INTRODUCTION

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION SUMMARY REFERENCES

Central alveolar hypoventilation is a rare syndrome that has been associated with a variety of insults to brain-stem respiratory centers (1). Patients with this syndrome manifest hypoventilation during sleep, sometimes accompanied by hypoventilation during periods of wakefulness (1). The most comprehensive studies of respiratory control and respiratory sensation in patients with central hypoventilation have been done in patients with congenital central hypoventilation syndrome (CCHS). Children with CCHS lack a ventilatory response to hypercapnia (2, 4) and progressive hypoxia (4), but increase their ventilation normally in response to exercise (5, 6). These patients also have extremely long breathholding times, and report no air hunger during a prolonged breathhold or while breathing CO₂ (2), thereby suggesting that the central chemoreceptors are essential for the sensation of air hunger (2). However, since few studies have been done in patients with other forms of central hypoventilation, it is uncertain whether conclusions based on CCHS patients can be generalized to patients with central hypoventilation arising from other causes.

We recently encountered a young woman with central hypoventilation caused by a brain-stem tumor. During the course of her evaluation, she underwent detailed physiologic testing. The results indicate that central hypoventilation syndromes may differ significantly in their effects on respiratory control and respiratory sensation.

	CASE REPORT

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION SUMMARY REFERENCES

The patient had been well until age 18 yr, when she presented with headaches and vertigo and was found upon magnetic resonance imaging to have a mass in the medulla. A biopsy of the mass revealed a ganglioglioma that was subsequently treated with external beam radiation. Over the next 3 yr the patient had only slight worsening of her neurologic function, as manifested by the development of a nasal quality to her voice (as a consequence of soft palate dysfunction) and mild dysphagia. Three and a half years after her initial presentation, she developed dyspnea during the 26th week of an otherwise normal pregnancy. Arterial blood gas values measured during an evaluation at that time were pH = 7.37, PCO₂ = 41 mm Hg, and PO₂ = 187 mm Hg (on an FI_O2 of 0.4). Within a few days, the patient's dyspnea resolved spontaneously, and no etiology was ever determined for her symptoms. Ten months later she was admitted to the hospital with a 1-wk history of headache and drowsiness; her arterial blood gas values at the time were pH = 7.27, PCO₂ = 91 mm Hg, and PO₂ = 71 mm Hg. Overnight oximetry revealed severe and repetitive arterial oxygen desaturations to values as low as 50 to 60%, which were attenuated by supplemental oxygen. Magnetic resonance images obtained during that hospitalization are shown in Figure 1. The patient was unable to tolerate noninvasive ventilatory support (bilevel positive airway pressure), and was discharged on acetazolamide, medroxyprogesterone, and nighttime oxygen. Her blood gas values at the time of discharge were unchanged from those at the time of her admission.

View larger version (121K): [in this window] [in a new window]   Figure 1.   Gadolinium-enhanced T1-weighted transverse (top panels) and sagittal (bottom panels) magnetic resonance images demonstrate tumor involvement of the dorsal medulla right of the midline (tumor appears white). For the sagittal images, the left-hand image was obtained 7.0 mm to the left of the midline, the center image represents the midline, and the right-hand image was obtained 7.0 mm to the right of the midline.

Three weeks after her discharge from this hospitalization the patient underwent a formal sleep evaluation that showed frequent central apneas (apnea-hypopnea index of 94 events/h) accompanied by severe oxygen desaturation, particularly during rapid eye movement (REM) sleep (Figure 2). There were no obstructive apneas.

View larger version (54K): [in this window] [in a new window]   Figure 2.   (A) Tracing 4 min in length, taken from a period of REM sleep and demonstrating the repetitive, cyclic nature of the patient's oxygen desaturations. The scale is such that the maximum SaO2 on the tracing is 90% and the minimum SaO2 is 75%. (B) Tracing taken from the same period as in (A) but shown on a slightly more expanded scale (2 min) demonstrates absence of rib cage and abdominal motion during apneas, confirming that the apneas were central in origin. EOG = electrooculogram; EFF THX = thoracic displacement; EFF ABD = abdominal displacement.

