Familial Respiratory Chemosensitivity Does Not Predict Hypercapnia of Patients with Sleep Apnea-Hypopnea Syndrome 1-3
SHAHROKH JAVAHERI, GREGORY COLANGELO,4 BRUCE CORSER,4 and MOHAMMAD R. ZAHEDPOUR5
Introduction
In the face of various respiratory diseases there is a wide variation in arterial Pe02 (Paco.), with hypoventilation occurring only in a limited number of patients. Because chemical ventilatory drives (the hypercapnic and hypoxic ventilatory responses) vary considerably among normal individuals (1, 2), it has been suggested that hypoventilation in patients may be related to their inherent level of chemosensitivity. Thus, normal individuals with decreased chemical drive would be more likely to develop hypercapnia in the face of a lung disease (3). The variability in ventilatory drives noted among unselected normal individuals diminishes considerably within family members (4), among whom strong correlations in ventilatory drives (5, 6) have been reported. The clustering and correlation of ventilatory drives (particularly the hypoxic ventilatory drive) suggest a familial (presumably genetic) influence on chemical ventilatory control. Further evidence for genetic influences on ventilatory control is the significant correlation found between the hypoxic ventilatory response (HVR) of monozygotic twins compared with that of nonidentical twins (7, 8). Similarly, diminished ventilatory drive has been found in healthy family members of hypoventilating patients with various respiratory disorders (3, 9-12). Among patients with sleep apneahypopnea syndrome (SAHS), the level of Paeo2 varies considerably (13, 14), with a limited number of the patients suffering from chronic hypercapnia. The specific aim of the present study was to investigate if a familial blunted ventilatory drive could account for the hypercapnia observed in some patients with SAHS. Methods
Patients with SAHS Patients were men referred to the sleep labo-
SUMMARY The mechanisms of hypercapnia observed In som8 patients with sleep apnea-hypopnea syndrome (SAHS) are not known. In chronic obstructive lung disease (COLD), hypercapnic and hypo oxic ventilatory responses (HCVR/HVR) are decreased In normal family members of hypercapnic patients compared with those of non.hypercapnlc patients. This suggests a familial (presumably genetic) diminished chemosensitivity predisposing to hypercapnia. In this stUdy we Investigated the possibility of a similar mechanism In SAHS. Based on PaC02 , 29 patients with polysomnograph. ic evidence of SAHS were divided Into those with chronic hypercapnia (PaC02 ~ 45 mm Hg, n 13) and those with normocapnla (PaC02 < 45 mm Hg, n 16). We studied healthy adult (~ 17 yr) immediate family members of these patients. Family members were required to have normal splrom. etry and be on no medications. In Group I, there were 32 family members of hypercapnic patients and In Group 1/,26 family members of normocapnlc patients. In Group I, the mean (± SO) of age (yr) was 36 ± 12, weight (kg) 82 ± 22, FEV1 (l) 3.1 ± 0.8, VC02 (ml/mln) 228 ± 63, slope (Umln) of HCVR 2.0 ± 0.8, and slope (UmlnN% saturation) of HVR -1.20 ± 0.82. Respective values In Group 1/were 34 ± 14, 83 ± 16, 3.2 ± 0.8, 233 ± 63, 2.0 ± 1.0, and -1.34 ± 1.20. There were no statistically significant differences In measured variables between the two groups. Furthermore, there were no significant correlations between Paco 2 of patients and slopes of HCVR or HVR of their family members. In contrast, the mean values of slopes of HVR (-0.32 versus -1.15 Umln/1% saturation) and HCVR(1.04versus 2.31 Umln) were significantly lower In hypercapnic patients eempared with normocapnlc patients. Our results do not support the hypothesis that familial diminished chemosensitivity to hypercapnia or hypoxemia could explain hypercapnia In patients with SAHS.
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ratory of the Veterans Affairs Medical Center with clinical findings consistent with SAHS (including loud snoring, excessive daytime sleepiness, and obesity) and who were found to have sleep apneas and irypopneas (with an index> 5 h:') associated with oxyhemoglobin desaturation on full-night polysomnography. Sleep studies were performed using standard polysomnographic techniques (two-channel electroencephalogram, two-channel electrooculogram, one-chin electromyogram, onechannel nasooral airflow, thoracoabdominal excursions using inductive plethysmography, and arterial oxyhemoglobin saturation) (15, 16). Patients weredivided into those with hypercapnia (Paco:z ~ 45 mm Hg during wakefulness, n = 13)and normocapnia (Paco, < 45 mm Hg, n = 16). All patients in the former group had chronic hypercapnia as evidenced by either multiple arterial Pco, measurements and/or high plasma [HCO;] and appropriate plasma pH consistent with chronic respiratory acidosis.
Healthy Family Members Healthy adult (age ~ 17 yr) immediate family members (parents, siblings, and children) were encouraged to take part in the study.
Family members were required to have normal spirometry and be on no medications. The family members were questioned for various disorders, such as SAHS, but no unusual family disorders were reported. All interested family members except for a few(one with emphysema, one with hypothyroidism on replacement therapy, and one taking oral contraceptives) were tested. On the day of the study, they were instruct-
(Received in original form May 31, 1991 and in revised form October 24, 1991) 1 From the Sleep Disorders Laboratory, Veterans Affairs Medical Center, and the Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. 2 Supported in part by grants from the Department of Veterans Affairs. 3 Correspondence and requests for reprints should be addressed to S. Javaheri, M.D., Director, Sleep Disorders Laboratory (lllF), Department of Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220. 4 Work during fellowship, Division of Pulmonary and Critical Care Medicine. S Work during research fellowship, Sleep Disorders Laboratory, VeteransAffairs Medical Center.
