Hypercapnic and Hypoxic Ventilatory Responses in Parents and Siblings of Children with Congenital Central Hypoventilation Syndrome 1-3

CAROLE L. MARCUS, 4 FLOYD R. LIVINGSTON, SARAH E. WOOD, and THOMAS G. KEENS

Introduction SUMMARY Children with congenital central hypoventllatlon syndrome (CCHS)have abnormal ven-

Congenital central hypoventilation syntilatory responses to metabolic stimuli. As there Is a genetically determined component of drome (CCHS), also known as Ondine's chemoreceptor sensitivity, parents and siblings of children with CCHS may also have blunted venCurse, is a rare congenital disorder of tilatory responses to hypercapnea and hypoxia. To test this, we studied hypercapnic ventilatory central control of ventilation. Classicalresponses and hypoXic ventilatory responses In six mothers, four fathers, and five siblings (8 to ly, patients with this condition have ade49 yr of age) of seven children with CCHSand compared them with 15ag. and sex-matched control quate ventilation while awake but severe . subjects (5 to 47yr of age). Pulmonary function tests were not different between relatives of children with CCHSand contralsubJects. To measure hyPercapnic ventilatory responses, subjects rebre8thed hypoventilation when asleep, necessitat5% CO2/95% O2 until PAC02 reached 80 to 70 mm Hg. To measure hypoxic ventll8tory responses ing the use of mechanical ventilatory sup(Umln/% Sa02), subjects rebreathed 14% 02n% CO2/balance N2 at mixed venous pc02 until Sa0 2 port. Children with CCHS have deprestell to 75%. All tests were completed In le88 than 4 min. Instantaneous minute ventll8tlon, mean sed or absent ventilatory responses to Inspiratory flow (tidal volume/Inspiratory time), and respiratory timing (Inspiratory tlmlngltotal rehypercapnea and hypoxia during both spiratory cycle timing) were calculated on a bre8th-by-bre8thbasis. Hyp8rc8pnlc ventilatory responses sleep and wakefulness (1-8). were 1.97 ± 0.32L/mln/mm Hg PAc0 21n children with CCHS rel8tlves and 2.23 ± 0.23 Umlnlmm Hg The genetic control of chemosensitivPAC021n control subJects. Hypoxic ventilatory responses were -1.99 ± 0.37 Umln/% Sa0 21n the ity is not fully understood. Beral and relatives and -1.54 ± 0.25 Umln/% Sa0 2 In the control subjects. There was no significant differRead (9) demonstrated decreased ventilaence between the relatives and the control subJects. We conclude that parents and siblings of chiltory responses to hypercapnia in New dren with CCHSdo not have subclinical abnormalities of ventll8tory control. Wespecul8te th8t CCHS Is not genetically determined. AM REV RESPIR DIS 1891; 144:138-140 Guinea natives as compared with caucasians, suggesting that chemosensitivity may be genetically determined. Relatives of endurance athletes, as well as the ath- ent life-threatening events may have ab- respiratory control. We therefore tested letes themselves, have been shown to have normal regulation of ventilation (18, 19), hypercapnic and hypoxic ventilatory redecreased hypoxic (10) and hypercapnic although other investigators have disput- sponses in parents and siblings of chil(11) ventilatory responses. Collins and co- ed this (20-23). Subsequent siblings of dren with CCHS. workers (12) showed a significant corre- victims of SIDS have been shown to have lation for hypoxic ventilatory responses, abnormal ventilatory patterns (24, 25). although not for hypercapnic ventilato- These suggest that other types of abnorry responses, in pairs of monozygotic malities of respiratory control may have (Received in originalform November 11, 1990 and in revisedform February 21, 1991) twins as compared with dizygotic twins. a genetic basis. CCHS is congenital; however, the etiHowever, Arkinstall and coworkers (13), 1 From the Division of Neonatology and Pedistudying similar populations, conclud- ology is as yet undetermined. It has been atric Pulmonology, ChildrensHospital LosAngeles, ed that most of the variability in the tid- reported in monozygotic twins (26), sib- University of Southern California School of Medial volume response to hypercapnea was lings (4), and half-siblings (27). In addi- cine, Los Angeles, California. attributable to genetic factors. tion, we are aware of another pair of 2 Supported in part by Grant I ROI HD-22696Decreased hypoxic and hypercapnic monozygotic twins that has not been DIAl from the National Institute of Child Health ventilatory responses have been observed reported in the literature. Fleming and and Human Development" by the National Center for the Prevention of Sudden Infant Death Synin clusters of family members of patients coworkers (1)studied ventilatory respons- drome (Baltimore, MD), the Greater Los Angeles with a variety of pulmonary diseases, in- es in the parents of one child with CCHS and Washington State Chapters of the National cluding chronic obstructive pulmonary and found that the mother had low nor- Sudden Infant Death Syndrome Foundation, the disease with CO 2 retention (14),obstruc- mal responses to both hypercapnea and Los Angeles County, Orange County, Inland Emand Kern County Chapters of the Guild for tive sleep apnea syndrome (15),and asth- hypoxia, although the father was normal. pire, Infant Survival, the Junior Women's Club of Orma (16). Decreased ventilatory respons- Although the role of inheritance in ange, and the Ruth and Vernon'Iaylor Foundation. es to hypoxia or hypercapnia in family CCHS is unknown, some investigators 3 Correspondence and requests for reprints members of patients with central hy- have suggested that it may be genetically should be addressed to Thomas G. Keens, M.D., poventilation have been reported (17). determined (4, 26, 28). As ventilatory re- Division of Neonatology and Pediatric Pulmonology, Box 83, Childrens Hospital Los Angeles, 4650 Furthermore, some studies suggest that sponses have a familial component, it is Sunset Boulevard, Los Angeles, CA 90027. parents of victims of sudden infant death possible that relatives of children with 4 Recipient of a Research Fellowship Support syndrome (SIDS) or infants with appar- CCHS may have subtle abnormalities of Grant from the Childrens Hospital Los Angeles. 136

