiol. 1967;22:71-85. 13. Whipp BJ, Wasserman K. Carotid bodies and ventilatory control dynamics in man. Fed Proc. 1980;39: 2668-2673. 14. Hagberg JM, Coyle EF, Carroll JE, Miller JM, Martin WH, Brooke MH. Exercise hyperventilation in patients with McArdle’s disease. Appl Physiol. 1982; 52:991-994. 15. Springer C, Barstow T, Wasserman K, Cooper D. Oxygen uptake and heart rate responses during hypoxic exercise in children and adults. Med Sci Sports Exer. 1991;23:71-79. 16. Springer C, Cooper DM, Wasserman K. Evidence that maturation of the peripheral chemoreceptors is not complete in childhood. Respir Physiol. 1988;74: 55-64.
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Progress in Pediatric Cardiology
Exercise 17. Weber KT, Janicki JS.Cardiopulmonary Testing- Physiologic Principles and Clinical Applications. Philadelphia: WB Saunders; 1986. 18. Wade OL, Bishop JM. Cardiac Output and Regional Blood Flow. Philadelphia: FA Davis: 1962. 19. Astrand PO, Rodahl K. Text Book of Work Physiology. Physiotogic Basis of Exercise. New York: McGraw-Hill; 1986. 20. Freedman S. Sustained maximum voluntary ventilation. Respir Physiol. 1970;8:230-244. 21. Braden DS, Strong WB. Cardiovascular response and adaptations to exercise in childhood. In: Gisolfi CV, Lamb DR, eds. Perspectives in Exercise Science and Sports Medicine. Youth Exercise and Sport. Indianapolis: Benchmark Press; 1989:293-333. 22. Bar-Or 0. Pediat~c Sports Medicine for the Practitioner. From PhysioJo~c P~ncipZes to Clinical Ap-
plications. New York: Springer-Verlag; 1983. 23. Washington RL, Van Gundy JC, Cohen CR, Sondheimer HM, Wolfe RR. Normal aerobic and anaerobic exercisedata for North American school-age children. J Fediatr. 1988;112:223-233. 24. HoIloszy JO. Adaptations of muscular tissue to training. Progr Cardiovas Dis. 1976;18:445-458. 25. Washington RL. Anaerobic threshold in children. Pediatr Exer Sci. 1989;1:244-256. 26. Rowland TW. Exercise and Children’s Health. Champaign, ILL: Human Kinetics; 1990, 27. Godfrey S. Exercise Testing in Children: Applications in Health and Disease. London: WB Saunders; 1974. 28. Davies CTM, Barnes C, Godfrey S. Body composition and maximal exercise performance in children. Hum Biot. 1972;44:195-214.
REGINALD
1. WASHINGTON
Division of Pediatric Cardiology University of Colorado School of Medicine Denver, Colorado
VENTILATORY CONTROL Precise control of ventilation is required during rest and exercise to maintain normal arterial oxygen content and acid-base balance. Although control of breathing in adults has been extensively investigated, few studies are available to define differences in children. However, mechanisms of control probably are the same in children and adults. Normal ventilation is accomplished by inspiration and expiration produced by alternate contraction and relaxation of the diaphragm with quiet breathing. During exercise, accessory muscles are used in varying degrees depending upon the intensity of activity. The movement of these muscle groups is regulated by somatic motor neurons in the spinal cord under the control of respiratory centers located in the medulla oblongata and the pons in the brain stem. The respiratory center is influenced by both neural and humoral receptors. Respiratory
Control
Center
The stimulus for inspiration and expiration comes from neurons within the respiratory control center, acting in a reciprocal way to produce a rhythmic pattern of breathing.l At rest, the cycle of voluntary inspiration and passive expiration is intrinsic Address correspondence to Reginald L. Washington, M.D., Presbyterian/St. Luke’s Medical Center, 1601 E. 19th Avenue, Suite 5600, Denver, CO 80218.