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ed not to smoke and to refrain from caffeinecontaining beverages and foods. Individuals were also required to have slept normally the night before. Studies were performed at least 2 h postprandially. All family members signed the consent form, and the study was approved by the Institutional Review Board of the University of Cincinnati Medical Center.
Ventilatory Studies After spirometric tests, ventilatory measurements including carbon dioxide production (Veo2), hypercapnic ventilatory response (HCVR), and hypoxic ventilatory response were made. The ventilatory tests were measured in the sitting position with the subject wearing nose clip and breathing through a mouthpiece connected to a low-resistance two-way valve. Details of the tests as performed in our laboratory have been published elsewhere (17). Measurements started after achievement of steady state as evidenced by stable and endtidal Pco.. After measuring ventilation and mixed-expired Pco., hyper oxic HCVR was performed (17) using the rebreathing method of Read (18). Linear regression was used in the equation V = S(Peo2 - B), where S is the slope of HCVR and B is the intercept (on abscissa, Pco, axis) of the line that relates ventilation to Pco.. Isocapnic HVR was performed 15 min later by the rebreathing method of Rebuck and Slutsky (2), as detailed elsewhere (17). The slope of HVR was calculated by least-squares regression analysis relating ventilation to arterial oxyhemoglobin saturation (2). Statistical Analysis A two-tailed unpaired t test was used to determine significance (p ~ 0.05) between two variables (Group I versus Group II). We also determined Pearson linear correlations between certain variables, and p ~ 0.05 was considered significant. Data are presented as mean ± standard deviation (SO). The SAS computer system of the University of Cincinnati was used for calculations. Results
Patients with SAHS The mean values for age (53 ± 10versus 56 ± 8 yr), body mass index (38.3 ± 7.8 versus 36.9 ± 6.8 kg/m') (19), and apneahypopnea index (45 ± 32 versus 52 ± 22 h- 1 ) werenot significantly different between hypercapnic and normocapnic patients. The apnea-hypopnea index varied from 9.4 to 102 events h- 1 in the hypercapnic patients and from 19 to 91 h- 1 in normocapnic patients. In the former group, the supine baseline mean arterial oxyhemoglobin saturation was 88 ± 70/0 and the lowest was 50 ± 24%. Respective values in normocapnic patients were 93 ± 3070 and 71 ± 8070. In hypercapnic patients, the mean Pao2, Paco2' plasma [HCO;], and pH
were 57 ± 7 mm Hg, 51 ± 7 mm Hg, 31 ± 4 mmol/L, and 7.39 ± 0.06, respectively. Respective values in eucapnie patients were 73 ± 11 mm Hg, 38 ± 5 mm Hg, 24 ± 3 mmol/L, and 7.42 ± 0.03. The mean values for Pao., Paco., and plasma [HCO;] but not pH were significantly different between the two groups. The higher plasma [HCO;] and normal pH in hypercapnic patients confirm that the hypercapnia was of a chronic nature. Patients with hypercapnia had significant impairment in lung function tests (table 1), and the chemosensitivitytests wereconsiderably and significantly diminished compared with those of normocapnic patients (table 1).
Family Members There were 26 immediate family members in the normocapnic group. There were 14 males and 12 females, which included six brothers, eight sons, four sisters, and eight daughters. There were 32 family members in the hypercapnic group. There were 14 males and 12 females, which included two brothers, 10 sons, one mother, eight sisters, and 11 daughters. The anthropometric and spirometric data and the slopes of HCVR and HVR are shown in tables 2 and 3. There were no statistically significant differences between respective variables when family members of hypercapnic patients were compared with family members of eucapnic patients. In addition, when the slope of HCVR or HVR was corrected for FVC, body surface area (BSA), or Vco 2, mean values did not differ significantly. As stated in METHODS, all family members were encouraged to take part in the study, and the mean values in tables 2 and 3 were calculated with each family member regarded as a separate subject. Because there were variable numbers of
family members for each patient, wealso calculated the arithmetic mean of slopes of HCVR and HVR for each family as a whole. The mean values of slopes of HCVR and HVR were 1.94 ± 0.62 L/min/mm Hg PC02 and -1.24 ± 0.76 L/min/l % saturation for family members of hypercapnic patients. The values were not significantly different from those (1.91 ± 0.90 for HCVR and -1.22 ± 0.92 for HVR) in family members of eucapnic patients. Similarly, when these slopes were corrected for FVC, Vco2, or BSA and the values were compared between the two groups of family members, no statistical significance was noted. Because there were more female family members of hypercapnic patients than eucapnic patients, values were also compared according to gender between the two groups. No significant differencesbetween respective variables were detected. Linear correlations werecalculated between Pac02 of patients and slopes of HCVR and HVR of the family members. For HCVR, the r was 0.13 with p = 0.5; for HVR, r was -0.14 with p = 0.5.
Family Members of Patients with Lowest and Highest Ventilatory Responses We also compared data from family members of hypercapnic patients with lowest slopes of HVR and HCVR with the family members of normocapnic patients with highest HVR and HCVR. In the subgroup of hypercapnic patients the slopes of HVR ranged from - 0.007 to - 0.314 L/min/l % saturation (mean ± SD = -0.19 ± 0.11) and the slopes of HCVR varied from 0.0 to 0.73 L/min (mean ± SD = 0.49 ± 0.24). These values were significantly and considerably lower than those in the subgroup of normocapnic patients, in whom HVR ranged from -1.02 to -1.89 (mean
TABLE 1 SPIROMETRIC AND VENTILATORY CHEMOSENSITIVITY TESTS IN PATIENTS WITH SLEEP APNEA-HYPOPNEA SYNDROME Normocapnic Patients FEV" LIs FEV" % of predicted FVC, L FVC, % of predicted FEV,/FVC, % Slope, HVR, L/min/1 % saturation Slope, HCVR, Llmin/1 mm Hg PC0 2
2.8 81 3.6 85 77 -1.15 2.31
± ± ± ±
0.7 18 0.8 16 ± 7 ± 0.53 ± 1.51
Hypercapnic Patients
2.1 58 2.8 59 74 - 0.32 1.04
± ± ± ± ± ± ±
0.9* 25* 1.0* 20t 12 0.26t 0.79t
Definition of abbreviations: HVR = hypoxic ventilatory response; HCVR = hypercapnic ventilatory response. • p < 0.05. t p < 0.005.