137

VENTILATORY RESPONSES IN PARENlS AND SIBLINGS OF CHILDREN WITH CCHS

Methods Study Group Parents of children with CCHS currently followed in our clinic were recruited for the study. In addition, siblings old enough to cooperate with testing (in general, those older than 6 yr of age) were eligible for the study. Each subject was matched with a control of the same sex and similar age (within 2 yr). Control subjects were recruited from members of the hospital staff and their families. Subjects were instructed to refrain from caffeine-containing beverages on the day of study.

Pulmonary Function Tests In order to adequately evaluate ventilatory responses, one must ensure that there is no mechanical limitation of the pulmonary system. Therefore, all subjects underwent pulmonary function testing. Tests were performed in the pulmonary function laboratory of Childrens Hospital Los Angeles, located at sea level (mean atmospheric pressure, 751 mm Hg), All measurements for each subject were performed on the same day. The vital capacity and its subdivisions were measured from a slow exhalation with a Wedge~ spirometer (Model 3000; Med-Science Electronics, St. Louis, MO). FVC, FEV., FEF1 5 _ 75 , and maximal expiratory flow volume curves were obtained from forced expiration into the wedge spirometer. Functional residual capacity was measured with a body pressure plethysmograph (2800 Autobox; Sensormedics, Yorba Linda, CAl by the methods of Dubois and coworkers (29). Individual test results were analyzed and considered abnormal if they were greater than ± 2 SO from available reference values appropriate for age, height, and sex (30-34).

