Depression of Hypoxic and Hypercapnic Ventilatory Drives in Severe Asthma*

Transcription

1 Depression of Hypoxic and Hypercapnic Ventilatory Drives in Severe Asthma* David W. Hudgel, M.D., and John V. Weil, M.D. Because of the previous finding of an attenuated hypoxic ventilatory drive in a teenager with severe asthma, the ventilatory responses to hypoxia and hypercapnia were examined during remission in 16 patients with the history of severe asthma. Spirometric and body plethysmographic pulmonary functions were normal or nearly normal just prior to ventilatory drive testing. The ventilatory responses to progressive isocapnic hypoxia and to hyperoxic hypercapnia were studied. Both hypoxic and hypercapnic drives were sipificantly depressed in the asthmatic patients. Factors known to blunt the ventilatory drives were not present in this group of patients. Hence, the etiology of these changes is unclear. n some patients, these depressed respiratory drives might contribute to hypoventilation, to severe hypoxemia, and to respiratory failure during severe asthma. Recently, we observed an adolescent asthmatic patient in whom hypoventiation existed during bronchospasm. Ventilatory response to hypoxia was markedly depressed in this patient. 1 Others have described abnormalities in control of ventilation in asthmatic patients.r" Rebuck and Head" produced data that suggested a lowered ventilatory response to carbon dioxide predisposed asthmatic patients to hypercapnia during bronchospastic attacks. Thus, the attenuation of hypoxic or hypercapnic ventilatory drives may contribute to the derangement of arterial blood gas measurements during bronchospastic attacks in these patients. Since the status of ventilatory drives in asthma may have clinical implications, this study sought to define both the hypoxic and hypercapnic drives in a group of 16 patients with the history of severe asthma. Subjects METHODS Sixteen patients with intermittent reversible airway obstruction were arbitrarily selected from the adult inpatient population of the Allergy and Clinical mmunology Service, National Jewish Hospital and Research Center in Denver. The mean age was 32 years, with a range of 15 to 59 years. Thirteen of 16 were adrenocorticosteroid-dependent. All were maintained on maximally tolerated dosages of theophylline preparations in addition to ephedrine, inhaled bronchodilators, cromolyn sodiwn, triacetyloleandomycin (TAO), and antihistamines as indicated. Patients who had received From the National Jewish Hospital and Research Center and Webb-Waring nstitute, University of Colorado Med eal Center, Denver. This work was supported by National nstitutes of Health grants A and HL oorecipient of a Research Career Development Award from the National Heart nstitute. Manuscript received November 22; revision accepted February 14. maximum benefit from medical therapy were chosen. They were studied during a clinically stable period in which interruption of the therapeutic program for at least six hours did not cause symptoms. Spirometric or lung volume data, or both, were obtained by standard methods in all patients just prior to ventilatory drive testing (Table 1). A control group was composed of 44 healthy residents of Denver. These subjects had no long-term altitude exposure and had no competitive athletic experience or formal physical conditioning. 5 The mean age was 32 years, with a range of 22 to 51 years. nformed consent was obtained from all subjects. Measurement of Ventilatory Drive Details of the hypoxic drive measurement during isocapnic progressive hypoxia have previously been outlined.f The semirecwnbent or seated subject breathed through a one-way system containing an infrared C02 analyzer (Beckman LB 1) and a fuel-cell 02 analyzer. Ventilation was measured by a heated pneumotachygraph, nitially, 40 percent oxygen in nitrogen was breathed with subsequent addition of nitrogen such that the end-tidal alveolar oxygen tension (PA02) fell from 120 to 40 over five to ten minutes. As ventilation increased, the end-tidal CO2 tension ( PAC02 ) was held at the resting alveolar level by the addition of 100 percent C02. The mean ventilation of three successive breaths was plotted against end-tidal PA02 during progressive hypoxia. n order to compare individual responses, ventilation is related to PA02 by the equation, VE = VE o + A (P A02-32 ), where VEo is the asymptote for ventilation at infinitely high PA02 obtained by extrapolation, and the constant 32 represents the PA02 at which the slope of the VE-PA02 curve approaches infinity. The parameter A describes the shape of the hyperbolic relationship of ventilation to PA02 such that the higher the A value, the greater the hypoxic ventilatory response; and, conversely, the lower the A value, the more depressed the ventilatory response. Thus, A is the index used to compare the ventilatory response to hypoxia between individuals or between groups of individuals (Fig 1). n order to assess the validity of end-tidal as an estimate of arterial oxygenation in these patients, P002 radial artery catheters were placed in four patients. At a PA02 of 40, the alveolar-arterial difference was 3.0 ± 2.6 (SE), a figure not statistically different from CHEST, 68: 4, OCTOBER, 1975 HYPOXC AND HYPERCAPNC VENTLATORY DRVES N ASTHMA 493

