Study of the ventilatory response to hypoxia in man is

Transcription

1 Safety Considerations t should be possible to put a subject either on a bed or floor and a bag and mask with a large flow of oxygen should be immediately at hand. We keep airways, endotracheal tubes, and larygoscopes handy. We monitor the state of consciousness and the presence of cyanosis. t is probably a good idea to measure the arterial cuff pressure during the hypoxia run both as for safety and also to monitor whether the patient's hypoxic chemosensitivity includes a pressor response. t may be a good idea to display the electrocardiogram with oscilloscopic monitor in patients, but see no direct indication for this. Cardiac arrhythmias are not induced by hypoxia and cardiac arrest from hypoxia would occur long after central nervous system depression. There are special problems involved in the testing of hypoxic response in the presence of depressants, anesthetics, and narcotics. Presently, we do not feel justified in undertaking direct measures of hypoxic response in man. This would be desirable since it is now established that anesthetics such as halothane selectively depress the hypoxic response even more than the CO 2 response. n particular, the interaction of these two is eliminated. Weiskopf et al showed that the response to CO 2 which is usually steepened by hypoxia is completely flattened by hypoxia in the presence of 1 percent halothane (just sufficient to produce surgical anesthesia). On the other hand, our evidence suggests that narcotics do not depress the response to hypoxia as much as they depress the response to CO 2, n the dog, ventilation in the presence of large amounts of narcotic is initiated by the falling arterial Po 2 To summarize, a step hypoxia method for testing response of patients has been described. t involves a well-trained operator who must observe the patient while monitoring and adjusting alveolar oxygen and CO 2 tensions. The advantages of the step test are that the time effects can be examined and that quantitative information in a steady-state can be obtained in a relatively short period of time. t can be done at several different levels of CO 2, REFERENCES 1 Lloyd BB, Jukes MGM, Cunningham DJC: The relation between alveolar oxygen pressure and the respiratory response to carbon dioxide in man. Quart J Exp Physiol 43:214, Edelman NH, Epstein PE, Lahiri S, et al: Ventilatory responses to transient hypoxia and hypercapnia in man. Resp Physiol 17:302, Kronenberg R, Hamilton FN, Gabel R, et al: Comparison of three methods for quantitating respiratory response to hypoxia in man. Resp Physiol 16: 9, Nielsen M, Smith H: Studies on the regulation of respiration in acute hypoxia. Acta PhysiolScand 24:293, Read DJC: A clinical method for assessing the ventilatory response to CO 2 Australas Ann Moo 16:20, Weil JV, Byrne-Quinn E, Sodal E, et al: Hypoxic ventilatory drive in normal man. J Clin nvest 49: 61, Kronenberg RG, Drage CW: Attentuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal man. J Clin nvest 52:1812, Assessment of Ventilatory Response to Hypoxia Methods and nterpretation* John V. Wea, M.D. and Clifford W. Zwillich, M.D. Study of the ventilatory response to hypoxia in man is contributing important information concerning the physiology of ventilatory control and providing new insights concerning the pathogenesis of respiratory failure. Assessment of ventilatory responses to hypoxia in man may be carried out using a variety of procedures. Most commonly, such responses are measured under conditions in which arterial carbon dioxide tension remains unchanged so that the response of ventilation to hypoxia may be examined independent of inhibiting effects which hyperventilation-induced hypocapnia would have on such a response. Several techniques are used, but methods employed generally fit into one of four categories. Steady-state techniques involve measurement of ventilation during stepwise decrement of inspired O 2 tension where each step is of several minutes' duration.' Second is the technique of progressive hypoxia. Because the ventilatory response to hypoxia has a relatively short time constant of approximately 18 seconds, the ventilatory response can be described as a continuous function while the oxygen tension of the gas being breathed is gradually lowered." This technique yields data comparable to steady-state method." There is concern that these first two methods entail relatively persistent hypoxia which may in time result in depression of ventilation. Hence, a number of investigators have used a third technique-rapid tests involving