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FAMILIAL VENTILATORY RESPONSES AND SLEEP APNEA-HYPOPNEA SYNDROME
TABLE 2 ANTHROPOMETRIC AND PULMONARY FUNCTION DATA OF FAMILY MEMBERS OF PATIENTS WITH SLEEP APNEA-HYPOPNEA SYNDROME·
n
Group
M/F
Age (yr)
Height (cm)
Weight (kg)
BMI (kglm 2 )
32 12/20 36 ± 12 168 ± 9 82 ± 22 29.3 ± 8.5 26 13/13 35 ± 14 167 ± 9 83 ± 16 29.4 ± 5.1
II
FVC, L FEV,/FVC FEV" LIs (% of predicted) (% of predicted) (%)
3.1 (79 3.2 (82
± ± ± ±
0.8 10) 0.8 6)
3.8 (104 3.9 (104
± ± ± ±
0.9 29) 1.0 16)
82 ± 8 83 ± 5
Definition of abbreviations: M = male; F = female; 8MI = body mass index. • Values are mean ± SO. Except for excess number of females in Group I, there were no statistically significant differences between respective variables of Group I (family members of hypercapnic patients) versus Group II (family members of normocapnic patients).
TABLE 3 VENTILATORY TESTS OF FAMILY MEMBERS OF PATIENTS WITH SLEEP APNEA-HYPOPNEA SYNDROME·
Group
I II
VC02
VC02 /BSA
(ml/min)
(ml/mZ)
228 ± 63 117 ± 21 233 ± 63 122 ± 27
SHCVR SHCVR/FVC SHVR SHVR/FVC (Llmin/mm Hg) (Llminlmm Hg/L) (Llmin/1 % saturation) (Llmin/1 % saturation/L)
2.00 ± 0.78 1.97 ± 1.01
0.53 ± 0.20 0.54 ± 0.29
-1.18 ± 0.81 -1.34 ± 1.20
-0.31 ± 0.23 -0.38 ± 0.38
Definition of abbreviations: HCVR = hypercapnic ventilatory response; HVR = hypoxic ventilatory response. • Values are mean ± SO. There were no statistically significant differences between respective variables of Group I (family members of hypercapnic patients) versus Group II. "co 2 is expressed in standard temperature pressure saturated (STPD) and ventilatory responses in body temperature pressure saturated (BTPS).
± SD = -1.58 ± 0.31) and HCVR ranged from 1.75 to 6.22 (mean ± SD = 3.24 ± 1.5). The mean values of slopes of HVR (-1.44 ± 0.92 versus -1.02 ± 0.74) and HCVR (1.95 ± 0.97 versus 1.99 ± 0.92) of the family members of the patients were not significantly different from each other.
Family Members of Normoxic and Normocapnic Patients Because the mean Pa02 of the eucapnic group was low, we selected a subgroup of normoxic encapnic patients with normal Pao2. There were five eucapnic patients with mean Pao, = 87 ± 5 (range 82 to 93) mm Hg. The slopes of HVR and HCVR of the seven family members of these patients were compared with the family members of hypercapnic patients; the slopes of HCVR (1.99 ± 0.77 versus 1.57 ± 1.3 L/min) and HVR (-1.2 ± 0.8 versus -0.8 ± 0.5 L/min/l07o saturation) were not significantly different from each other.
Family Members of Patients with Similar FE~ and FVC Because of differences in pulmonary function tests of normocapnic and hypercapnic patients, we selected subgroups of patients with similar lung function tests. There were 8 hypercapnic patients (FEV 1 2.5 ± 0.7 L; FVC = 3.3 ± 0.7 L) and 14 normocapnic patients (FEV = 2.6 ± 0.6; FVC = 3.4 ± 0.7). The slopes of HVR (-1.4 ± 1.2 versus - 0.9 ± 0.5 L/min/
l07o/saturation) and HCVR (1.9 ± 1.0 versus 1.9 ± 0.9 L/min) of the family members (n =. 22 and 23) did not differ significantly from each other.