Ventilatory Responses Ventilatory responses were measured using rebreathing techniques. All tests were performed with the subjects seated comfortably and breathing through a mouthpiece. During the test, end-tidal 0 1 and COl were sampled continuously at the mouth and analyzed using a mass spectrometer. Flow was measured using a heated pneumotachograph and transducer. Minute ventilation was obtained by analog integration of the flow signal. Oxygen saturation was measured using a Nellcor N 200 pulse oximeter (N ellcor Inc., Hayward, CAl, and only saturation values associated with a satisfactory pulse wave form were analyzed. All outputs were recorded on a Gould polygraph strip chart recorder (Gould Inc., Rolling Meadows, IL). The ventilatory response to hypercapnea was determined using the hyperoxic hypercapnic rebreathing technique of Read (35). The subject rebreathed from a 13-L bag ruled with 70 ml/kg of a gas mixture with the initial composition of 95070 0 1 and 5070 COl. The subject was asked to breathe room air through the mouthpiece for 3 to 4 min to establish baseline values, and was then turned into the bag at the end of a normal expiration. The

test was continued until the subject could not continue or PACOl reached 65 to 70 mm Hg. The final PACOl was greater than 55 mm Hg in all cases. All tests were completed within 4 min so that significant respiratory acidosis would not occur. Tidal volume (VT), inspiratory time (11), and total time (not) were measured for each breath. From this, the instantaneous minute ventilation (VE), mean inspiratory flow rate (VT/lI), and duty cycle(Tt/Ttot) were calculated. Ventilatory responses to hypercapnea were expressed as VE, respiratory rate, VT, VT/Tt, and Ti/Ttot versus PAC01 • The ventilatory response to hypoxia was determined by the isocapnic hypoxic rebreathing technique of Rebuck and Campbell (36). In this test, the subject rebreathed from a 13-L bag filled with 130 ml/kg of a gas mixture with the initial composition of 7070 COl' 14070 0 1 , and the balance nitrogen. Between 15and 20 s after the start of rebreathing, an endtidal (mixed venous) plateau was attained. The PACOl was then maintained at the mixed venous level ± 3 mm Hg using a variable flow COl-absorbing bypass circuit. The resistance of the circuit is 0.016 L/min/cm H 1 0 . The test was continued until the subject stopped voluntarily or the saturation fell below 75070. The final Sao1 was less than 80070 in most cases, but it was only 86070 in one relative of a child with CCHS and 88070 in one control subject. All tests werecompleted within 4 min. VT, Tr, and not were measured for each breath. From this, VE, VT/lI, and 'It/Ttot were calculated. Ventilatory responses to hypoxia were expressed as VE, respiratory rate, VT, VT/lI, and Tt/Ttot versus Sao1 • Hypoxic ventilatory responses were performed after hypercapnic responses to avoid any potential depressant effect 0 f hypoxia on the hypercapnic response (37). Voluntary breathholding was performed by having the subject breathe through a mouthpiece to total lung capacity and then hold his or her breath for as long as possible. Each subject underwent at least two trials of breathholding. Subjects were not allowed to view a clock during the procedure. The data from the longest effort were used. Flow, Paco1 , and Sao, were measured using the same apparatus described earlier. The duration of breathholding, PACOl of the first breath after the breathhold, and S~ at termination of breathholding were measured. Informed consent was obtained from each subject. In the case of siblings who were minors, informed consent was obtained from their parents, and assent was obtained from the child himself or herself. The study was approved by the Institutional Review Board of Childrens Hospital Los Angeles.

Statistical Methods Ventilatory responses were analyzed by performing a least squares linear regression. The slope and correlation coefficient of the line were then used to characterize a particular subject's response. All parameters were compared between the relatives and the matched control subjects using the unpaired t test.

Results

Study Group Fifteen relatives of seven children with CCHS agreed to participate. These included six mothers, four fathers, and five siblings. Both parents of three of the children with CCHS participated. One parent only of each of the remaining four children with CCHS was able to participate because of marital separation or work and travel commitments. No relatives of children with CCHS or control subjects had any health problems or were receiving any medications. Four of the relatives smoked cigarettes; none of the control subjects smoked. There was no significant difference in age, height, or weight between the relatives and the control subjects. Pulmonary Function Tests Pulmonary function tests were similar between the two groups, with the exception of the FEVt/FVC and FEF2s - 7s , which were lower in the control subjects (table 1). However, these values were unlikely to be low enough to be clinically significant. Thus, mechanical abnormalities would not be expected to affect the ventilatory responses. Ventilatory Responses There were no significant differences in the ventilatory responses to hypercapnea and hypoxia between relatives ofchildren with CCHS and control subjects (tables 2 and 3; and figures 1 and 2). Assuming that a difference in the slope of the ventilatory response to hypoxia of 1 LI minlOJo Sao, was significant, the statistical power of this study was 0.88. The power of the ventilatory response to hypercapnea was 0.83. Typical examples