to the neural activity of the medulla. Two additional areas in the pons- the apneustic area and the pneumotaxic area-contribute to respiratory controL2 The apneustic area communicates directly with neurons in the rhythmicity center to stop transmission, functioning as an inspiratory cutoff switch. Respiratory neurons in the pneumotaxic area function to fine tune the activity of the apneustic center, and the two centers function together to regulate the depth of breathing.3 Humoral
Chemoreceptors
Chemoreceptors are specialized neurons that respond to changes in the internal environment; they are described according to their location as central or peripheral. Central chemoreceptors located in the medulla are effected by changes in carbon dioxide tension and hydrogen ion concentration of the cerebrospinal fluid. An increase in either one results in central chemoreceptor stimulation of afferent transmission to the respiratory center to increase ventilation. Peripheral chemoreceptors located in the aortic arch (aortic bodies) and at the bifurcation of the common carotid artery (carotid bodies) respond to increases in arterial carbon dioxide tension and hydrogen ion concentrations. The carotid bodies are sensitive to decreases fn arterial oxygen tension and are more prominent.4 There is evidence that in certain animals, including humans, specialized chemoreceptors in the lungs respond to Prog Pediatr Cardiol 1993: 2(2):24-30 Copyright 0 1993 by Andover Medical
Ventilation and Oxygen Uptake
venous carbon dioxide tensions to change ventilation5 In healthy individuals breathing at sea level, changes in arterial oxygen tensions exert little effect on the control of ventilation.6 However, in environments with barometric pressures below sea level, reduced arterial oxygen tensions stimulate the carotid bodies, signaling the respiratory center to increase ventilation. In humans, aortic and central chemoreceptors do not respond to changes in oxygen tension.
25
both neural and humoral input to the respiratory center is most likely. It seems that neural mechanisms produce the primary drive to breathe during exercise, while humoral chemoreceptors provide a means for precise matching of ventilation with the amount of carbon dioxide produced from muscle metabolism. Because determinants of ventilation change with both the duration and intensity of exercise, it is useful to consider three phases of exercise ventilation: (1) an early dynamic phase, (2) a late dynamic phase, and (3) a steady-state phase.9
Neural Input to the Respiratory Control Center
Neural transmission to the respiratory center passes through both efferent and afferent pathways. During exercise, afferent input originates from one of several peripheral receptors, including muscle spindles and joint pressure receptors2 Moreover, it is possible that special muscle chemoreceptors respond to changes in potassium or hydrogen ion concentrations by sending afferent information to the respiratory center. Recent evidence also suggests that receptors in the right ventricle of the heart send afferent information to the respiratory control center in response to exercise-induced increases in cardiac output .7 Temperature
Increases in body temperature directly stimulate neurons in the respiratory center and probably exert some control over ventilation during prolonged exercise. At the beginning and end of exercise, however, changes in ventilation occur too rapidly to be accounted for by changes in core temperature.8
PULMONARY
GAS EXCHANGE
Muscular exercise imposes a potent and sustained stress on pulmonary gas exchange. The regulation of ventilation is responsible for the transfer of oxygen from the alveoli to the blood at speeds to match utilization rates in muscles. In addition, ventilation is responsible for rapid clearance of carbon dioxide from the body to maintain normal acid-base blood concentrations. There is no agreement on the primary mechanism controlling exercise ventilation. Some studies suggest neural mechanisms are responsible2 and others indicate humoral controls, particularly with carbon dioxide-sensitive receptors. A combination of
Early Dynamic Phase I
The rapid increase in ventilation with exercise has been considered neurogenic, originating in working muscles. However, the magnitude of this initial hyperpnea is nearly constant over a wide range of progressively increasing workloads, indicating that the change in ventilation is not simply proportional to the number of motor units recruited. Gogh and LindhardlO were the first to document systematically that ventilation increases in virtual synchrony with the onset of dynamic muscular exercise. They reasoned that this might be associated with an increase in pulmonary blood flow because oxygen consumption also rose rapidly before muscle metabolites could influence mixed venous blood gas tensions. Subsequently, others showed that pulmonary blood flow and ventilation increase rapidly in an almost precise proportion at the onset of exercise.9 Further evidence of the proportionality between initial ventilation and pulmonary blood flow is found when an increment in work rate is imposed on a background of light exercise, i.e., with limbs already moving. In this condition the rapid component of hyperpnea is limited, despite additional motor unit recruitment.ll This response, although inconclusive, suggests a triggering link between the cardiovascular changes and the hyperpnea, mediated by mechanisms originating in the right ventricle. Evidence suggests a parallel activation of cardiovascular and neurogenic mechanisms that results in the early hyperpnea of exercise during phase I. Later Dynamic Phase 11