Correlations of Ventilatory Responses of Patients versus Their Family Members To determine familial chemosensitivity among patients versus their family members, linear correlations between related ventilatory responses were determined. The strongest correlations occurred when slopes of chemosensitivity tests were corrected for BSA; for HCVR, p = 0.0096 and r = 0.38; for HVR, p = 0.047 and r = 0.34. Discussion
The reasons for hypoventilation in some patients with SAHS remain unclear. Ventilatory responses to hypoxia and hypercapnia are decreased in some patients with SAHS (13, 20), but this could be due to multiple mechanisms. Factors that influence ventilatory responses may be divided into the patient's inherent chemosensitivity antedating the development of SAHS and factors associated with SAHS. The latter are multiple and may include such factors as an obstructive airways defect (21), presence of chronic hypoxemia (22, 23) or hypercapnia (24), and sleep deprivation (25, 26). For these reasons, interpretations of measurements of chemical drives in the face of SAHS is difficult. Specifically, deficits
in ventilatory drives may not necessarily be the cause of hypercapnia. However, because inherent respiratory chemosensitivity may contribute to the development of hypercapnia and cannot be precisely quantitated in the face of lung disease (or SAHS) and because the inherent chemosensitivity of immediate family members may be similar (presumably genetic influence), investigators have tested the chemosensitivity of normal healthy family members to assess the contribution of diminished chemosensitivity antedating disease to morbid hypercapnia. Pioneering studies conducted by Weil, Zwillich, and their colleagues (3, 10, 27) and those by Fleetham and coworkers (11) and Kawakami and associates (12) suggested that familial (probably genetic) factors may influence the development of hypercapnia. Thus, those patients with inherent diminished chemosensitivity will develop hypercapnia in the face of the lung disease. The present study was designed to determine if normal adult family members of hypercapnic patients with SAHS may have decreased chemosensitivity to progressive hypoxemia and hypercapnia compared with family members of eucapnic patients with SAHS. If so, this may explain the development of hypercapnia in some patients with SAHS. We encouraged all immediate adult family members of each patient to take part in the study, to assure that each patient was represented maximally by his family members insofar as familial chemosensitivity is concerned. We used strict methodologic techniques in assuring uniform criteria in regard to exogenous factors that may affect chemosensitivity, including fasting state, caffeine intake, smoking, medications, quality of sleep the night before the study, and normal spirometry. Although we found significant familial correlations between slopes of HVR and HCVR of the patients with their related family members, the mean values of the slope of both HCVR and HVR were similar in family members of hypercapnic and eucapnic patients with SAHS. Similar findings were noted when the slope was corrected for Vco2, BSA, or FVC. Furthermore, we found no significant correlations between Paco2 of patients and the slopes of HVR or HCVR of their family members. Finally, it was conceivable that family members of subgroups of patients with highest and lowest slopes of HVR and HCVR may best demonstrate the familial
840
influence of chemosensitivity; our analysis of those subgroups did not show any significant differences. We also failed to show any familial differences in subgroups of (1) normoxic eucapnic patients versus hypoxemic hypercapnic patients and (2) patients with similar lung function tests. In a previous study (28), we investigated the hypothesis that variability in HCVR antedating the development of lung disease may contribute to morbid resting Pac02 in hamsters with elastaseinduced emphysema. In that study (28), we measured steady-state HCVR in normal unanesthetized hamsters that later received intratracheal elastase. Approximately 45 days later when emphysema had developed, steady state arterial blood samples were obtained from chronically cannulated animals. We failed to show a significant correlation between premorbid HCVR and morbid PacOr In that study (28), we did not measure the premorbid HVR of hamsters. Diminished familial HVR has been shown to correlate strongly (and more significantly than HCVR) with morbid hypercapnia in patients with chronic obstructive lung disease (3, 12). In the present study, however, we failed to show any corre~a tions between HVR or H CVR of family members and Pac02 of patients with SAHS. Factors mediating hypercapnia of patients with SAHS remain unclear. Bradley and colleagues (14) suggested that associated lung function abnormalities may predispose patients with SAHS to develop hypercapnia; the limited data obtained in the present study as well as our preliminary data (29) of a larger number of patients with SAHS are consistent with this notion. However,further studies are needed to elucidate the mechanisms of hypercapnia. Acknowledgment The authors thank Mrs. Saundra K. Eversole for her excellent secretarial assistance.
JAVAHERI, COLANGELO, CORSER, AND ZAHEDPOUR
References 1. Hirshman CA, McCullough R, Weil J. Normal values for hypoxic and hypercapnic ventilatory drives in man. J Appl Physiol1975; 38:1095-8. 2. Rebuck AS, Slutsky AS. Measurement of ventilatory responses to hypercapnia and .hypoxia. I~: Hornbein TH ed. Regulation of breathing. Lung biology in health and disease. New York: Marcel Dekker, 1981; 745-72. 3. Mountain R, Zwillich CW, Weil JV. Hypov~~ tilation in obstructive lung disease:the role of familial factors. N Engl J Med 1978; 298:521-5. 4. Weil JV. Pulmonary hypertension and corpulmonale in hypoventilating patients. In: Weir EK, Reeves JT, eds. Pulmonary hypertension. Mount Kisco, NY: Futura Publishing 1984; 321-40. . 5. Scoggin CH, Doekel RD, Kryger MH, ZwIllich CW, WellJV. Familial aspects of decreased hypoxic drive in endurance athletes. J Appl Physiol 1978; 44:464-8. 6. Saunders NR, Leeder SR, Rebuck AS. Ventilatory response to carbon dioxide in young athletes: a family study. Am Rev Respir Dis 1976; 113: 497-502. 7. Collins DD, Scoggin CH, Zwillich CW, Weil JV. Hereditary aspects of decreased hypoxic response. J Clin Invest 1978; 62:105-10. 8. Kawakami Y,Yoshikawa T, Shida A, Asanuma Y, Murao M. Control of breathing in young twins. J Appl Physiol 1982; 52:537-42. 9. Rebuck AS, Read J. Patterns of ventilatory response to CO 2 during recovery from severe asthma. Clin Sci 1971; 41:13-21. 10. Hudgel DW, Weil JV. Asthma associated with decreased hypoxic ventilatory drive. A family study. Ann Intern Med 1974; 80:622-5. 11. Fleetham JA, Arnup ME, Anthonisen NR. Familial aspects of ventilatory control in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1984; 129:3-7. 12. Kawakami Y, Irie T, Shida A, Yoshikawa T. Familial factors affecting arterial blood gas values and respiratory chemosensitivity in chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 125:420-5. 13. Garay SM, Rapoport D, Sorkin B, Epstein H, Feinberg I, Goldring RM. Regulation of ventilation in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1981; 124:451-7. 14. Bradley TD, Rutherford R, Lue F, et al. Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea. Am Rev Respir Dis 1986; 134:920-4. 15. Dowdell WT, Javaheri 50 McGinnis W. Cheyne-