TABLE 1 POPULATION CHARACTERISTICS AND PULMONARY FUNCTION TESTS·

Age, yr Range Females, n/% Height, em Weight, kg TLC, % pred FVC, % pred RV, % pred RVITLC, % FEV1 , % pred FEFU - 71 , % pred FEV1IFVC, %

Relatives of Children with CCHS (n =- 15)

Control Subjects (n =- 15)

28 ± 4

29 ± 4 5-48 9/60

6-49 9/60 160 ± 59 ± 105 ± 107 ± 103 ± 27 ± 113 ± 89 ± 85 ±

* All data are means ± SEM.

t p < 0.05.

5

158 ± 5

5

58 ± 5 104 ± 3 110 ± 4 98 ± 8 26 ± 2 111 ± 5 74 ± 5t 83 ± at

2 2 7 1

4 5

1

138

MARCUS, LIVINGSTON, WOOD, AND KEENS

TABLE 2 SLOPES OF VENTILATORY RESPONSES TO HYPERCAPNEA* Relatives of Children with CCHS

Control Subjects

Highest PAc02, mm Hg

62.7 ± 1.3

62.9 ± 0.8

Ve versus

1.97 ± 0.32 0.84 ± 0.02

2.23 ± 0.23 0.86 ± 0.02

PAC02, Umin/mm Hg/PAC0 2

r

Ve = 0 mm

37.6 ± 1.5

37.5 ± 1.6

Respiratory rate versus PAC02, breaths/min/mm Hg PAC02

0.39 ± 0.11 0.48 ± 0.09

0.48 ± 0.12 0.57·± 0.09

VT versus PAC02, Umm Hg PAC02

0.07 ± 0.01 0.79 ± 0.03

0.07 ± 0.01 0.78 ± 0.03

VTITI versus PAc02, Us/mm Hg PAC02

0.07 ± 0.01 0.79 ± 0.05

0.08 ± 0.01 0.83 ± 0.02

PAC02 intercept where

Hg

r

r

r

VE =

=

minute ventilation; VT = tidal volume; TI inspiratory time; r = correlation coefficient. * Values are group means :t SEM. There were no significant differences between relatives of CCHS and control sUbjects.

Definition of abbreviations:

TABLE 3 SLOPES OF VENTILATORY RESPONSES TO HYPOXIA* Relatives of Children with CCHS

Control Subjects

75.9 ± 0.9

76.5 ± 1.1

-1.99 ± 0.37 -0.79 ± 0.02

-1.54 ± 0.25 -0.74 ± 0.06

-0.56 ± 0.11 -0.63 ± 0.06

-0.65 ± 0.19 -0.66 ± 0.08

-0.05 ± 0.02 -0.59 ± 0.09

-0.02 ± 0.01 -0.45 ± 0.11

-0.07 ± 0.01 -0.74 ± 0.04

-0.05 ± 0.01 0.62 ± 0.11

Lowest Sa0 2, 0/0

Ve slope, r

L/min/% Sa0 2

Respiratory rate, breaths/min/% S802

r VT, L/% Sa0 2

r VTITI, L/s/% Sa02

r

For definition of abbreviations, see table 2. * Values are group means ± SEM. There were no significant differences between relatives of CCHS and control subjects.

8

6

\IE (L1min/mm~lg

•

4

PACO 2)

2

• •••

....•• ~

... *......

Fig. 1. The slopes of individual ventilatory responses to hypercapnea are shown for relatives of children with CCHS and control subjects. Group means are represented by bars. There are no significant differences between the relatives and the control subjects. Ve minute ventilation (Umin/mm Hg PAC02)·

=

01...---------1----------CCHS Controls relatives

o

,.:•

1" -4

-6

.... ..