One month later the patient was readmitted to the hospital after a 2- to 3-d history of cough, sore throat, and fever. Her blood gas values on admission are shown in Table 1. Over the next 24 h her PCO₂ rose and she developed increasing somnolence, leading to intubation and mechanical ventilation. After the initiation of mechanical ventilation, her PCO₂ decreased into the hypocapnic range, and she was extubated approximately 18 h later. Within 12 h after extubation her PCO₂ had risen to 65 mm Hg, and it remained elevated thereafter (Table 1). The acetazolamide and medroxyprogesterone were deemed therapeutic failures and were discontinued.

During subsequent follow-up to the time of this writing, the patient has remained intolerant of any form of noninvasive ventilatory support and has refused tracheotomy. She continues to experience chronic headaches. Clinically, the only other evidence of progressive brain-stem dysfunction has been worsening dysphagia and weight loss that necessitated placement of a feeding jejunostomy tube. The patient has no evidence of peripheral muscle weakness.

Physiological Studies

At the time of the studies, the patient's weight was 50 kg and her height was 155 cm. With the exception of the exercise study, all measurements were made while the patient sat erect in a chair, wearing nose clips. Sa_O2 was measured with a pulse oximeter (Oxyshuttle; SensorMedics, Yorba Linda, CA), and PET_CO2 was measured with an infrared capnometer (microSpan 8800; Biochem International, Waukesha, WI).

The patient's lung volumes were measured by plethysmography (SensorMedics 2800), and flow rates and the diffusing capacity for carbon monodixe (DL_CO) were measured with a computerized pulmonary function system (SensorMedics 2200). Ventilatory muscle strength was assessed by measuring the maximal inspiratory pressure (PI_max) at FRC and the maximal expiratory pressure (PE_max) at TLC. All pressures were measured with a transducer (MP 45 ± 140 cm H₂O; Validyne, Inc., Northridge, CA); an 18-gauge needle was inserted into the mouthpiece to provide a small leak, thereby minimizing the influence of the buccal muscles on the measurements. We measured PI_max and PE_max three times, and report the maximum value of each.

The patient breathed through a mouthpiece connected to a three-way stopcock. After a period of quiet breathing, the stopcock was turned and the patient was instructed to perform a maximum breathhold. When the patient signaled that she was unable to continue the breathhold, the stopcock was opened and she was instructed to exhale fully. Breathholds were performed at TLC with the patient breathing room air and 100% oxygen, at FRC while breathing room air, and at FRC following a 5- to 10-s period of voluntary hyperventilation. The patient was given a 5-min rest between each of the breathholding measurements.

The ventilatory response to progressive isocapnic hypoxia was assessed through the rebreathing method of Rebuck and Campbell (7). The patient underwent two trials separated by a 10-min rest period. Data from the two runs were combined and used for analysis.

The patient also performed progressive, incremental exercise on a cycle ergometer while breathing room air. Expired gases were analyzed on a breath-by-breath basis with a metabolic cart (Vmax 29; SensorMedics) to determine minute ventilation (E), oxygen consumption (O₂), and carbon dioxide production (CO₂).

Supine and standing blood pressures were measured with a mercury sphygmomanometer. The patient's heart rate (HR) and blood pressure (BP) responses to the Valsalva maneuver were measured with a digital photoplethysmograph (2300 Finapres Blood Pressure Monitor; Ohmeda, Englewood, CO).

For the breathholding studies, assessment of hypoxic ventilatory response (HVR), and assessment of cardiovascular responses, the flow, FET_CO2, pulse oximeter (Sa_O2), and BP signals were digitized at a sampling rate of 75 Hz, using a computerized data acquisition and analysis system (SuperScope II software and MacAdios II A/D converter; GW Instruments, Somerville, MA), and were stored on a computer (Macintosh Centris 650; Apple Computer, Cupertino, CA) for off-line analysis. VT was obtained by electrical integration (SuperScope II, GW Instruments) of the digitized flow signal. The respiratory variables were measured on a breath-by-breath basis and the BP signal on a beat-to-beat basis.