2 Table -Pulmonary Funetion Te.'. in A., l asubjec.. m a l i ~ FEV1 VC FEV1/VC % MMEF MVV TGV Raw Gaw/VL Observedv" 2.9 ± ± ± ± ± ± ± ± 0.01 Predicted 3.1 ± ± > ± ± 0.2 < 2.5 > 0.14 % Predicted FEV, one second forced expiratory volume (L); VC, vital capacity (L); MMEF, maximal midexpiratory flow rate (L/sec); MVV, maximal voluntary ventilation (L/min); TGV, thoracic gas volume (L); Raw, Airway resistance (em H 20/L/sec); and Gaw/VL, specific conductance (L/cm H 20/sec). Mean ± SEe that found in controls, 0.4 ± Blood gas data on (TGV), moderate increase in mean airway resisthe remainder of the subjects were collected during an asymp- tance (Raw), and mild decrease in specific conductomatic period prior to testing. The hypercapnic drive was studied by a rebreathing tech- ( G ) ( bl ) Chro h tance aw/vl Ta e 1 Die resting ypernique similar to that of Head.? A 5L reservoir bag containing ventilation existed in these patients. Alveolar carbon 40 percent oxygen was used. Data collection began after the dioxide tension was rom Hg (SE) in the inspired carbon dioxide tension reached the basal alveolar asthmatic patients, compared to a control value of 36 carbon dioxide tension ( PAC0 2). n a five- to ten-minute ± 1 (P < 0.(01). The hypocapnia was period, the PAC02 rose 15 to 20 mm "g. The PA02 full ed b a al H 7 43 remained in the hyperoxic range during this rebreathing y compensat y a norm arteri p " ±. period. The ventilatory response was plotted against the 0.01 (SE), compared to a Denver normal value of PAC02, and this relationship is described by the equation, The asthmatic patients' mean arte- VB = S(PAC02-B ), where B is the extrapolated intercept on rial oxygen (Pa02) was 69 ± 2 (SE), abscissa, and S is the slope of the linear response line. 8 The identical to the Denver normal value of 69 ± 1 rom higher the S value, the greater the ventilatory response to Hg.10 Anthropometric, historical, and ventilatory hypercapnia; S, the index of hypercapnic drive, is used to compare the results of individuals or groups of individuals. drive data are shown for each individual test subject Gas volumes were expressed as standard temperature and in Table 2. pressure, dry (STPD). Differences were tested by the two- Hypoxic ventilatory drive was moderately desample t-test. 9 pressed in these asthmatic patients. Parameter A REsULTS averaged 55 ± 10.5 (SE), less than half the oontrol The status of remission of these patients' asthma is value of 128 ± 8.6 (P < 0.(01) (Fig 2). There was a indicated by the finding that spirometric pulmonary significant positive correlation between the level of function results were normal or nearly normal, hypoxic ventilatory response and the adrenocorti- There was minimal increase in thoracic gas volume costeroid dosage, subject age, and maximal volun- 'V e = ~ o +A PA02-32 v; /min STPD..... A= ~. ~ , ~ - :. ~ AO AO AO P A0 2 FGURE 1. Alveolar oxygen tension-minute ventilation curves in three subjects with accentuated ( left) slightly depressed (middle), and markedly depressed (right) responses to progressive isocapnic hypoxia. Each point represents mean value for PA02 and VE for three successive breaths. See text for explanation of fonnula and A value. 484 HOOGEL, WElL CHEST, 68: 4, OCTOBER, 1975

3 Table 2-Anlhropometric, Hi.torica' and "enti'atory Dri"e Data Asthma Previous Hy- Patient Age, yr Height, em Duration, yr poxic Episodes A* S** Many SO Mean ± SE 32 ± ± ± ± ± 0.14 Control Mean ± BE 32 ± ± ± 0.13 *A, ndex of ventilatory response to hypoxia (see text). **S, Slope of ventilatory response to hypercapnia (see text). tary ventilation (P < 0.05). There was no correlation with duration of disease or other pulmonary function measurements. There was also an attenuated response to hypercapnia in the asthmatic patients. The mean slope of the hypercapnic response, S, was 1.04 ± 0.14 (SE) compared to a controi value of 1.83 ± 0.13 (P < 0.01). There was no significant correlation between hypercapnic yentilatory response and disease duration, medication dosage, subject age, or pulmonary function measurements. There was no correlation between A and S values. DSCUSSON This study demonstrated decreased ventilatory response to hypoxia and hypercapnia in chronic HYPOXA HYPERCAPNA VE /min STPD , / +,-,,'" "". " FGURE 2. Ventilatory responses to hypoxia (left) and to hypercapnia (right) in the asthmatic patients (broken line) and normal subjects (solid line). The responses to hypoxia are depressed in the asthmatic patients (P <0.(01) as are the responses to hypercapnia (P <0.01). CHEST, 68: 4, OCTOBER, 1975 HYPOXC AND HYPERCAPNC VENTLATORY DRVES N ASTHMA 495