Stokes respiration presenting as sleep apnea syndrome: clinical and polysomnographic features. Am Rev Respir Dis 1990; 141:871-9. 16. Dowdell WT, Javaheri S. Lack of effect of external warming on sleep architecture in sleep apneahypopnea syndrome. Am Rev Respir Dis 1992; 145:137-40. 17. J avaheri S, Guerra LF. Effects of domperidone and medroxyprogesterone acetate on ventilation in man. Respir Physiol 1990; 81:359-70. 18. Read DJC. A clinical method for assessing the ventilatory response to CO 2 • Aust Ann Med 1967; 16:22-32. 19. Van !tallie TB. Health implications of overweight and obesity in the United States. Ann Intern Med 1985; 103:983-8. 20. Zwillich CW, Sutton FD, Pierson DJ, Creagh EM, Weil JV. Decreased hypoxic ventilatory drive in the obesity hypoventllation syndrome. Am J Med 1975; 59:343-8. 21. Cherniack RM, Snidal DP. The effect of obstruction of breath on the ventilatory response to CO 2 • J Clin Invest 1956; 35:1286-90. 22. Weil JV, Bryne-Quinn E, Sodal IE, Filley GF, Grover RF. Acquired attenuation of chemoreceptor function in chronically hypoxic man at high altitude. J Clin Invest 1971; 50:186-95. 23. Bradley CA, Fleetham JA, Anthonisen NR. Ventilatory control in patients with hypoxemia due to obstructive lung disease. Am Rev Respir Dis 1979; 120:21-30. 24. Kepron W, Cherniack RM. The ventilatory response to hypercapnia and to hypoxemia in chronic obstructive lung disease. Am Rev Respir Dis 1973; 108:843-50. 25. Cooper KR, Phillips BA. Effectof short-term sleep loss on breathing. J Appl Physiol 1982; 53: 855-8. 26. White D, Douglas NJ, Pickett CK, Zwillich CW, Weil JV. Sleep deprivation and the control of ventilation. Am Rev Respir Dis 1983; 128:984-7. 27. Moore GC, Zwillich CW, Battaglia JD, Cotton EK, WellJV. Respiratory failure associated with familial depression of ventilatory response to hypoxia and hypercapnia. N Engl J Med 1976; 295: 861-5. 28. Javaheri S, Lucey EC, Snider GL. Premorbid ventilatory response to hypercapnia is not related to resting arterial Pe02 in hamsters with elasteinduced emphysema. Am Rev Respir Dis 1985; 132:1055-9. 29. Colangelo G, Javaheri S. Sleep apnea-hypopnea syndrome: hypercapnia versus normocapnic patients. Chest 1991; l00(S):58.
SHAHROKH JAVAHERI, GREGORY COLANGELO,4 BRUCE CORSER,4 and MOHAMMAD R. ZAHEDPOUR5
Introduction
In the face of various respiratory diseases there is a wide variation in arterial Pe02 (Paco.), with hypoventilation occurring only in a limited number of patients. Because chemical ventilatory drives (the hypercapnic and hypoxic ventilatory responses) vary considerably among normal individuals (1, 2), it has been suggested that hypoventilation in patients may be related to their inherent level of chemosensitivity. Thus, normal individuals with decreased chemical drive would be more likely to develop hypercapnia in the face of a lung disease (3). The variability in ventilatory drives noted among unselected normal individuals diminishes considerably within family members (4), among whom strong correlations in ventilatory drives (5, 6) have been reported. The clustering and correlation of ventilatory drives (particularly the hypoxic ventilatory drive) suggest a familial (presumably genetic) influence on chemical ventilatory control. Further evidence for genetic influences on ventilatory control is the significant correlation found between the hypoxic ventilatory response (HVR) of monozygotic twins compared with that of nonidentical twins (7, 8). Similarly, diminished ventilatory drive has been found in healthy family members of hypoventilating patients with various respiratory disorders (3, 9-12). Among patients with sleep apneahypopnea syndrome (SAHS), the level of Paeo2 varies considerably (13, 14), with a limited number of the patients suffering from chronic hypercapnia. The specific aim of the present study was to investigate if a familial blunted ventilatory drive could account for the hypercapnia observed in some patients with SAHS. Methods
Patients with SAHS Patients were men referred to the sleep labo-
SUMMARY The mechanisms of hypercapnia observed In som8 patients with sleep apnea-hypopnea syndrome (SAHS) are not known. In chronic obstructive lung disease (COLD), hypercapnic and hypo oxic ventilatory responses (HCVR/HVR) are decreased In normal family members of hypercapnic patients compared with those of non.hypercapnlc patients. This suggests a familial (presumably genetic) diminished chemosensitivity predisposing to hypercapnia. In this stUdy we Investigated the possibility of a similar mechanism In SAHS. Based on PaC02 , 29 patients with polysomnograph. ic evidence of SAHS were divided Into those with chronic hypercapnia (PaC02 ~ 45 mm Hg, n 13) and those with normocapnla (PaC02 < 45 mm Hg, n 16). We studied healthy adult (~ 17 yr) immediate family members of these patients. Family members were required to have normal splrom. etry and be on no medications. In Group I, there were 32 family members of hypercapnic patients and In Group 1/,26 family members of normocapnlc patients. In Group I, the mean (± SO) of age (yr) was 36 ± 12, weight (kg) 82 ± 22, FEV1 (l) 3.1 ± 0.8, VC02 (ml/mln) 228 ± 63, slope (Umln) of HCVR 2.0 ± 0.8, and slope (UmlnN% saturation) of HVR -1.20 ± 0.82. Respective values In Group 1/were 34 ± 14, 83 ± 16, 3.2 ± 0.8, 233 ± 63, 2.0 ± 1.0, and -1.34 ± 1.20. There were no statistically significant differences In measured variables between the two groups. Furthermore, there were no significant correlations between Paco 2 of patients and slopes of HCVR or HVR of their family members. In contrast, the mean values of slopes of HVR (-0.32 versus -1.15 Umln/1% saturation) and HCVR(1.04versus 2.31 Umln) were significantly lower In hypercapnic patients eempared with normocapnlc patients. Our results do not support the hypothesis that familial diminished chemosensitivity to hypercapnia or hypoxemia could explain hypercapnia In patients with SAHS.