Results of Physiological Studies

The patient's spirometry readings, lung volumes, DL_CO, and maximum respiratory muscle pressures were all normal (Table 2). Although her arterial PO₂ was mildly decreased, the alveolar-arterial oxygen difference was normal (Table 1, Day 102).

The patient's breathing pattern remained irregular even after a period of acclimation to breathing through the mouthpiece (Figure 3). Although the patient's spontaneous FET_CO2 generally ranged between 8% and 9%, she could quickly lower her FET_CO2 to 4% to 5% when asked to hyperventilate. The mean values and coefficients of variation (CVs) for several ventilatory variables are given in Table 3.

View larger version (88K): [in this window] [in a new window]   Figure 3.   Tracings showing a sample of the patient's spontaneous breathing. The final portion of each tracing was taken during a brief period of voluntary hyperventilation, and demonstrates the patient's ability to rapidly normalize her FETCO2. There is a brief interruption of the FETCO2 tracing caused by accidental disconnection of the capnometer.

The patient's breathholding times were short and were not significantly affected by lung volume, by hyperventilation prior to the breathhold, or by breathing 100% oxygen (Table 4). When asked to describe her sensation during breathholding, the patient reported that she experienced an uncomfortable sensation in her chest, "a strong urge to breathe."

The patient's HVR is shown in Figure 4. The mean slope for the ventilatory response was 0.37 L/min/Sa_O2. This response lies within the range observed in normal subjects (7). The ventilatory response consisted of significant increases in both respiratory frequency (f) and VT. End-tidal CO₂ was successfully held constant (albeit at an increased level) throughout the hypoxic trials (data not shown). During the hypoxic trials the patient reported that her "breathing was more laboredlike breathing with a cloth over my mouth." She also experienced "hot flashes" and felt sleepy at the end of the hypoxic periods.

View larger version (19K): [in this window] [in a new window]   Figure 4.   Hypoxic ventilatory response. There was a significant inverse relationship between ventilation and SaO2.

The patient's ability to exercise was limited by muscle spasms and cramps in her legs. As a result, she achieved only a modest level of exercise. Nonetheless, her ventilation was linearly related to O₂ consumption (Figure 5, top panel ) and CO₂ production (not shown) during exercise. The increase in her ventilation with exercise occurred almost exclusively through an increase in VT; there was only a slight and statistically insignificant tendency for her respiratory rate to increase during exercise (Figure 5, bottom panel ). There was also a small but significant increase in her PET_CO2 as exercise intensity increased (Figure 6). As was observed during spontaneous breathing, there was marked variability in the patient's ventilatory pattern during exercise: the CVs for VT and f were 43.2% and 30.9%, respectively. The patient denied breathlessness or any other respiratory discomfort during exercise.

View larger version (13K): [in this window] [in a new window]   Figure 5.   Exercise ventilation. The ventilatory response calculated on a breath-by-breath basis ( E) demonstrates a linear relationship between ventilation and oxygen consumption (top graph). There was no significant correlation between respiratory rate and oxygen consumption (bottom graph).

View larger version (13K): [in this window] [in a new window]   Figure 6.   End-tidal CO2 during exercise. Increasing exercise intensity was accompanied by a small but significant rise in CO2.

With the patient in the supine position, her HR and BP were 110/min and 122 / 76 mm Hg, respectively. With the patient in the standing position, the corresponding values for HR and BP were 118/min and 110 /86 mm Hg. Because of her short breathholding time, she was able to sustain the Valsalva maneuver for only 7 to 8 s, and it was therefore not possible to distinguish all phases of the Valsalva response. Nonetheless, during (and particularly following) the Valsalva maneuver, there was an inverse relationship between HR and BP that is characteristic of the normal Valsalva response (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION SUMMARY REFERENCES

Our patient presented with a unilateral brain-stem tumor causing severe daytime hypoventilation accompanied by a marked disturbance in respiration during sleep. We did not formally test the patient's ventilatory response to inhaled CO₂ because we felt that it was not ethically justified to administer CO₂ to a patient with a brain tumor who had previously required mechanical intubation because of CO₂ retention and who suffered from chronic headaches. However, we think the evidence that the patient lacked ventilatory sensitivity to CO₂ is compelling: there were no derangements in lung, chest wall, or respiratory muscle function that could explain her hypercapnia; she could quickly reduce her FET_CO2 to a normal value by voluntary hyperventilation; and after a brief period of hypocapnia induced by mechanical ventilation, she quickly reestablished her baseline level of hypercapnia. The principal findings in the physiologic studies of the patient were a normal ventilatory response to hypoxia and near normal ventilatory response to exercise; preserved cardiovascular reflexes; and a short breathholding time accompanied by a sensation of air hunger. We discuss the implications of these findings in the following sections.