::

~

..

CCHS relatives

Fig. 2. The slopes of individual ventilatory responses to hypoxia are shown for relativesof children with CCHS and control sUbjects. Group means are represented by bars. There are no significant differences between the relatives and the control subjects. Ve minute ventilation (Umin/% Sa0 2) .

=

~-----..-..------"""---

Controls

of ventilatory responses to hypercapnea (figure 3) and hypoxia (figure 4) from the parents of children with CCH8 are shown. Results were analyzed separately for adults (parents and their matched control subjects) and children (siblings and their matched control subjects). This was done to account for the disparity in size between the children and the adults. Also, as siblings are more likely than parents to be closely matched genetically to the patients with CCHS, we wanted to determine whether siblings would be more likely than parents to have ventilatory abnormalities. However, as there were no significant differences between the adult and child groups, all results were combined and are presented together. There was no correlation between Tr/Ttot and hypercapnea or hypoxia in either the relatives (r = 0.01 for hypercapnea, r = - 0.12 for hypoxia) or the control subjects (r = 0.08 for hypercapnea, r = -0.18 for hypoxia). The ventilatory response to isocapnic hypoxia has been shown to correlate with the ventilatory response to hypercapnea in the same subject (38). The correlation coefficient between the ventilatory response to hypoxia and the ventilatory response to hypercapnea was - 0.55 in both the relatives and the control subjects. There was no significant difference in the duration of voluntary breathholding or the PAC02 or Sao, at termination of breathholding between the relatives of children with CCHS and the control subjects (table 4). There was no correlation between the ventilatory responses to hypoxia or hypercapnea and the duration of breathholding or to the PAC02 or 8a02 at the termination of breathholding for either the relatives or the control subjects. Discussion We have shown that parents and siblings of children with CCHS have normal ventilatory responses to hypercapnea and hypoxia. In order to detect subtle abnormalities of ventilatory control, we examined the relationship between a number of ventilatory parameters in response to changes in PAC02 and Sao 2. These included instantaneous VE,respiratory rate, tidal volume, mean inspiratory flow rate, and duty cycle. None of these parameters differed between relatives of children with CCHS and control subjects. Therefore, parents and siblings of children with CCH8 do not have abnormalities of ventilatory control detectable by ventilatory responses.

VENTILATORY RESPONSES IN PARENTS AND SIBLINGS OF CHILDREN WITH CCHS

139

60

50

Fig. 3. Typical example of a ventilatory responseto hypercapnea from the parent of a child with CCHS.Minuteventilationis plotted onthe ordinate, andendtidal carbon dioxide tension is plotted on the abscissa. Ve = minute ventilation (Umin); PAC0 2 = end tidal carbon dioxide tension(mm Hg). r = 0.95; P < 0.001.

• 40

V E

(LIm In)

30

20

10

o

-h--"T--r-r-T--r-r-T--r-r-T-'-'-'---rr-1-.-r-1--'-'--'rrT"1--'-'--'rT""T"1rrT"1--'-'--'rrT"1rrr-r-r-r-rr

42

62

140 •• 120

Fig. 4. Typical example of a ventilatory responseto hypoxiafrom the parentof a child of CCHS. Minute ventilation is plottedon the ordinate, and arterial oxygensaturation is plottedon the abscissa. VE = minute ventilation (Umin); Sa02 = arterial oxygensaturation (0/0). r = -0.96; P < 0.001.

100

\IE

.......

80

may be genetically determined (4, 26, 28). As there is a significant genetic determinant of ventilatory responses to hypoxia and hypercapnea, it is theoretically possible that parents or siblings of children with CCHS may themselves be heterozygous and have subclinical abnormalities of ventilatory control. However, this is not what we observed in our study. An alternative explanation for a familial occurrence of CCHS may be an abnormal factor in the intrauterine environment, as has been suggested for cases of SIDS occurring in twins (40), although this is speculative. The results of this study suggest that parents and siblings of children with CCHS do not have subclinical abnormalities of ventilatory control. We therefore speculate that there is not a genetic component of CCHS.