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AM REV RESPIR DIS 1992; 145:837-840
ratory of the Veterans Affairs Medical Center with clinical findings consistent with SAHS (including loud snoring, excessive daytime sleepiness, and obesity) and who were found to have sleep apneas and irypopneas (with an index> 5 h:') associated with oxyhemoglobin desaturation on full-night polysomnography. Sleep studies were performed using standard polysomnographic techniques (two-channel electroencephalogram, two-channel electrooculogram, one-chin electromyogram, onechannel nasooral airflow, thoracoabdominal excursions using inductive plethysmography, and arterial oxyhemoglobin saturation) (15, 16). Patients weredivided into those with hypercapnia (Paco:z ~ 45 mm Hg during wakefulness, n = 13)and normocapnia (Paco, < 45 mm Hg, n = 16). All patients in the former group had chronic hypercapnia as evidenced by either multiple arterial Pco, measurements and/or high plasma [HCO;] and appropriate plasma pH consistent with chronic respiratory acidosis.
Healthy Family Members Healthy adult (age ~ 17 yr) immediate family members (parents, siblings, and children) were encouraged to take part in the study.
Family members were required to have normal spirometry and be on no medications. The family members were questioned for various disorders, such as SAHS, but no unusual family disorders were reported. All interested family members except for a few(one with emphysema, one with hypothyroidism on replacement therapy, and one taking oral contraceptives) were tested. On the day of the study, they were instruct-
(Received in original form May 31, 1991 and in revised form October 24, 1991) 1 From the Sleep Disorders Laboratory, Veterans Affairs Medical Center, and the Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. 2 Supported in part by grants from the Department of Veterans Affairs. 3 Correspondence and requests for reprints should be addressed to S. Javaheri, M.D., Director, Sleep Disorders Laboratory (lllF), Department of Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220. 4 Work during fellowship, Division of Pulmonary and Critical Care Medicine. S Work during research fellowship, Sleep Disorders Laboratory, VeteransAffairs Medical Center.
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JAVAHERI, COLANGELO, CORSER, AND ZAHEDPOUR
ed not to smoke and to refrain from caffeinecontaining beverages and foods. Individuals were also required to have slept normally the night before. Studies were performed at least 2 h postprandially. All family members signed the consent form, and the study was approved by the Institutional Review Board of the University of Cincinnati Medical Center.
Ventilatory Studies After spirometric tests, ventilatory measurements including carbon dioxide production (Veo2), hypercapnic ventilatory response (HCVR), and hypoxic ventilatory response were made. The ventilatory tests were measured in the sitting position with the subject wearing nose clip and breathing through a mouthpiece connected to a low-resistance two-way valve. Details of the tests as performed in our laboratory have been published elsewhere (17). Measurements started after achievement of steady state as evidenced by stable and endtidal Pco.. After measuring ventilation and mixed-expired Pco., hyper oxic HCVR was performed (17) using the rebreathing method of Read (18). Linear regression was used in the equation V = S(Peo2 - B), where S is the slope of HCVR and B is the intercept (on abscissa, Pco, axis) of the line that relates ventilation to Pco.. Isocapnic HVR was performed 15 min later by the rebreathing method of Rebuck and Slutsky (2), as detailed elsewhere (17). The slope of HVR was calculated by least-squares regression analysis relating ventilation to arterial oxyhemoglobin saturation (2). Statistical Analysis A two-tailed unpaired t test was used to determine significance (p ~ 0.05) between two variables (Group I versus Group II). We also determined Pearson linear correlations between certain variables, and p ~ 0.05 was considered significant. Data are presented as mean ± standard deviation (SO). The SAS computer system of the University of Cincinnati was used for calculations. Results
Patients with SAHS The mean values for age (53 ± 10versus 56 ± 8 yr), body mass index (38.3 ± 7.8 versus 36.9 ± 6.8 kg/m') (19), and apneahypopnea index (45 ± 32 versus 52 ± 22 h- 1 ) werenot significantly different between hypercapnic and normocapnic patients. The apnea-hypopnea index varied from 9.4 to 102 events h- 1 in the hypercapnic patients and from 19 to 91 h- 1 in normocapnic patients. In the former group, the supine baseline mean arterial oxyhemoglobin saturation was 88 ± 70/0 and the lowest was 50 ± 24%. Respective values in normocapnic patients were 93 ± 3070 and 71 ± 8070. In hypercapnic patients, the mean Pao2, Paco2' plasma [HCO;], and pH
were 57 ± 7 mm Hg, 51 ± 7 mm Hg, 31 ± 4 mmol/L, and 7.39 ± 0.06, respectively. Respective values in eucapnie patients were 73 ± 11 mm Hg, 38 ± 5 mm Hg, 24 ± 3 mmol/L, and 7.42 ± 0.03. The mean values for Pao., Paco., and plasma [HCO;] but not pH were significantly different between the two groups. The higher plasma [HCO;] and normal pH in hypercapnic patients confirm that the hypercapnia was of a chronic nature. Patients with hypercapnia had significant impairment in lung function tests (table 1), and the chemosensitivitytests wereconsiderably and significantly diminished compared with those of normocapnic patients (table 1).