hypoxic periods lasting no more than a few breaths. The increase in tidal volume of subsequent breaths is used to gauge the response.' These latter tests in general suffer from the disadvantage that the stimulus is so rapidly changing and so transient that its precise magnitude cannot be accurately assessed. n addition, the response is also fleeting and it is not certain that the response has become fully developed. Although some investigators have shown reasonably good agreement between transient and steady-state results," transient tests are generally considered less quantitatively rigorous. A fourth method for measuring hypoxic responses depends upon the fact that hypoxia augments the ventilatory response to hypercapnia. The ventilatory response to carbon dioxide is measured at high and low oxygen tensionss-" and the change in slope of the hypercapnic response is used as a measure of the hypoxic drive. No matter what method is used, suitable transducers must be available for measurement of minute ventilation as well as oxygen and carbon dioxide tensions. For each measurement, several current possibilities exist. Minute ventilation may, of course, be measured using discrete From the University of Colorado Medical Center, Cardiovascular Pulmonary Research Laboratory Denver. Reprint requests: Dr. Wea, 4200 East Ninth Avenue, Denver CHEST, 70: 1, JULY, 1976 SUPPLEMENT

2 bag collections with subsequent volume determinations using a device such as a spirometer. This suffers from the disadvantages of producing discontinuous data and is laborious. A pneumotachograph with integration produces continuous data of good quality. More recently, various types of mass flowmeters, such as the hot film anemometer, are used because they are less influenced by changing gas composition, are more stable, and have a lower noise level than the pneumotachograph. When a flowmeter is used in conjunction with a computer, the How signal may be re-zeroed after each breath, thereby greatly reducing errors due to drift which otherwise would be summed during the integration process. n those techniques in which end-tidal gas tensions are measured, carbon dioxide tension can be measured with a conventional infrared analyzer or with a mass spectrometer, while oxygen tension can be measured with either a polarographic electrode, a fuel cell oxygen analyzer," or mass spectrometer. Any analyzer used should have a 95 percent rise time of no greater than 140 milliseconds in order to provide a reliable estimate of alveolar gas tensions. Measurement of gas tensions in the blood can be done on discrete samples using polarographic electrodes. However, this has the disadvantage of not providing real-time information, and hence, does not permit the adjustment of inspired gas composition during the study to maintain isocapnia and to produce the desired level of hypoxia. A number of techniques 'E 11m in. STPD.'" '...'... : ~ :- ~., \. :a..':\.... e : , -:'. # # involving the use of intra-arterial electrodes and mass spectrometer probes have been suggested, but it is not clear that any are yet satisfactory for general use. A typical ventilatory response to hypoxia in a normal subject is shown in Figure 1. A vexing problem is the question of how to quantify such responses once the data have been obtained. The difficulty is that these responses are not linear, but instead, are exponential" or hyperbolic- in configuration. One solution is to compare the ventilation at a high oxygen tension with that during a single level of hypoxia. The most commonly used hypoxic oxygen tension is 40 mm Hg, and produces the index called t:av 40 9 This index has the disadvantage that only one point during hypoxia is used, and this point usually fals on a steep portion of the ventilatory response curve where ventilation is likely to vary greatly with small changes in oxygen tension. Hence it is very sensitive to errors in oxygen tension measurement. To meet this objection, other indices have been used to describe the entire curve relating minute ventilation and oxygen tension. n our experience, exponential and hyperbolic indices seem to provide descriptions of comparable accuracy. For the sake of mathematical simn=44 n=44 HYPOXC RESPONSES : 5=176 :t.13 (SEM (A FGURE 1. The ventilatory response to hypoxia in normal man. Decreasing PA02, produces little increase in ventilation with oxygen tensions near the normal range, but as PA02 approaches 40 mm Hg, the response becomes very steep. n this figure each point represents the mean of three successive breaths. Such responses are always curvilinear, although when the response is strikingly depressed, it may approach a horizontal straight line. HYPERCAPNC RESPONSES (S figure 2. Distribution of values for ventilatory response to hypoxia (above) and hypercapnia (below) collected in 44 normal subjects excluding all participants in athletic events. The distribution for both responses is quite broad and its shape is suggestively bimodal. Note that in this group no hypoxic responses were observed for values below A = 40 suggesting that this may be an abnormal or pathologic range. CHEST, 70: 1, JULY, 1976 SUPPLEMENT 125