CO₂ Chemosensitivity

The ventrolateral medulla has traditionally been viewed as the site of CO₂ chemosensitivity, although chemoreceptor cells have never been identified unequivocally in this region (8). Our patient presented with a lack of CO₂ chemosensitivity resulting from a lesion that, at least within the spatial resolution of magnetic resonance scanning, spared the ventral medulla and primarily involved the right half of the dorsal medulla. In those few patients with central alveolar hypoventilation in whom histopathologic examination of the brainstem has been performed, or in whom the site of a lesion was known from imaging studies done while the patient was alive, the most common findings were bilateral involvement of the medullary reticular formation in the region of the nucleus tractus solitarius (NTS) and the nucleus ambiguus (NA) (9). Unilateral medullary brain-stem lesions involving the NTS and NA (9, 10), as in our patient, or lesions involving only the NA (9), have also been associated with hypoventilation.

This clinical histopathologic correlation of central alveolar hypoventilation and absent CO₂ chemosensitivity is at odds with studies of CO₂ chemosensitivity in anesthetized and decerebrate animals, and raises questions about the location of CO₂ chemoreceptors within the brain stem and about the role of putative CO₂ chemoreceptor sites in the ventral medulla. More recent evidence from animal studies suggests that CO₂-chemosensitive regions may also exist in other areas of the brain stem, including the ventral medulla (11), NTS (12) and locus coeruleus (11). Chronic, bilateral lesions in the ventrolateral NTS were found to diminish the CO₂ responses in anesthetized cats (12). Furthermore, intrinsically CO₂-sensitive cells have been identified in the NTS in studies of rat brain-stem slices (13). Hence, involvement of the NTS and NA in patients with alveolar hypoventilation, such as our patient, may be essential because these nuclei contain chemosensitive cells. We are not aware of any reports of isolated unilateral or bilateral lesions in the ventral medulla causing central alveolar hypoventilation in humans; the essential neural substrate of central alveolar hypoventilation in patients seems to consist of lesions involving the NTS and/or the NA.

The NTS and the NA contain premotor neurons whose axonal projections impinge on spinal respiratory motor neurons. Furthermore, afferent projections from a variety of receptors, which may include CO₂ chemoreceptors, terminate in the NTS. Hence, damage to premotor neurons in the NTS or NA might produce severe deficits by eliminating the final integrative area for chemoreceptor afferents, rather than by destroying the chemoreceptors per se. In this case, hypoventilation might originate to a greater extent from a failure of integration of CO₂-chemosensitive afferents into the respiratory output than from a loss of CO₂ sensitivity. This latter argument is hard to sustain in the case reported here, because the integration of the patient's responses to hypoxia and exercise was normal or near normal, and her respiratory rhythm was no more irregular during wakefulness than in normal subjects with intact CO₂ sensitivity. Hence, loss of CO₂ sensitivity alone is the more parsimonious hypothesis for this patient's hypoventilation.

Hypoxic Ventilatory Response

When patients with CCHS are given a hyperoxic or hypoxic gas mixture, they show an appropriate ventilatory response in the first few breaths after the gas mixture is inhaled (1, 14). However, CCHS patients lack a ventilatory response to progressive hypoxia (4). The findings in our patient differ from those in CCHS patients in that our patient had an intact ventilatory response to progressive, isocapnic hypoxia. This is consistent with the hypothesis of separate sites being involved in "transduction" of the CO₂ stimulus (i.e., the central chemoreceptors) and in the processing or integration of inputs from the central chemoreceptors. The tumor in our patient appears to have involved the central chemoreceptors but to have spared the integrating function within the medulla, thereby eliminating CO₂ chemosensitivity but leaving the response to hypoxia intact. In contrast, the defect in CCHS patients may, in theory, involve the integrative areas, leading to loss of both the hypercapnic and hypoxic ventilatory responses.