During exercise, alterations in mixed venous gas tensions from increased muscle metabolic activity lead to a second response of ventilation and gas
Progress in Pediatric Cardiology
26
exchange that has been termed phase II.9 This slower, delayed hyperpnea is thought to involve humoral mediation, because it begins with a time delay consistent with the limb-to-lung transient delay. Important features of the relationship between ventilation and pulmonary gas exchange emerge from phase II response profiles. The dynamic response of ventilation is highly correlated with carbon dioxide exchange in the lung and probably is not influenced by oxygen exchange in the lung or by the rate of tissue carbon dioxide production.12 It has been shown that for steady-state work, ventilation changes are more linearly related to carbon dioxide production than to oxygen consumption. The distribution of ventilation response to carbon dioxide production is narrow, compared to the wider range observed when ventilation is related to oxygen consumption.” The closeness with which ventilation changes in relationship to carbon dioxide production appears to depend on controls mediated by the carotid body. In humans, peripheral chemoreceptor gain is increased by hypoxia or metabolic acidemia during moderate exercise, resulting in a faster ventilatory response, both in absolute terms and in relationship to carbon dioxide production.’ When peripheral chemosensitivity is reduced by hyperoxia or metabolic alkalemia, the kinetics of the ventilatory response to exercise are slowed. This is especially obvious if the carotid bodies have been removed.9 These receptors, therefore, are probably most important in modulating the dynamics of ventilation in response to changes in carbon dioxide production, effecting the tightness with which arterial carbon dioxide tension is regulated throughout the nonsteady-state phase of muscular exercise. Steady-State
during this phase. Proposed mechanisms have included chemoreceptors that respond to (1)mixed venous carbon dioxide content; (2) carbon dioxide flux across the lung from the pulmonary arteriole to the alveolar gas phase; and (3) carbon dioxide flux across the lung from pulmonary arteries to pulmonary veins.9 Above the threshold for oxygen consumption at which sustained lactic acidemia develops, the dynamic characteristics of ventilatory response to exercise become more complex and steady states are highly nonlinear and often unattainable. During such high-intensity exercise, metabolic lactic acidemia leads to an additional ventilatory drive that provides respiratory compensation of the acidemia. In patients who have had both carotid bodies resected, the increase in ventilatory drive at these work rates is significantly reduced.13 Lactic acidemia is not, however, the exclusive mediator for the additional ventilatory drive above lactate thresholds. Circulating catecholamines, high body temperature, and increased blood osmolarity also may operate at these high work rates. Furthermore, patients with McArdle’s syndrome, who are unable to produce lactic acid because of an enzyme deficiency, hyperventilate and develop respiratory alkalemia at low absolute work rates.14 Integrated
Regulation
The control of breathing during exercise is not the result of a single factor but the combined and probably simultaneous effect of several stimuli. A complex system is responsible for the coordination and synchronization of respiration with tissue metabolic requirements, allowing for appropriate tissue supply of oxygen and elimination of carbon dioxide.
Phase Ill
During moderate exercise the steady-state ventilatory response is a summation of mechanisms operating in phase I and of those superimposed during phase II, resulting in maintenance of arterial carbon dioxide tensions close to resting levels. In analyzing these responses, the hyperventilation that occurs in some resting patients when they begin to breathe through a mouthpiece and valve should be considered, particularly when studying children. Evidence of regulation of arterial carbon dioxide tensions during moderate exercise has prompted the search for a mechanism for humoral control
Studies
in Children
Few studies have evaluated ventilatory control in children. During moderate exercise, children exhibit faster responses than adults for both minute ventilation and carbon dioxide excretion. The kinetics of adjustment for oxygen consumption, however, are the same for children and adults, despite slower kinetics for heart rate in children.15 Thus, in spite of age differences in the control of ventilation and production of carbon dioxide, the regulation of intracellular oxidative metabolism is independent of age.
Ventilation and Oxygen Uptake
The relative contribution of peripheral chemoreceptors to the total ventilatory drive of exercise appears greater in children than in adults, according to studies in 6- to lo-year-olds.16 Additional investigation in children is necessary to identify other possible maturational differences of respiratory control.
