Techniques for Measuring the Responsiveness of the Ventilatory Apparatus in Man in Disease

Techniques for Measuring the Responsiveness of the Ventilatory Apparatus in Man in Disease* Gerard M. Turino, M.D. and Roberta M. Goldring, M.D.

presence of disease of the ventilatory apparatus T hecompounds the difficulty in understanding the role of

various components in the regulation of ventilation. Abnormalities of the ventilatory apparatus or its regulation may arise from primary pathogenetic factors in the lungchest wall system, the central nervous system or secondarily from the consequences of hypercarbia and hypoxemia. In this article, and the following, we shall discuss ventilatory stimuli and responsiveness in disease. Study of the responsiveness of the ventilatory apparatus in a patient should give information on the overall effect· of a disease on the patient's system of ventilatory regulation, but should also define precisely the disturbed components in the regulation of ventilation. On both scores, the standard techniques for studying the regulation of ventilation are inconclusive. What is required is a separation and quantification of the multiple pathogenetic factors which impose their effects on the regulation of ventilation and what in fact we obtain by present testing methods are composite effects. Also, the standard responses to testing which separate normal from abnormal are broad and therefore often illdefined. Some of these pathogenetic factors are demonstrated in Figure 1. To the left in this figure, we have listed the usual, accepted stimuli to ventilation (input functions) which occur in disease and can be imposed in the testing situation. That is, reduced arterial Po 2 , increased hydrogen ion concentration and increased arterial Pco., However, superimposed on these factors and often unrecognized are peripheral neurogenic stimuli, changes in the metabolic state and the level of catecholamine stimulation in the blood and tissues. On the side of the ventilatory response in disease (output functions, Fig 1), we are primarily concerned with two kinds of mechanical limitations. The first is mechanical loading induced by disease such as increased airway obstruction, reduced compliance and changes in chest configuration; a second mechanical limitation is the state of the ventilatory apparatus with respect to muscle function of the chest wall and abdomen. The latter are factors which at the present time can only be approximated. They include the state of conditioning of the musculature in these locations in association with chronic disease, the loss of tissue mass of muscle as a

°From the Departments of Medicine, Columbia-Presbyterian

Medical Center and New York University-Bellevue Medical Center, New York City. Supported in part by Grants from the USPHS-HL 15832, the New York Lung Association, the American Lung Association, the Health Research Council of the City of New York U 2237, and the New York Heart Association. Reprint requests: Dr. Turino, 630 West 168th Street, New York City 10032

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result of disuse atrophy, and finally, the occurrence of actual neuromuscular dysfunction which may be an associated feature of the disease or a consequence of pharmacologic interventions. Also, a change in state of inflation of configuration of the chest and lungs may effect both response and stimulus by affecting chest muscle and pulmonary afferent neural pathways. Ultimately new techniques to study the regulation of ventilation in disease should identify and quantify each specific component in addition to overall responsiveness. Overall ventilatory responsiveness to stimuli such as increased inspired CO 2 or exercise are a necessary and important part of the evaluation of the patient, but can be only part of the analysis. No one technique for studying the regulation of ventilation at present answers all the questions which arise in understanding either the patient or the disease process in the patient. I should like to illustrate the limitations of our current approaches to the study of ventilatory responsiveness in disease by considering studies in four different categories of clinical abnormality: 1) airway obstructive disease; 2) obesity; 3) hyperthyroidism and hypothyroidism, and 4) a note on ventilatory responsiveness in interstitial lung disease.