(LIm In) 60 40 20 OL.l-L..L...L..L.JL..l.-..L.J--l.....1-J.--I....L..l....L-..L..L~...1....L...I-~.L.L..I-L..L.L.JL..-l.-..l-I-l.....1-l--l....L..l....L-..L..L~~...I..-

76

96

TABLE 4 VOLUNTARY BREATHHOLDING* Relatives of Children with CCHS Length of breathhold, s Mean ± SEM Range PAC02 at termination of breathhold, mm Hg Mean ± SEM Range Sa02 at termination of breathhold, 0/0 Mean ± SEM Range

Control Subjects

58 ± 7

60 ± 9

21-123

14-141

47 ± 1

43-56

49 ± 1

43-60

98 ± 1

98 ± 1

94-100

88-100

* There were no significant differences between relatives of CCHS and control subjects.

As CCHS is rare, it is difficult to obtain a large study group. The normal range of ventilatory responses to hypoxia and hypercapnea is large. Wetherefore assumed that a difference in the slope of the ventilatory responses to hypoxia and hypercapnea of 1 L/min/OJo Sao, and 1 L/min/mm Hg PACOl was significant. On this basis, the statistical power of our study was 0.88 for hypoxic responses and 0.83 for hypercapnic responses. A statistical power of 0.80 is usually considered acceptable. This indicates that our study had sufficient sample size to detect a real difference in ventilatory responses between the groups if such a difference existed.

The duration of breathholding is related to metabolic factors (POl and Pco.), lung volumes, and behavioral control (39). Afferent stimuli from the lungs and/or the chest wall are thought to play a part in determining the break point of breathholding (39). Weused breathholding as an additional method to try to identify any differences in ventilatory control between the two groups. There was no difference between the relatives and the control subjects in duration of breathholding or the Sao, or PAC02 at termination of breathhold. On the basis of the few case reports of twins and siblings with CCHS, some investigators have speculated that CCHS

Acknowledgment The writersthank Mary Jansen, LVN, for help in coordinating the study; Charles W. Sargent, BS, RPFT, for technical assistance; Michael Stabile, MS, RPFT, Adriana Rachel, RPFT, Kate Tannenbaum, BS, and Sandra Bailey, BS, for performing pulmonary function testing; and Linda S. Chan, PhD, for statistical assistance. They are grateful to the children and parents who participated enthusiastically in this study. References 1. Fleming PJ, Cade D, Bryan MH, Bryan AC. Congenital central hypoventilation and sleep state. Pediatrics 1980; 66:425-8. 2. Nattie EE, Bartlett D, Rozycki AA. Central alveolar ventilation in a child: an evaluation using a whole body plethysmograph. Am Rev Respir Dis 1975; 112:259-66. 3. Oren J, Kelly DH, Shannon DC. Long-term follow-up of children with congenital central hypoventilation syndrome. Pediatrics 1987; 80: 375-80. 4. Haddad GG, Mazza NM, Defendini R, et al. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine 1978; 57:517-26. 5. Wells HH, Kattwinkel J, Morrow JD. Control of ventilation in Ondine's curse. J Pediatr 1980; 96:865-7. 6. Barnhart BJ, Reynolds JW, Lees MH. Sleepventilation correlates in congenital central hypoventilation syndrome (CCHS) (abstract). Coo Res 1980; 28:120A. 7. Shannon DC, Marsland DW, Gould JB, Callahan B, Todres IB, Dennis J. Central hypoventilation during Quiet sleep in two infants. Pediatrics 1976; 57:342-6. 8. Paton JY, Swaminathan S, Sargent CW, Keens TG. Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome. Am Rev Respir Dis 1989; 140: 368-72. 9. Beral V, Read DJC. Insensitivity of respiratory centre to carbon dioxide in the Enga people of New Guinea. Lancet 1971; 2:1290-4. 10. Scoggin CH, Doekel RD, Kryger MH, Zwil-

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MARCUS, LIVINGSTON, WOOD, AND KEENS

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