Spontaneous Breathing

Although the central chemoreceptors mediate the ventilatory response to hypercapnia, it is unclear what role, if any, they play during spontaneous (unstimulated) breathing. Normal individuals show significant variability in their spontaneous breathing pattern (15), which appears to be greater for the "drive" than for the timing components of ventilation (16). The basis for the temporal variability in breathing pattern is uncertain, but reduced variability of the respiratory pattern in a pattern with "locked-in syndrome" (17) is evidence that during wakefulness, much of the variability in breathing pattern arises from cortical inputs to respiration. Central chemosensitivity was intact in the patient with locked-in syndrome described by Heywood and colleagues (17), and the patient had a sharp CO₂ threshold below which apnea and increased respiratory irregularity were present. Hence, respiratory drive originating from CO₂ stimulation seemed to provide a tonic, stabilizing influence on the patient's respiratory output.

In our patient, the CVs for most respiratory variables during wakefulness were within the range previously reported in normal subjects (16) and were similar to that reported in CCHS patients (6, 18). These findings are consistent with the hypothesis that variability in breathing pattern is governed primarily by cortical influences during wakefulness. The patient reported by Heywood and colleagues (17) with locked-in syndrome could not be studied during sleep, but in our patient, the marked irregularity of the respiratory pattern observed when cortical influences diminished during sleep may have been caused by absence of the stabilizing effect of the CO₂ stimulus to breathe. In the absence of the waking stimulus and CO₂ sensitivity, hypoxic stimulation alone provides an alinear and unstable stimulus to breathe (19). Hence, hypoxia, cortical inputs, and the waking stimulus (if the waking stimulus is greater than cortical inputs alone) provide respiratory drive sufficient to sustain ventilation in the absence of CO₂ sensitivity, and given the cortical input, the respiratory pattern is appropriately variable. However, when both the waking stimulus and the CO₂ drive for ventilation are lost during sleep, the residual drive for ventilation is unstable, and the respiratory pattern may be quite variable. One further difference between our patient and CCHS patients is that respiratory instability was greater during REM sleep in our patient, whereas respiratory instability is greater during non-REM sleep in CCHS patients (20).

Exercise

Our patient increased her ventilation progressively during exercise, but her PET_CO2 was quite variable, and overall, her ventilatory response was not truly isocapnic. This parallels what has previously been reported in CCHS patients, who also show increased ventilation during exercise (5, 6) and demonstrate greater variability in PET_CO2 than do control subjects (6). Some CCHS patients also have a significant increase in PET_CO2 during exercise (6). Bennett and Fordyce (21) suggested that the CO₂ controller "fine tunes" the ventilatory response during exercise, and to the extent that CO₂ sensitivity is reduced or absent, the ventilatory response may not be isocapnic. Therefore, the lack of a strictly isocapnic response to exercise is consistent with the absence of CO₂ sensitivity both in our patient and in patients with CCHS.

In some respects, our patient differed from CCHS patients. In contrast to CCHS patients, in whom ventilation during exercise increases primarily as a result of an increase in respiratory rate (5), the increase in ventilation with exercise in our patient occurred almost exclusively through an increase in VT. Our patient also exhibited greater variability in breathing during exercise than in spontaneous breathing, whereas in CCHS patients, variability in breathing is greater at rest than during exercise (6). Our patient's increased variability in breathing during exercise was a surprise to us: we thought that the addition of another ventilatory stimulus, such as exercise, might regularize her respiratory pattern. We are unable to explain this unexpected finding.