Airway Obstructive Disease The major dilemma in understanding the regulation of ventilation in airway obstructive disease has been to separate alterations in the sensitivity of the CNS respiratory centers from the increased mechanical resistances imposed by obstruction of airways, It has been known since the time of Scott" that patients with airway obstructive disease demonstrated a reduced ventilatory response to breathing carbon dioxide. It soon became clear from the work of Chemiack and Snidal- and Eldridge and Davis" that the increase in airway resistance per se was capable of reducing the ventilatory response to breathing CO 2 , Also, it could be shown that if mechanical work of breathing done on the lung during the ventilatory response was plotted as the response rather than total minute ventilation, then normal subjects breathing CO 2 or normal subjects with an added increase in airway resistance and the patients with obstructive lung disease all had similar slopes of mechanical work of breathing per minute versus arterial PC02 • 3 , . This occured even though the intercept for PaC0 2 for patients with obstructive disease was higher than for normal subjects. However, it is equally clear that when a separation is made of patients who have distinctly elevated values of arterial Pco, and serum bicarbonate that the response of the ventilation to inspired CO 2 is below normal even when expressed in terms of the work per minute.s-"? In most studies, it can be shown that the airway resistance of patients with elevated arterial Pco, and serum bicarbonate values are also higher than patients with obstructive disease who have normal arterial Pco, and bicarbonate levels so that the use of either minute ventilation or mechanical work to separate factors of mechanical limitation to ventilation or a reduced output of the respiratory center was not possible from these measure-

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FACTORS IN DISEASE EFFECTING VENTILATORY CONTROL STIMULI

(INPUT FUNCTIONS)

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ALTERED H+, Pe0I-HCOi RELATIONSHIP

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SYMPATHOADRENAL EFFECTS GENERAL AND CNS METABOLIC STATE BODY TEMPERATURE PHARMACOLOGIC DEPRESSION AND EXCITATION CIRCULATORY LAGS ALTERED PERIPHERAL STIMULI

RESPONSES

(OUTPUT FUNCTIONS) NON- ELASTIC AND ELASTIC RESISTANCES OF LUNGS,THORAX AND ABDOMEN COl OUTPUT ( VT • f,

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VENTILATORY MUSCLE FUNCTION DECONDITIONING ATROPHY NEUROMUSCULAR DYSFUNCTION PHARMACOLOGIC PRIMARY SYMPATHOADRENAL EFFECTS LUNG INFLATION AND THORACIC CONFIG.

FIGURE 1. Factors influencing ventilatory stimuli and responses in disease in man (see text).

ments alone. The use of measurements of oxygen cost of breathing as the response provided information which is not qualitatively different from that provided by the measurements of mechanical work on the Iung.t-" These measurements can be more difficult and one assumes that the efficiency of the oxygen cost in terms of the development of mechanical work is the same when breathing room air as breathing CO 2 in the same individual and when comparing different individuals. This assumption is not readily subject to validation. It was on the basis of the continued dilemma in separating reduced central nervous system output from increased mechanical limitation. to ventilation that the technique of electromyography of the diaphragm was introduced into studies of the regulation of ventilation in disease. Using this technique, it could be clearly shown that individuals with elevated arterial Pco, and bicarbonate showed reduced electromyographic activity as compared with normal subjects or patients with obstructive lung disease who had normal values for arterial PC0 2 • 9 It may be accepted, therefore, that individuals with elevations of extracellular HC0 3- can have reduced neural drive which is the consequence of decreased hydrogen ion generation as CO 2 tension increases, and is a reversible state. With respect to techniques, however, while electromyography offers the prospect of defining the nervous output of the respiratory center, it is technically difficult to do. The quantification of electromyographic activity is imprecise and one can only determine whether activity is comparable to normal or above or below with no good way of providing a quantifying number which can be related to the nervous activity or translation of that nervous activity into muscular activity given normal muscle function. It was from this background that a noninvasive technique which could represent neural output and which could be subject to quantification in terms of muscle activity was particularly welcomed and thus mouth occlusion pressure measurements appeared on the scene. to A few studies have been done measuring mouth pres~HEST,