3 plicity, we have preferred the hyperbolic approach and have used the equation ~E = ~o + A (PA02-32) in which minute ventilation in liters per minute is related to alveolar oxygen tension in mm Hg. The parameter v0 is the minute ventilation to be expected at infinitely high oxygen tension and is obtained by extrapolation while the parameter A provides a useful index of curve shape such that the higher the value for A, the more vigorous the ventilatory response to hypoxia. The number 32 is the oxygen tension at which the slope of the curve would be expected to approach infinity, and was found to be the value which produced an optimal curve fit by the Oxford group' and by us. We leave this number constant as this is necessary if values for A are to be compared to one another. Changing this parameter greatly changes the value calculated for A in any given response. However, we have found that this procedure produces curves which fit the data exceedingly well over a wide range of responses from very steep to very flat with errors of 4 percent or less. n practice, the curvefitting procedure may be carried out by relating V.. to 1/Po 2-32 which produces a linear relationship with a slope of A and an intercept of Vo. The evaluation of parameters is done by a linear test least squares technique. Minute ventilation during hypoxia may be measured in terms of arterial oxygen saturation rather than tension. This suggestion has great appeal because minute ventilation during hypoxia is related in a linear fashion to arterial oxygen saturation'? as well as arterial oxygen content." This obviates the problem of how best to quantitate the hypoxic response. n addition, the use of '.'Hl MO... St$"1 an ear oximeter provides an estimate of arterial oxygen saturation which is noninvasive and available in real time. A potential disadvantage of this approach arises from a consideration of the fundamental nature of the stimulus to ventilation during hypoxia. With one exception,"! studies in which arterial oxygen content has been lowered by administration of carbon monoxide with no associated decrease in arterial oxygen tension have shown no chemoreceptor or ventilatory response H These results seem to indicate that the stimulus to ventilation during hypoxia is a reduction in arterial oxygen tension rather than oxygen content. Hence, in those tests in which minute ventilation is related to reductions in arterial oxygen saturation, it is questionable whether the response is being related to the true stimulus. t seems possible that misleading results could be found in the presence of factors which alter the position and shape of the oxygen-hemoglobin dissociation curve. Ventilatory responses to both hypoxia and to hypercapnia are highly variable in normal man 1 5 (Fig 2). n addition, the distribution of values for both responses appears bimodal. t is of note that while the range for hypoxic ventilatory responses is very wide, none of the normal subjects had values for A less than 40. This is an important fact in that, as we will discuss, subjects drawn from groups in which clinically significant hypoventilation occurs are frequently in the zero to 40 range, suggesting that values in this range may be of pathologic significance. There are several possible factors which might contribute to the broad distribution of values. First, the magnitude of the hypoxic response seems to be correlated with body size 1 5 and perhaps with vital MOTHf' 1'",1 1'''' NOMA_,.tllNT _.: -1 J ~ ~.. 'V E min P"02 mm Hg fa'''' 0'_ ls'" 1'_ 1'_ 1'"" Y j mm Hg P"C0 2 FGURE 3. Ventilatory responses to hypoxia and to hypercapnia in six immediate relatives of a young patient with unexplained respiratory failure. n both parents and two siblings, responses to hypoxia were strikingly depressed with values for A that were less than 40. Some variable depression in hypercapnic response was also observed, but this appeared not to be as striking or as commonas depression of hypoxic response CHEST, 70: 1, JULY, 1976 SUPPLEMENT