Respiratory Sensation

Many individuals report a sensation of air hunger while breathing CO₂ (22), and most individuals experience a similar sensation during a maximum breathhold. The origin of the sensation of air hunger is uncertain, but it may be related to perception of increased chemoreceptor activity (2). Patients without CO₂ chemosensitivity provide a unique opportunity to examine the relationship between the central chemoreceptors and the sensation of air hunger. Some patients with central hypoventilation have reported "dyspnea" (9, 23) during hypercapnia, but this discomfort may have been the result of coexistent respiratory disorders (e.g., pneumonia, upper airway obstruction) rather than of hypercapnia per se. Some investigators have reported an absence of dyspnea in patients with central hypoventilation (3, 24), but in most such cases the specific questions asked of the patients about their respiratory sensations are not stated, making it difficult to draw any firm conclusions. The most detailed studies of respiratory sensation in patients without CO₂ chemosensitivity have been done by Shea and colleagues in patients with CCHS (2). They found that CCHS patients had much longer breathholding times than did age-matched controls. Of the five children they studied, three reported no respiratory discomfort during a breathhold; one subject reported sensations akin to air hunger, although his responses were inconsistent; and the fifth subject, an 8-yr-old boy who had the shortest breathholding times in the group, ended his breathhold because he felt "air pushing up." The subjects offered similar descriptions of their sensations while breathing CO₂: one subject reported a clear "urge to breathe" and another subject was inconsistent in her reports of air hunger. Shea and colleagues interpreted these comments as indicating a lack of air-hunger sensation in their CCHS patients, and concluded on the basis of these findings that the sensation of air hunger during breathholding arises either from direct cortical projection of chemoreceptor activity or from indirect projection of such activity via a corollary discharge (27).

The results in our patient contrast with those of Shea and colleagues (2): our patient had a strikingly short breathholding time and reported a strong urge to breathe as the factor causing her to terminate breathholds. What can account for these discrepant findings? One possibility is that our patient was reporting the sensations she had expected she would have on the basis of her prior experience, when still healthy, in which she had felt air hunger during breathholding. However, if she were simply offering descriptions based solely on her past experience of respiratory sensations, one might also have expected her to report breathlessness during exercise, which she did not report. Nonetheless, we cannot exclude the possibility that our patient's report of air hunger reflected only past experience. Alternatively, the air hunger reported by our patient but absent in CCHS patients may have a true physiologic basis. We have previously discussed the hypothesis that the defect in CCHS involves the integration of chemoreceptor inputs, whereas the preserved hypoxic response in our patient suggests an abnormality involving the chemoreceptors per se but which spares mechanisms that integrate other respiratory afferents. If the sensation of air hunger were to arise either from direct cortical projection or from a corollary discharge from the site of integration rather than from the central chemoreceptors, one would predict that the sensation of air hunger would be absent in CCHS patients but present in our patient. We believe that this modification of the hypothesis offered by Shea and colleagues (2) represents the best explanation for the seemingly contradictory findings in their patients and our patient.

Cardiovascular Responses

Medullary neurons involved in cardiovascular regulation have been identified in the same region as neurons involved in respiratory control, raising the question of whether the same neurons are involved in the control of both systems (8). The normal or near-normal baroreceptor function in the setting of absent CO₂ sensitivity in our patient indicates that although the neurons involved in respiratory and cardiovascular control may lie in close anatomic proximity in the ventral medulla, separate pathways are involved in CO₂ chemosensitivity and cardiovascular control during wakefulness.

	SUMMARY

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION SUMMARY REFERENCES

Our patient raises questions about the anatomic origin of CO₂ chemosensitivity in humans. The finding of a preserved hypoxic response in the absence of CO₂ sensitivity supports the theory that the brain stem contains functionally distinct groups of cells involved in chemoreception and integration of chemoreceptor output. Our study suggests that CO₂ chemosensitivity is not essential for the sensation of air hunger, leading us to hypothesize that air hunger originates in the activity of the integrative regions in the brain stem. Any effort to localize the CO₂ chemoreceptors in our patient must be tempered by awareness of the limited resolution of current magnetic resonance imaging scanners. However, our patient's lesion was predominantly unilateral, and spared the ventrolateral medulla, as best we could discern. Finally, the patient's preserved cardiovascular reflexes indicate that CO₂ chemosensitivity and cardiovascular control are not mediated by identical groups of cells during wakefulness.