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sure after airway occlusion and the ventilatory response to breathing CO 2, The work of Maranetra and Payne' ' shows data on the CO 2 response by a rebreathing technique and occlusion pressure within the first 200 milliseconds of inspiration. The occlusion pressure of patients with obstructive lung disease whose resting arterial Pco, is elevated (mean 51 mm Hg) had significantly lower occlusion pressures than patients with obstructive lung disease whose arterial Pco, was in the normal range (40 mmHg). A further role for the effect of elevations of body buffering as a crucial mechanism for blunting the ventilatory response to CO 2 carried out by any technique is the work of Schaefer et a}12 in normal dogs exposed to 3 percent CO 2 for several days and the work of Chapin et a}13 in which normal men were exposed to CO 2 in the inspired gas for 72 hours. The changes in the total buffering capacity in limiting the increment in H + ion with increases in CO 2 in these normal subjects would seem to be adequate to explain the reversible diminution of ventilatory responsiveness in normal man and animals. It can be predicted, therefore, that tests of ventilatory responsiveness in any subject who has a significantly elevated Pco, and bicarbonate will demonstrate a reduced ventilatory response and probably reduced ventilatory drive. However, we need methods which can quantify the proportion of the reduced ventilatory response which derives from reduced neural output and that which comes from mechanical loads and muscle weakness. These last components are crucial to the study of ventilatory regulation in other diseases apart from airway obstruction syndromes. It is noteworthy that mouth occlusion pressure during the first 200 milliseconds of inspiration also may not distinguish inspiratory muscle weakness from reduced ventilatory drive.

Obesity Studies of ventilatory control in obese patients are particularly complex because of changes in total body endogenous oxygen consumption and CO 2 production associated with weight gain and weight loss and also the influence of obesity on lung function, ie a tendency

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toward lower lobe collapse, reduced expiratory reserve volume, regional ventilation-perfusion imbalance and reduced compliance of the thorax.>' The number of patients with obesity who manifest the obesity-hypoventilation syndrome are few, relative to the number of individuals who are obese and the correlations of the degree of obesity with the occurrence of this syndrome are poor. H • 1 5 However, once the syndrome is established, it seems clear that weight loss per se does improve ventilatory responsiveness to the CO 2 stirnuIUS. 16 • 19 Studies of the actual effect of weight loss on the ventilatory response to CO 2 breathing in patients with obesity who are not hypoventilators indicates that weight loss per se has no effect on either the responsiveness to CO 2 breathing or to induced hypoxia.t? However, recent studies of hypoxic ventilatory drive in those patients with the obesity-hypoventilation syndrome show a decreased hypoxic drive of unknown etiology which might, however, be an important initiating factor in the development of the hypoventilation in this syndrome. 2 l , 22 The coincident abnormalities of lung function associated with the obese state, ie reduced ERV, lower lobe collapse and regional ventilation-perfusion imbalances makes the interpretation of increases or decreases in slope of the total ventilation, arterial Pco, relationship especially difficult in terms of respiratory center function with weight loss. In the obese state, because of less efficient elimination of CO 2 by the lungs, the total ventilation will be higher for a given change in arterial Pco, while breathing carbon dioxide than when the subject has lost weight and his lung function has become more normal. Thus, the slope of total minute ventilation against arterial Pco; will become reduced in such subjects who possess normal responsiveness to ventilation, but have an improved state of gas exchanging efficiency for CO 2 , This could appear to indicate a reduced respon-

siveness after weight loss by virtue of a lower total ventilation for the same increase in arterial Pco.. Such a result would be mainly a function of the ability of the lungs to expire a CO 2 load rather than any change in the responsiveness of the central respiratory centers. Such results have been demonstrated by Emirgil and Sobol'" in obese individuals who did not have the alveolar hypoventilation syndrome, but who had undergone substantial weight loss (62 to 150 lb). The data from this study are shown in Figure 2. Whether the ventilatory response to breathing CO 2 is plotted in terms of total ventilation or ventilation corrected for body surface area or body weight, the slopes are Hatter after weight loss than before weight loss. Analysis of ventilatory responses in terms of alveolar ventilation rather than total ventilation could give further insights into such patients and might better demonstrate the lack of a change in ventilatory response in the two states. Hyperthyroidism The response to breathing CO 2 has been found by Engel and Hitchie> to be different in subjects who are hyperthyroid as compared to their euthyroid state after treatment. The basis of this change is of interest in trying to understand the factors which can influence ventilatory control in disease and which can effect responses to breathing CO 2 in normal subjects as well. In the study by Engel and Ritchie, a rebreathing method was used which showed a significant increase (mean change 40 percent) in the slope of the response with respect to alveolar Pco, in the hyperthyroid state, but without, however, a change in the horizontal axis intercept. They also demonstrated that the slope was largely increased by an increase in breathing frequency rather than tidal volume. In hyperthyroidism, the metabolic rate is increased with respect to the euthyroid state which could conceivably effect the rate of rise of ventilation when rebreathing. However, in normal subjects, it has been