OXYGEN UPTAKE The previous section reviewed the control of ventilation and how it changes during exercise to maintain the homeostasis that ensures the transfer of oxygen from the atmosphere to metabolizing cells and the elimination of carbon dioxide into the atmosphere. This interchange of respiratory gases between the atmosphere, alveoli, and pulmonary capillaries has been termed external respiration. Internal respiration is the interchange or diffusion of these gases between systemic capillaries and metabolizing cells. Integration of external and internal respiration requires synchronization of the ventilatory and cardiovascular systems. This section will review oxygen utilization and how oxygen uptake is increased during exercise. Oxygen Utilization The principal source of intracellular energy is from the oxidation of carbohydrates, fats, and proteins. Mammals are obligate aerobic organisms, requiring a match of oxygen demands and supply to the tissue. Anaerobic sources of energy are inadequate and inefficient, especially during conditions of stress such as exercise, fever, anemia, or elevated ambient temperature. Proteins, fats, and carbohydrates are oxidized to form chemical energy through a series of complex, enzymatically controlled intracellular biochemical reactions involving adenosine triphosphate. However, maximal exercise, solely dependent on intracellular stores of adenosine triphosphate, can be performed only for a few seconds. Once adenosine triphosphate has been hydrolyzed to form adenosine diphosphate, it must be resynthesized. This process requires oxygen that must be readily available for exercise to continue. Muscular work places large demands on energy stores, and the intensity and duration of exercise determine the amount of energy transferred from potential stores and whether aerobic metabolism can sustain the energy requirements.17
27
Oxygen consumption varies widely in different body organs. These variations often differ dramatically from the relative amounts of blood flow to these organs.is For example, little oxygen is used by the kidney to filter blood, excrete urea, and regulate blood pressure, but the kidney receives at least 20 % of the total cardiac output. On the other hand, the heart has a high demand for oxygen and receives only 3% of the total cardiac output. Each tissue meets its need for oxygen by extracting variable amounts from the blood it receives. Body tissue extracts 25% of the oxygen presented and the difference in oxygen content between arterial and mixed venous blood is 4 ml/d1 to 5 ml/dl. If necessary, each organ can extract 80% to 90% of the arterial oxygen content. Once oxygen extraction has reached its physiologic limit, any additional need must be met solely by increased blood flow.17 During physical activity, oxygen consumption in muscles can become enormous and muscles can require a large part of the total cardiac output to function normally. The mechanisms used for transporting oxygen through the blood have been extensively reviewed and will not be presented here.2,8,9J9 Muscular work increases the total oxygen demand of the body and, in particular, the oxygen consumption of working muscles. To sustain aerobic metabolism, minute ventilation and oxygen delivery must increase at proportional rates to meet the level of oxygen demand. With strenuous work, minute ventilation is 8 to 10 times its resting value. In healthy individuals, ventilation rarely limits aerobic work performance .*7,20During progressive exercise the rate and extent of increase in cardiac output are much less than the increase in minute ventilation. In untrained children, cardiac output often increases only 3 to 5 times resting values.21,22 Unlike the lung, the heart has a limited capacity to perform maximal aerobic work, and enhanced oxygen extraction and circulatory autoregulation play important roles to ensure that oxygen is available during exercise and physical activity.15 The physiologic limits of cardiac output and tissue oxygen extraction determine the aerobic capacity of untrained patients. Beyond these limits, additional increments in work are not accompanied by elevations in oxygen utilization. Accordingly, a plateau in oxygen consumption is obtained during vigorous incremental exercise that is termed the
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Progress in Pediatric Cardiology
maximal oxygen uptake. This plateau is rarely observed in children.= In physically fit athletes, higher levels of maximal oxygen uptake are found in association with greater cardiac reserves and enhanced oxidative metabolism in trained musclesz4 Carbon dioxide is a product of oxidative metabolism. Any elevation in carbon dioxide creates respiratory acidemia with a decrease in pH that must be buffered to prevent serious intracellular damage. As reviewed in the previous section, carbon dioxide is a major respiratory stimulant. During prolonged muscular work, oxygen consumption may increase too quickly for cardiovascular accommodations and anaerobic skeletal muscle metabolism will be less efficient in producing energy. This anaerobic metabolism produces lactate that is quickly buffered by bicarbonate and transformed to carbon dioxide, which further stimulates respiration. The corresponding level of work and oxygen uptake at which anaerobic metabolism predominates is termed the anaerobic threshold.15r23f25 ~e~o~~nu~ic Alteration and Oxygen Consumption During isotonic-dynamic exercise, oxygen consumption is increased in exercising muscles but not in resting muscles. However, isotonic exercise produces a blood volume challenge to the heart in which its pumping function must increase to handle the increase in venous return and to meet increased peripheral oxygen demands.19 On the other hand, isometric-static exercise is associated mainly with a pressure challenge to the left ventricle. Blood flow to isometrically contracting muscles is markedly decreased because systemic vascular resistance does not fall in those muscles. Isometric exercise results in an increase of heart rate, systolic pressure, and diastolic pressure. However, these changes do not effectively increase the oxygen supply to working muscles, because systemic blood flow is not delivered to working muscles, and the cardiovascular responses are thereby wasted. During isometric exercise, oxygen consumption does not increase to the levels obtained with isotonic exercise.17 When exercise is initiated from rest, at least two phases of oxygen demand are observed. The initial component, lasting 15 to 20 seconds, has been attributed to abrupt augmentation of venous return and cardiac output. l1 This occurs also during Phase
I of ventilation. The increase in oxygen consumption with the beginning of exercise may be related to an increase in pulmonary blood flow. This abrupt increase during the first several seconds of exercise is not observed when exercise is initiated from a background of light exercise or in conditions associated with a decreased systemic venous return such as lying supine.]’