Family Members There were 26 immediate family members in the normocapnic group. There were 14 males and 12 females, which included six brothers, eight sons, four sisters, and eight daughters. There were 32 family members in the hypercapnic group. There were 14 males and 12 females, which included two brothers, 10 sons, one mother, eight sisters, and 11 daughters. The anthropometric and spirometric data and the slopes of HCVR and HVR are shown in tables 2 and 3. There were no statistically significant differences between respective variables when family members of hypercapnic patients were compared with family members of eucapnic patients. In addition, when the slope of HCVR or HVR was corrected for FVC, body surface area (BSA), or Vco 2, mean values did not differ significantly. As stated in METHODS, all family members were encouraged to take part in the study, and the mean values in tables 2 and 3 were calculated with each family member regarded as a separate subject. Because there were variable numbers of
family members for each patient, wealso calculated the arithmetic mean of slopes of HCVR and HVR for each family as a whole. The mean values of slopes of HCVR and HVR were 1.94 ± 0.62 L/min/mm Hg PC02 and -1.24 ± 0.76 L/min/l % saturation for family members of hypercapnic patients. The values were not significantly different from those (1.91 ± 0.90 for HCVR and -1.22 ± 0.92 for HVR) in family members of eucapnic patients. Similarly, when these slopes were corrected for FVC, Vco2, or BSA and the values were compared between the two groups of family members, no statistical significance was noted. Because there were more female family members of hypercapnic patients than eucapnic patients, values were also compared according to gender between the two groups. No significant differencesbetween respective variables were detected. Linear correlations werecalculated between Pac02 of patients and slopes of HCVR and HVR of the family members. For HCVR, the r was 0.13 with p = 0.5; for HVR, r was -0.14 with p = 0.5.
Family Members of Patients with Lowest and Highest Ventilatory Responses We also compared data from family members of hypercapnic patients with lowest slopes of HVR and HCVR with the family members of normocapnic patients with highest HVR and HCVR. In the subgroup of hypercapnic patients the slopes of HVR ranged from - 0.007 to - 0.314 L/min/l % saturation (mean ± SD = -0.19 ± 0.11) and the slopes of HCVR varied from 0.0 to 0.73 L/min (mean ± SD = 0.49 ± 0.24). These values were significantly and considerably lower than those in the subgroup of normocapnic patients, in whom HVR ranged from -1.02 to -1.89 (mean
TABLE 1 SPIROMETRIC AND VENTILATORY CHEMOSENSITIVITY TESTS IN PATIENTS WITH SLEEP APNEA-HYPOPNEA SYNDROME Normocapnic Patients FEV" LIs FEV" % of predicted FVC, L FVC, % of predicted FEV,/FVC, % Slope, HVR, L/min/1 % saturation Slope, HCVR, Llmin/1 mm Hg PC0 2
2.8 81 3.6 85 77 -1.15 2.31
± ± ± ±
0.7 18 0.8 16 ± 7 ± 0.53 ± 1.51
Hypercapnic Patients
2.1 58 2.8 59 74 - 0.32 1.04
± ± ± ± ± ± ±
0.9* 25* 1.0* 20t 12 0.26t 0.79t
Definition of abbreviations: HVR = hypoxic ventilatory response; HCVR = hypercapnic ventilatory response. • p < 0.05. t p < 0.005.
839
FAMILIAL VENTILATORY RESPONSES AND SLEEP APNEA-HYPOPNEA SYNDROME
TABLE 2 ANTHROPOMETRIC AND PULMONARY FUNCTION DATA OF FAMILY MEMBERS OF PATIENTS WITH SLEEP APNEA-HYPOPNEA SYNDROME·
n
Group
M/F
Age (yr)
Height (cm)
Weight (kg)
BMI (kglm 2 )
32 12/20 36 ± 12 168 ± 9 82 ± 22 29.3 ± 8.5 26 13/13 35 ± 14 167 ± 9 83 ± 16 29.4 ± 5.1
II
FVC, L FEV,/FVC FEV" LIs (% of predicted) (% of predicted) (%)
3.1 (79 3.2 (82
± ± ± ±
0.8 10) 0.8 6)
3.8 (104 3.9 (104
± ± ± ±
0.9 29) 1.0 16)
82 ± 8 83 ± 5
Definition of abbreviations: M = male; F = female; 8MI = body mass index. • Values are mean ± SO. Except for excess number of females in Group I, there were no statistically significant differences between respective variables of Group I (family members of hypercapnic patients) versus Group II (family members of normocapnic patients).
TABLE 3 VENTILATORY TESTS OF FAMILY MEMBERS OF PATIENTS WITH SLEEP APNEA-HYPOPNEA SYNDROME·
Group
I II
VC02
VC02 /BSA
(ml/min)
(ml/mZ)
228 ± 63 117 ± 21 233 ± 63 122 ± 27
SHCVR SHCVR/FVC SHVR SHVR/FVC (Llmin/mm Hg) (Llminlmm Hg/L) (Llmin/1 % saturation) (Llmin/1 % saturation/L)
2.00 ± 0.78 1.97 ± 1.01
0.53 ± 0.20 0.54 ± 0.29
-1.18 ± 0.81 -1.34 ± 1.20
-0.31 ± 0.23 -0.38 ± 0.38
Definition of abbreviations: HCVR = hypercapnic ventilatory response; HVR = hypoxic ventilatory response. • Values are mean ± SO. There were no statistically significant differences between respective variables of Group I (family members of hypercapnic patients) versus Group II. "co 2 is expressed in standard temperature pressure saturated (STPD) and ventilatory responses in body temperature pressure saturated (BTPS).
± SD = -1.58 ± 0.31) and HCVR ranged from 1.75 to 6.22 (mean ± SD = 3.24 ± 1.5). The mean values of slopes of HVR (-1.44 ± 0.92 versus -1.02 ± 0.74) and HCVR (1.95 ± 0.97 versus 1.99 ± 0.92) of the family members of the patients were not significantly different from each other.