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FIGURE 2. The effect of weight reduction on the ventilatory response to breathing 3 percent and 5 percent C02 in room air plotted for A) total minute ventilation, B) ventilation corrected for body surface area, C) ventilation corrected for body weight. Each symbol represents the mean for four subjects studied who were obese, but did not have the obesity-hypoventilation syndrome. Closed circles before weight reduction and open circles after weight reduction. The slope of the ventilatory response is diminished after weight reduction for total or corrected ventilatory volumes. (From Emirgil and Sobol.23)

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demonstrated that deliberate lowering of the rate at which arterial Pco, increases by the use of a very large rebreathing bag, does not alter the slope of the ventilation-alveolar Pco, relationship even when the increase is reduced by a factor of two-thirds."; Since there is no evidence that factors such as changes in mechanics of the lung and chest wall are significantly different in hyperthyroidism and euthyroidism.>" and since there is no evidence to implicate a difference in the rate of rise of Pco, in the medullary chemoreceptors as compared to arterial Pco, in the rebreathing method in hyperthyroidism.>' it seems likely that other inHuences are present which can explain this difference in ventilatory responsiveness in the hyperthyroid state. These other influences may be an increased rate of secretion of adrenalin and noradrenalin in hyperthyroidism and the increased secretion of catecholamine during the breathing of carbon dioxide acutely. During CO 2 inhalation, the plasma concentrations of adrenalin and noradrenalin are measurably increased when the end-expiratory Pco, exceeds 50 mm Hg.27 The changes in concentrations of these substances in the plasma are positively correlated with the changes in Pco., Also it is clear that intravenous infusion of physiologic doses of catecholamines 10 p.g/min in normal subjects produces increases in ventilations" and a lowering of alveolar tension of CO 2 , In addition, in hyperthyroidism, the adrenal medulla has been shown to have a greater reserve and more rapid secretion of catecholamine.w Also, urinary secretion of both adrenalin and noradrenalin has been shown to be increased after exposure to CO 2 of hyperthyroid rats as compared with euthyroid animals.w It may be suggested, therefore, that the increased ventilatory response to rebreathing in hyperthyroidism is related to the greater adrenosympathetic activity and circulating levels of catecholamines during breathing CO 2 in the hyperthyroid state. It is' also possible that techniques of breathing CO 2 to study ventilation which result in larger changes in blood hydrogen ion concentration would result in greater changes in catecholamine secretion. Nahas and Steinsland'" have shown an increase in adrenal medullary secretion results from increases in hydrogen ion in the isolated dog adrenal gland, as well as during induced respiratory acidosis in the rat. Thus, rebreathing methods which result in a greater reduction in blood pH may more easily stimulate increased catecholamine secretion in hyperthyroidism. The ability of CO 2 breathing to stimulate catecholamine secretion which itself increases ventilatory responsiveness in the normal subject could be a highly significant factor in determining the individual ventilatory response to breathing carbon dioxide and therefore the wide range of normal ventilatory responses which hasbeen observed in normal man.v Similarly, the state of catecholamine metabolism in other diseases in which ventilatory responsiveness is measured, such as obstructive lung disease, has not been evaluated and may be an important added factor in explaining differences between individuals or in the same individual at different

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sittings. The occurrence of alveolar hypoventilation in myxedema and in hypothyroidism may also be influenced by reduced adrenosympathetic activity. However, it has been demonstrated recently-" that there is a loss of hypoxic drive in myxedema which may be a critical factor in setting the stage for alveolar hypoventilation when the ventilatory system is stressed by airway obstruction and increased body weight in combination with reduced thyroid function. Also, the local metabolism of cellular substrates in the region of the medullary chemoreceptors in abnormal metabolic states such as hyperthyroidism and hypothyroidism may alter the amounts of CO 2 production locally and therefore the regional hydrogen ion concentration. These factors, though difficult to study, may be potentially important in abnormal ventilatory control in disease.