OXYGEN DELIVERY Ventilation In healthy adults, arterial concentrations of oxygen and carbon dioxide are maintained at normal levels throughout progressive exercise, as reviewed above, and peak ventilation does not tax the maximal ventilatory capacity. Limited studies suggest that these concepts apply to children as we11.26.27 In children and adults, values for maximal ventilation with exercise parallel those for absolute maximal oxygen uptake. Maximal ventilation progressively increases in males until 20 to 25 years of age.i9 In females the peak occurs around puberty.” These changes with age are related to body weight and parallel changes of indexed maximal oxygen uptake. Normal values for maximal ventilation range between 1.6 L/kg and 2.0 L/kg. Ventilatory oxygen equivalent is the ratio of the number of liters of air needed to ventilate the lungs to supply 1 L of oxygen consumption, In children, a high value is evidence of less efficient ventilation and it occurs with both maximal and submaximal exercise.26 From childhood to young adult years, there is a trend for a decrease in ventilatory oxygen equivalent, suggesting that maturational factors influence breathing economy during exercise. Ventilation appears adequate for maximal exercise in healthy children, but the added energy requirements created by a greater ventilatory equivalent and higher breathing rates could potentially limit their endurance capacity as compared to adults.19 Oxygen Up take The most commonly used index of maximal aerobic power is the measurement of maximal oxygen uptake, defined as the highest volume of oxygen that can be consumed by the body per unit of time. This value reflects the highest metabolic rate available from aerobic energy turnover.22 As stated above,
Ventilation and Oxygen Uptake
adults have a plateau of oxygen consumption during maximal exercise, which is rarely observed in children. There is an increase in maximal oxygen uptake with growth.= Until 12 years of age, values increase at the same rate in boys and girls, although boys have higher values as early as 5 years of age. As with ventilation, maximal oxygen uptake in boys continues to increase at least until 18 years of age, while in girls it usually plateaus by 14 years. Maximal aerobic power is strongly related to lean body mass. When maximal oxygen uptake is plotted against lean leg volume, the regression line is almost identical for both genders.28 It is desirable to express maximal aerobic power in relative, not absolute, terms. The most useful term for maximal oxygen uptake is milliliters per kilogram,22,23 because there are no appreciable differences with age. Although maximal oxygen consumption indexed for weight does not increase during childhood, the maximal ability to deliver oxygen to exercising muscle, expressed as a multiple of resting oxygen consumption, does increase progressively.26 This rise in the ratio of maximal-to-resting oxygen consumption occurs because maximal uptake remains unchanged with growth during a decline of resting metabolic rate indexed for body mass.27f28The increase in this value during growth may indicate an improvement in tissue oxygen delivery beyond that accounted for by organ growth alone.26
CONCLUSIONS The control of ventilation is vital in maintaining homeostasis during vigorous exercise. Oxygen must be provided to exercise tissues for appropriate metabolic processes to occur; this produces carbon dioxide that must be eliminated rapidly to prevent the development of respiratory acidemia. The mechanisms used to control ventilation have been reviewed here. The study of exercise ventilation in children is limited, and much of the research noted has been done in adults. The data collected so far, however, suggest that the mechanisms are identical in children and adults. Oxygen is vital for the production of energy required for exercise, and mechanisms of oxygen utilization during exercise appear to be the same in children and adults.