4 V capacity, as has been shown for hypercapnic responses.p There does not appear to be a significant 30 correlation with age, except perhaps at the extreme ends of the age rangey Another factor influencing hypoxic response may be the degree to which people engage in E n=4 athletic activities. n the athlete, hypoxic ventilatory responses are markedly decreased in comparison to normal sedentary subjects.>" t is not yet clear whether the /min 20 P a=475 mm Hg decreased hypoxic response is a consequence of athletic STPD conditioning or the decreased response precedes, and is perhaps a prerequisite for, athletic endurance by permitting more exercise with less dyspnea. Familial or genetic influences constitute another important factor which /min may contribute to the wide range of normal values. We 5.3~.32 /min have recently seen two instances in which hypoventilation in children was associated with depressed hypoxic responses in healthy members of the immediate family19,20 (Fig 3). The apparent bimodal distribution within the normal population is compatible with the idea that there may be an important heritable determinant of hypoxic response. Lastly, because a close association appears to exist between metabolic rate and ventilatory control, it may be that diherences in metabolic rate may explain some of the variation in hypoxic response. n FGURE 4. Comparison of minute ventilation during subacute (several days) of isocapnic hypoxia compared with exercise.s! hyperthermia, thyrotoxicosis, and in the postprandial state,22 increased metabolism, is associated measurements made during acute hypoxia. Simulated altitude was produced in a chamber with C02 replacement to with increased hypoxic ventilatory response. Conversely, maintain isocapnia over several days. Minute ventilation was in myxedema'" and starvation, hypometabolism is associated with decreased hypoxic response. Because of the measured and then the subject was switched for a few minutes into a high oxygen mixture and the ventilatory response to acute progressive hypoxia was measured over several effect of feeding, it is suggested that measurements of minutes. At the original PA02 = 63 mm Hg, the minute ventilatory response be carried out in the fasting subject. ventilation measured during acute progressive hypoxia was The question of whether acute measurements of hypoxic response predict longterm ventilatory adjustment significantly higher than that observed under basal conditions after several days. This suggests that acute measurements of hypoxic response may overestimate responses observed to hypoxia remains unanswered. As mentioned above, a under subacute or chronic conditions. number of investigators have been concerned that per ~ 1.~ t ~ 1.69 /min STPO L :T\ 25% DECREASE : \ \ \ L t~ 88~.99! \ \ \ : \ \ : \~ ~0~ ~.68 30% 02 30% 02 TME (MNUTES) FiGURE 5. Responses to persistent isocapnic hypoxia (PA02 = 45 mm Hg) in four subjects. There is an initial increase in minute ventilation to a peak lasting several minutes, but thereafter there is a decrease to a lower plateau about 25 percent below the peak. Ten minutes' exposure to high oxygen followed by hypoxia produces a return to the original peak value. These data suggest that in normal human subjects, hypoxia lasting more than a few minutes produces a decrease in ventilation which may be due to either central nervous system depression or arterial chemoreceptor accommodation, and that this effect can be abolished by brief periods of hyperoxia. CHEST, 70: 1, JULY, 1976 SUPPLEMENT 127

5 sistent hypoxia may have a depressant effect on ventilation. Hypoxia lasting several minutes did not depress ventilation in anesthetized chemoreceptor denervated dogs until very low arterial oxygen tensions (20 mm Hg) were reached.>' These results in laboratory animals are at variance with more recent findings in man. Reeves, Grover and McCullough, in our laboratory, studied humans after several days of simulated high altitude in a chamber in which the ambient air was enriched with carbon dioxide in order to prevent hypocapnia (Fig 4). The ventilation observed in the chamber was significantly below that which would have been predicted from the acute measurement of hypoxic response. n order to further investigate this question, prolonged exposures to hypoxia were carried out in human subjects using a mask (Fig 5). These studies also indicated that in man, persistent hypoxia produces a ventilatory response which is significantly less than that to acute hypoxia. t is not yet clear whether this decrease in response represents the result of depression of the central nervous system or whether it represents accommodation within the