Diffuse Pulmonary Fibrosis The study of ventilatory responsiveness in patients with diffuse interstitial disease, or pulmonary fibrosis, as it has been called, involves a combination of pathogenetic factors which are unique to this form of lung diseaser'" 1) airway resistance may be normal or only mildly increased; 2) lung volume is reduced with usually a lower mid-position of the thorax; 3) hypoxemia at rest is mild or not present and the arterial Pco, is not elevated and is commonly below normal; 4) the work of breathing is increased as a result of reduced lung compliance with usually well maintained airway conductance. The results of measurements of ventilatory response to breathing 5 percent CO 2 in a group of subjects with typical clinical and physiologic characteristics of interstitial disease of the lung are shown in Figure 3. It can be seen that: 1) the initial and final ventilations to breathing 5 percent CO 2 are generally higher in patients with pulmonary fibrosis than in normal subjects; 2) in general, the responses to breathing 5 percent CO 2 of patients lie to the left of the lines for the normal subject; and 3) while there is not a statistically significant difference in slope between the normal subjects and patients with diffuse fibrosis, there is some increase in slope as the room air values of resting arterial Pco, and bicarbonate move to lower levels. In Figure 4, the response to breathing 5 percent CO 2 in air of patients with diffuse pulmonary fibrosis is plotted against the resting level of whole blood carbon dioxide content while breathing room air. There is an excellent correlation between the level of resting CO 2 content and the ventilatory response plotted as percent increase in ventilation when breathing 5 percent CO 2 , In diffuse interstitial disease of the lung, there is often chronic hypocapnia, and as demonstrated in chronic hypercapnia, the ventilatory response to breathing carbon dioxide is determined in part by the starting concentration of buffer base in the extracellular fluid which becomes a modulator for the hydrogen ion response to breathing carbon dioxide. In cases of diffuse interstitial disease, at a time when

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FIGURE 3. Ventilatory responses of 12 normal subjects and of 15 patients with diffuse pulmonary fibrosis to breathing 5 percent of CO2 in air. Initial and final ventilations are generally higher in patients with diffuse fibrosis (right panel) than in normal subjects (left panel and shaded background of right panel). However, the slopes of the response curves do not differ significantly. Closed circles subjects breathing air; open circles subjects breathing 5 percent CO2 in air. ( From Lourenco et al34 )

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high resting minute ventilation can be demonstrated, the resting arterial P0 2 is only slightly reduced below normal and the administration of 40 percent oxygen in nitrogen does not lower the resting ventilation in most subjects. Taken together, these data then indicate an increased ventilatory drive in diffuse fibrosis which is most probably arising from the interstitium of the lung. The exact locus of such stimuli remains to be determined. It is noteworthy that Thompson and Reed,35 in normal subjects in whom chest strapping simulated a re-

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strictive abnormality of the lungs and chest wall, showed that minute ventilation at all levels of arterial Pco, while breathing a 7 percent CO 2 oxygen-enriched mixture was the same as in normal subjects and that chest strapping which diminished lung volume and increased chest wall compliance did not reduce the total ventilatory response to CO 2 breathing from that without strapping. These data indicate that increased mechanical loading of the normal ventilatory apparatus brought about by reduced lung or chest wall compliance does not diminish the ventilatory response to CO 2 breathing as occurs in mechanical loading by increased airway resistance.

SERUM

More complete understanding of the disturbances in the regulation of ventilation in disease must await techniques which can estimate the neural output of the respiratory centers and also the neural inputs. Some of these techniques, such as diaphragmatic electromyography, offer the prospect of clinical usefulness even now and newer techniques, such as mouth occlusion pressure, are promising but have just begun to be evaluated in disease. Despite the limited ability of current techniques to clearly distinguish abnormal central nervous system function of ventilatory control from peripheral mechanical limitations to ventilation, a useful interpretation of clinical tests of ventilatory responsiveness may be gained by an awareness of the many physiologic and pathogenetic factors which are interposed by disease. These factors may reinforce or diminish both stimuli and response. In chronic disease states, these modifying factors must be identified and evaluated for their role in altered ventila-