4 asthma. Few studies have analyzed the ventilatory response of asthmatic patients to these stimuli. Lugliani et al!' showed that five asthmatic patients responded similarly to ten controls after the inhalation of 12 percent oxygen in nitrogen. Because isocapnia was not maintained, the true response to hypoxia could not be identified. Previous measurements of hypercapnic drive have shown a normal or even heightened response in asthmatic patients Rebuck and Bead" demonstrated that asthmatic patients in remission and athletes had a similar ventilatory response to hypercapnia. Data from this laboratory have shown that athletes have depressed ventilatory responses to hypercapnia when compared to nonathlete control subjects." Therefore, a false conclusion may have been made concerning the normal status of hypercapnic ventilatory drive in asthmatic subjects. The etiology of the decreased ventilatory responses to hypoxia and hypercapnia in asthmatic patients is unclear. The use of ventilation as a measurement of ventilatory drive depends upon a subject's ability to freely increase his ventilation. Hence, only patients in good remission were studied. Although there was evidence of mild residual airway obstruction, there was no correlation between the degree of obstruction and the hypoxic or hypercapnic drive depression observed. Acute hypocapnia lowers the ventilatory response to hypoxia in normal subjects." Although resting asthmatic patients hyperventilate and are hypocapnic.v'" this hypocapnia is chronic and in our patients was fully compensated by a normal arterial ph. Tenney et als showed that equivalent hypoxic drives existed at sea level and after two weeks of acclimatization at 14,250 feet despite significant hypocapnia at that altitude. After two weeks, correction of the respiratory alkalosis has occurred. These findings suggest that hypoxic ventilatory drive is depressed by hypocapnic alkalosis, but not by hypocapnia with a normal arterial ph, the condition that existed in the patients presently studied. Previous studies from this laboratory have shown that long-term hypoxia leads to depression of hypoxic drive. t6.17 However, this depression takes several years to acquire.fr" n only one of the patients in the present study (patient 1) was there evidence of prolonged hypoxemia (Table 2). Hence, hypoxic exposure was probably not an important factor in diminishing the ventilatory response to hypoxia in these patients. Chronic ventilatory impairment might influence the response to these stimuli,t9 but we found no correlation between ventilatory responses and duration of asthma. 498 HUDGEL, WElL The possible role of medications was considered. There was a significant direct correlation (P < 0.02) between adrenocorticosteroid dosage and ventilatory response to hypoxia. The influence of adrenocorticosteroid therapy upon ventilatory drive has not been previously studied, so the meaning of this correlation is unclear. Sympathomimetic agents stimulate the ventilatory response to hypoxia O- Thus, residual medications present in these patients at the time of ventilatory drive testing probably would have resulted only in an increase in ventilatory response to hypoxia or hypercapnia. The increase in ventilation during hypoxia is dependent upon intact autonomic nervous function, as has been shown in subjects undergoing cervical vagal and glossopharyngeal nerve block and in patients with dysautonomic states Asthmatic patients also have generalized autonomic dysfunction, manifested by decreased,a-adrenergic responsiveness.f" Because of this generalized abnormality, the response to hypoxia and to hypercapnia may be limited. Other known causes of lowered responses to hypoxia, such as competitive athletics," cyanotic congenital heart disease,29.30 hypothyroidism,31 and brain-stem malformations.p were not present in these patients. The influence of heredity was not investigated in this study. Previously, we reported an asthmatic patient with a depressed hypoxic drive in whom heredity seemed to be a factor, since three of four healthy members of his immediate family also had depressed hypoxic drives. 1 This case, along with two patients with asthma of only a short duration and depressed drives (patients 13 and 15), suggests that some individuals may have a low ventilatory response to hypoxia prior to the onset of asthma, perhaps on a hereditary basis. ndividually, there were some interesting results worthy of comment. The most obese patient (patient 2) had the lowest response to both hypoxia and hypercapnia, but there were no clinical hints that this patient was a primary hypoventilator. n general, there was no correlation between the hypoxic and hypercapnic ventilatory drive results, as has been described in normal subjects by Rebuck et al. 33 n fact, responses were occasionally divergent, as exemplified by patients 1, 8, and 13. There was a general tendency for the hypoxic ventilatory drive to be more severely depressed than the hypercapnic drive; and so it would appear that the ventilatory control of hypoxia and hypercapnia can be separately deranged. n only one patient (patient 1), who had continuous cyanosis even when his asthma was in remission, was it ever suggested from clinical observation that a derangement in ventilatory con- CHEST, 68: 4, OCTOBER, 1975

5 tros existed. However, in two (7 and 15) of the three patients (7, 14, and 15) in this group who had experienced prior respiratory failure or respiratory arrest, or both, the ventilatory responses to hypoxia and hypercapnia were markedly impaired. Thus, it might be speculated that the depression of ventilatory drives could contribute to hypoventilation during bronchospasm. n addition to bronchospasm, a mechanical impediment to breathing, diminished sensory recognition of abnormal arterial gas tensions might contribute to insufficient ventilatory defense against hypoxemia or hypercapnia during asthma attacks. These combined factors might lead to the occurrence of severe hypoxemia or hypercapnia, culminating in respiratory failure. ACKNOWLEDGMENT: The authors wish to thank Mr. C. Hale and Mr. R. E. McCullough for their technical assistance. REFERENCES 1 Hudgel OW, Wei! JV: Asthma associated with decreased hypoxic ventilatory drive: A family study. 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