peripheral chemoreceptor. These studies of ventilatory responses to persistent hypoxia raise questions concerning the relevance of acute hypoxic responses to the longterm control of breathing. However, a number of circumstances have been demonstrated in which hypoventilation occurs in patients with little intrinsic lung disease and in whom decreased ventilatory response seems an important causal factor. These include morphine administration.p myxedema.s- the obesity-hypoventilation syndrome.v' natives to high altitudes" and idiopathic hypoventilation in which markedly depressed acute hypoxic ventilatory responses have been regularly found. Hence, it would appear that acute measurements of these responses may yield useful information concerning the importance of depressed ventilatory drive in the pathogenesis of respiratory failure. ACKNOWLEDGMENT: Dr. Weil is the recipient of a Research Career Development Award from the National nstitutes of Health. This work was supported in part by a program project grant (HL4985) and by a research training grant (HL05973), both from the National nstitutes of Health. REFERENCES 1 Cormack RS, Cunningham DJC, Gee JBL: The effect of carbon dioxide on the respiratory response to want of oxygen in man. Quart J Exp Physiol42:303, Weil ]V, Byrne-Quinn E, Sodal E, et al: Hypoxic ventilatory drive in normal man. J Clin nvest 49: 61, Kronenberg R, Hamilton FN, Gabel R, et al: Comparison of three methods for quantitating respiratory response to hypoxia in man. Respiration Physio16:9, Dejours P, Labrousse Y, Raynaud J, et al: Etude du stimulus gaz carbonique de la ventilation chez l'homme. J Physiol 50:239, Edelman NH, Epstein PE, Lahiri S, et al: Ventilatory responses to transient hypoxia and hypercapnia in man. Respir Physio17:302, Nielsen M, Smith H: Studies on the regulation of respira- 128 tion in acute hypoxia. Acta Physiol Scand 24:293, Lloyd BB, Jukes MGM, Cunningham DJC: The relation between alveolar oxygen pressure and the respiratory response to carbon dioxide in man. Quart J Exp Physiol 43:214, Weil JV, Sodal E, Speck RP: A modified fuel cell for the analysis of oxygen concentration of gases. J Appl Physiol 23:419, Severinghaus JW, Bainton CR, Carcelen A: Respiratory insensitivity to hypoxia in chronically hypoxic man. Respir Physiol 1:308, 1966 Edelman NH, Lahiri S, Braudo L, et al: The blunted ventilatory response to hypoxia in cyanotic congenital heart disease. N Engl J Moo 282:405, Mills E, Edwards MW JR: Stimulation of aortic and carotid chemoreceptors during carbon monoxide inhalation. J Appl Physiol25:494, Duke HN, Green JA, Neil E: Carotid chemoreceptor impulse activity during inhalation of carbon monoxide mixtures. J Physio1l8:520, Comroe JH jr, Schmidt CF: The part played by reflexes from the carotid body in the chemical regulation of respiration in the dog. Am J Physio121:75, Meyer JR, Grover RF, Weil ]V: Carbon monoxide and the control of ventilation. Physio15:215, Hirshman C, McCullough RE, Weil ]V: Normal values for hypoxic and hypercapnic ventilatory drives in man. J Appl Physio38:95, Rebuck AS, Rigg JRA, Kangalee M, et al: Control of tidal volume during rebreathing. J Appl Physiol 37:475, Kronenberg RG, Drage CW: Attentuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal man. J Clin nvest 52:1812, Byrne-Quinn E, Weil ]V, Soda! E, et al: Ventilatory control in the athlete. J Appl Physio30:91, Hudgel DW, Weil JV: Asthma associated with decreased hypoxic ventilatory drive: a family study. Ann ntern Moo 80:622, Moore GC, Zwillich CW, Battaglia J, et al: Familial blunting of chemoreceptor activity. Chest 68:3, Weil JV, Byrne-Quinn E, Sodal E, et al: Augmentation of chemosensitivity during mild exercise in normal man. J Appl Physiol 33:813, Zwillich CW, Weil]V: Effect of increased oxygen uptake independentof exercise in hypoxic and hypercapnic ventilatory drives. Clin Res 23: 139A, Zwillich CW, Pierson DJ, Hofeldt FD, et al: Ventilatory control in myxedema and hypothyroidism. N Engl J Moo 292:662, Morrill C, Meyer JR, Weil JV: Hypoxic ventilatory depression in dogs. J Appl Physio38:143, Weil JV, McCullough RE, Kline JS, et al: Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man. N Engl J Med 292: 13, Zwillich CW, Sutton FD, Pierson DJ, et al: Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med in press 27 Weil ]V, Byrne-Quinn E, Sodal E, et a1: Acquired attenuation of chemoreceptor function in chronica1ly hypoxic man at high altitude. J Clin nvest 50:186, Lakshminarayan S, Sahn SA, Hudson LD, et al: The effect of diazepam on ventilatory responses in man. (submitted) CHEST, 70: 1, JULY, 1976 SUPPLEMENT