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tory responsiveness. Frequently, therapeutic measures can induce substantial effects on these modifying factors, whereas primary disturbances of central nervous system function may be difficult to alter. For the above reasons, tests of ventilatory responsiveness which provide information focussed only on the normality or abnormality of responsiveness to CO 2 breathing from measurement of minute ventilation and alveolar Pco, in an unsteady state, as in the CO 2 rebreathing test, may, in a patient, require the addition of tests which allow more complete evaluation of these modifying factors. The state of arterial blood gases, hydrogen ion concentration, bicarbonate concentration, pulmonary function, ventilatory response to exercise, as well understanding of the state of body temperature, catecholamine secretion, the functional state of the muscles of ventilation, as well as the resistances to ventilation are all a necessary part of the evaluation.

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REFERENCES

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in obese persons. J Clin Invest 37: 1049, 1958 16 Fishman AP, Goldring RM, Turino GM: General alveolar hypoventilation: A syndrome of respiratory and cardiac failure in patients with normal lungs. Quart J Med 35: 262, 1966 17 Rochester DF, Enson Y: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Am J Med 57:402,1974 18 Pedersen J, Torp-Pedersen E: Ventilatory insufficiency in extreme obesity. Acta Moo Scand 167:343, 1960 19 Gilbert R, Sipple JH, Auchincloss JH, Jr: Respiratory control and the work of breathing in obese patients. J Appl PhysioI16:21, 1961 20 Kronenberger RS, Gabel RA, Severinghaus JW: Normal chemoreceptor function in obesity before and after ileal bypass surgery to force weight reduction. Am J Med 59:349, isrs 21 Vogel JHK, Hartley LH, Jamieson G, et al: Impairment of ventilatory response to hypoxia in individuals with obesity and hypoventilation: A concept of the Pickwiekian syndrome (P). Circulation 36:11, 1967 22 Zwillich CW, Sutton FO, Pierson OJ, et al: Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med 59:343,1975 23 Emirgil C, Sobol BJ: The effects of weight reduction on pulmonary function and the sensitivity of the respiratory center. Am Rev Respir Dis 108:831, 1973 24 Engel LA, Ritchie B: Ventilatory response to inhaled carbon dioxide in hyperthyroidism. J Appl Physiol3O: 173, 1971 25 Read OJC: A clinical method for assessing the ventilatory response to carbon dioxide. AustraIas Ann Med 16:20, 1967 26 Stein M, Kimbel P, Johnson RL: Pulmonary function in hyperthyroidism. J Clin Invest 40:348, 1961 27 Sechzer PH, Egbert LO, Linde HW, et al: Effect of C~ inhalation on arterial pressure, ECG, plasma catecholamines and 17-GH corticosteroids in normal man. J Appl PhysioI15:454, 1960 28 Whelan RF, Young 1M: The effect of adrenaline and noradrenaline infusions on respiration in man. Br J Pharmacol Chemother 8:98, 1953 29 Negoescu I, Stancu H, Chivu U, et al: The function of adrenal medulla in hyperthyroidism. In Current Topics in Thyroid Research. Proceedings of the Fifth International Thyroid Conference, Rome, 1965 (Cassano C, Andreoli M, eds). New York, Academic Press, 1965 p 10951106 30 Valtin H, Kahler JL: Epinephrine and norepinephrine levels in hyperthyroidism before and after exposure to carbon dioxide. Fed Proc 21: 191, 1962 31 Nahas GG, Steinsland OS: Increased rate of catecholamine synthesis during respiratory acidosis. Resp Physiol 5:108,1968 32 Patrick JM, Howard A: The influence of age, sex, body size and lung size on the control and pattern of breathing during C~ inhalation in Caucasians. Resp Physiol 16: 337, 1972 33 Zwillich CW, Pierson OJ, Hofeldt FO, et al: Ventilatory control in myxedema and hypothyroidism. N EngI J Med 292:662, 1975 34 Lourenco RV, Turino GM, Davidson LAG, et al: The regulation of ventilation in diffuse pulmonary fibrosis. Am J Med 38:199,1965 35 Thompson JG, Read OJC: Respiratory regulation during pulmonary restriction. Australas Ann Med 17: 193, 1968

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