Family Members of Normoxic and Normocapnic Patients Because the mean Pa02 of the eucapnic group was low, we selected a subgroup of normoxic encapnic patients with normal Pao2. There were five eucapnic patients with mean Pao, = 87 ± 5 (range 82 to 93) mm Hg. The slopes of HVR and HCVR of the seven family members of these patients were compared with the family members of hypercapnic patients; the slopes of HCVR (1.99 ± 0.77 versus 1.57 ± 1.3 L/min) and HVR (-1.2 ± 0.8 versus -0.8 ± 0.5 L/min/l07o saturation) were not significantly different from each other.
Family Members of Patients with Similar FE~ and FVC Because of differences in pulmonary function tests of normocapnic and hypercapnic patients, we selected subgroups of patients with similar lung function tests. There were 8 hypercapnic patients (FEV 1 2.5 ± 0.7 L; FVC = 3.3 ± 0.7 L) and 14 normocapnic patients (FEV = 2.6 ± 0.6; FVC = 3.4 ± 0.7). The slopes of HVR (-1.4 ± 1.2 versus - 0.9 ± 0.5 L/min/
l07o/saturation) and HCVR (1.9 ± 1.0 versus 1.9 ± 0.9 L/min) of the family members (n =. 22 and 23) did not differ significantly from each other.
Correlations of Ventilatory Responses of Patients versus Their Family Members To determine familial chemosensitivity among patients versus their family members, linear correlations between related ventilatory responses were determined. The strongest correlations occurred when slopes of chemosensitivity tests were corrected for BSA; for HCVR, p = 0.0096 and r = 0.38; for HVR, p = 0.047 and r = 0.34. Discussion
The reasons for hypoventilation in some patients with SAHS remain unclear. Ventilatory responses to hypoxia and hypercapnia are decreased in some patients with SAHS (13, 20), but this could be due to multiple mechanisms. Factors that influence ventilatory responses may be divided into the patient's inherent chemosensitivity antedating the development of SAHS and factors associated with SAHS. The latter are multiple and may include such factors as an obstructive airways defect (21), presence of chronic hypoxemia (22, 23) or hypercapnia (24), and sleep deprivation (25, 26). For these reasons, interpretations of measurements of chemical drives in the face of SAHS is difficult. Specifically, deficits
in ventilatory drives may not necessarily be the cause of hypercapnia. However, because inherent respiratory chemosensitivity may contribute to the development of hypercapnia and cannot be precisely quantitated in the face of lung disease (or SAHS) and because the inherent chemosensitivity of immediate family members may be similar (presumably genetic influence), investigators have tested the chemosensitivity of normal healthy family members to assess the contribution of diminished chemosensitivity antedating disease to morbid hypercapnia. Pioneering studies conducted by Weil, Zwillich, and their colleagues (3, 10, 27) and those by Fleetham and coworkers (11) and Kawakami and associates (12) suggested that familial (probably genetic) factors may influence the development of hypercapnia. Thus, those patients with inherent diminished chemosensitivity will develop hypercapnia in the face of the lung disease. The present study was designed to determine if normal adult family members of hypercapnic patients with SAHS may have decreased chemosensitivity to progressive hypoxemia and hypercapnia compared with family members of eucapnic patients with SAHS. If so, this may explain the development of hypercapnia in some patients with SAHS. We encouraged all immediate adult family members of each patient to take part in the study, to assure that each patient was represented maximally by his family members insofar as familial chemosensitivity is concerned. We used strict methodologic techniques in assuring uniform criteria in regard to exogenous factors that may affect chemosensitivity, including fasting state, caffeine intake, smoking, medications, quality of sleep the night before the study, and normal spirometry. Although we found significant familial correlations between slopes of HVR and HCVR of the patients with their related family members, the mean values of the slope of both HCVR and HVR were similar in family members of hypercapnic and eucapnic patients with SAHS. Similar findings were noted when the slope was corrected for Vco2, BSA, or FVC. Furthermore, we found no significant correlations between Paco2 of patients and the slopes of HVR or HCVR of their family members. Finally, it was conceivable that family members of subgroups of patients with highest and lowest slopes of HVR and HCVR may best demonstrate the familial
840
influence of chemosensitivity; our analysis of those subgroups did not show any significant differences. We also failed to show any familial differences in subgroups of (1) normoxic eucapnic patients versus hypoxemic hypercapnic patients and (2) patients with similar lung function tests. In a previous study (28), we investigated the hypothesis that variability in HCVR antedating the development of lung disease may contribute to morbid resting Pac02 in hamsters with elastaseinduced emphysema. In that study (28), we measured steady-state HCVR in normal unanesthetized hamsters that later received intratracheal elastase. Approximately 45 days later when emphysema had developed, steady state arterial blood samples were obtained from chronically cannulated animals. We failed to show a significant correlation between premorbid HCVR and morbid PacOr In that study (28), we did not measure the premorbid HVR of hamsters. Diminished familial HVR has been shown to correlate strongly (and more significantly than HCVR) with morbid hypercapnia in patients with chronic obstructive lung disease (3, 12). In the present study, however, we failed to show any corre~a tions between HVR or H CVR of family members and Pac02 of patients with SAHS. Factors mediating hypercapnia of patients with SAHS remain unclear. Bradley and colleagues (14) suggested that associated lung function abnormalities may predispose patients with SAHS to develop hypercapnia; the limited data obtained in the present study as well as our preliminary data (29) of a larger number of patients with SAHS are consistent with this notion. However,further studies are needed to elucidate the mechanisms of hypercapnia. Acknowledgment The authors thank Mrs. Saundra K. Eversole for her excellent secretarial assistance.
JAVAHERI, COLANGELO, CORSER, AND ZAHEDPOUR
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