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REFERENCES 1. Ricter D. Generation and maintenance of respiratory rhythm. 1 Exp Biol. 1982;100:93-107. 2. Powers SK, Howley ET. Exercise Physiology: Theory and Application to Fitness and Performance. Dubuque, Iowa: WC Brown; 1990. 3. Levitzky M. Pulmonary Physiology. New York: McGraw-Hill; 1987. 4. Dempsey J, Mitchell G, Smith C. Exercise and chemoreception. Am Rev Respir Dis. 1984;129:31-32. 5. Sheldon M, Green J. Evidence for pulmonary Co2 sensitivity on ventilation. 1 Appl Physiol. 1982;52: 1192-1197. 6. Bennett F. A role for neural pathways in exercise hyperpnea. 1 Appl Physiol. 1984;56:1559-1564. 7. Weissman ML, Jones PW, Oren A, Lamarra N, Whipp BJ, Wasserman K. Cardiac output increase and gas exchange at the start of exercise. J Appl Physiol. 1982;52:236-244. 8. McArdle WD, Katch FL, KatchVL. Exercise Physiology: Energy Nutrition and Human Performance. Philadelphia, PA: Lea and Febiger; 1991. 9. Whipp BJ, Ward SA. Coupling of ventilation to pulmonary gas exchange during exercise. In: Whipp BJ, Wasserman K, eds. Exercise: Pulmonary Physiology and Pathophysiology. New York: Marcel Dekker; 1991: 271-307. 10. Krough A, Lindhard J. The regulation of respiration and circulation during the initial stages of muscular work. ] Physiol. 1913:47:112-136. 11. Whipp B J, Ward SA, Lamarra N, Davis JA, Wasserman K. Parameters of ventilatory and gas exchange dynamics during exercise. 1 Appl Physiol. 1982;52: 1506-1513. 12. Wasserman K, Van Kessel AL, Burton GG: Interaction of physiologic mechanisms during exercise. 1 Appl Physiol. 1967;22:71-85. 13. Whipp BJ, Wasserman K. Carotid bodies and ventilatory control dynamics in man. Fed Proc. 1980;39: 2668-2673. 14. Hagberg JM, Coyle EF, Carroll JE, Miller JM, Martin WH, Brooke MH. Exercise hyperventilation in patients with McArdle’s disease. Appl Physiol. 1982; 52:991-994. 15. Springer C, Barstow T, Wasserman K, Cooper D. Oxygen uptake and heart rate responses during hypoxic exercise in children and adults. Med Sci Sports Exer. 1991;23:71-79. 16. Springer C, Cooper DM, Wasserman K. Evidence that maturation of the peripheral chemoreceptors is not complete in childhood. Respir Physiol. 1988;74: 55-64.
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Exercise 17. Weber KT, Janicki JS.Cardiopulmonary Testing- Physiologic Principles and Clinical Applications. Philadelphia: WB Saunders; 1986. 18. Wade OL, Bishop JM. Cardiac Output and Regional Blood Flow. Philadelphia: FA Davis: 1962. 19. Astrand PO, Rodahl K. Text Book of Work Physiology. Physiotogic Basis of Exercise. New York: McGraw-Hill; 1986. 20. Freedman S. Sustained maximum voluntary ventilation. Respir Physiol. 1970;8:230-244. 21. Braden DS, Strong WB. Cardiovascular response and adaptations to exercise in childhood. In: Gisolfi CV, Lamb DR, eds. Perspectives in Exercise Science and Sports Medicine. Youth Exercise and Sport. Indianapolis: Benchmark Press; 1989:293-333. 22. Bar-Or 0. Pediat~c Sports Medicine for the Practitioner. From PhysioJo~c P~ncipZes to Clinical Ap-
plications. New York: Springer-Verlag; 1983. 23. Washington RL, Van Gundy JC, Cohen CR, Sondheimer HM, Wolfe RR. Normal aerobic and anaerobic exercisedata for North American school-age children. J Fediatr. 1988;112:223-233. 24. HoIloszy JO. Adaptations of muscular tissue to training. Progr Cardiovas Dis. 1976;18:445-458. 25. Washington RL. Anaerobic threshold in children. Pediatr Exer Sci. 1989;1:244-256. 26. Rowland TW. Exercise and Children’s Health. Champaign, ILL: Human Kinetics; 1990, 27. Godfrey S. Exercise Testing in Children: Applications in Health and Disease. London: WB Saunders; 1974. 28. Davies CTM, Barnes C, Godfrey S. Body composition and maximal exercise performance in children. Hum Biot. 1972;44:195-214.