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| ABSTRACT |
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| TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES |
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Key Words: familial dysautonomia • hypoxia • hypotension • chemoreceptors • autonomic nervous system
| INTRODUCTION |
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Despite the high mortality in this population, only a few studies have analyzed respiratory control in a very small number of these patients (7, 8). Although central depression of respiration was hypothesized (7), it is still not known whether respiratory abnormalities relate to cardiovascular and cerebrovascular dysfunction. This has practical consequences, because a better knowledge of the complex mechanisms regulating cardiorespiratory control, oxygen transport, and cerebral perfusion may benefit not only subjects with FD but also patients with different types of cardiorespiratory and autonomic involvement.
In the present study, using standard rebreathing tests, we investigated whether chemoreflex responses are altered in subjects with FD. The cardiovascular and cerebrovascular responses to progressive hypoxia or hypercapnia were evaluated simultaneously. In addition, we studied the time course of these variables in response to hyperventilation to simulate events preceding the breath-holding episodes in subjects with FD, and to understand the mechanisms inducing syncope and respiratory arrest in this population.
| METHODS |
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Diagnostic criteria, therapy, and resting data are reported in the online supplement.
Subjects were studied supine. Electrocardiogram (ECG, D2 lead; Colin Corp., San Antonio, TX), noninvasive blood pressure (BP) (Colin Corp.), respiratory movements (Respitrace; Nims, Fl), oxygen saturation (SaO2) (Ohmeda, Louisville, CO), expired CO2 (Colin Corp.), and midcerebral artery blood flow velocity (MCFV) by a 2 mHz transcranial Doppler probe at a depth 35–55 mm through the temporal window (DWL, Sipplingen, Germany) were monitored. Subjects breathed through a mouthpiece connected to unidirectional valves either in air or into a rebreathing circuit; in the expiratory part, a heated pneumotachograph (Fleisch, Epalinges, Switzerland) was used to quantify expiratory flow.
Three tests were performed: (1) isocapnic progressive hypoxia (from resting values to 80% oxygen saturation); (2) hyperoxic hypercapnia (up to 15 mm Hg above resting values and under low oxygen flow to maintain SaO2 at 1–2% above resting level); and (3) monitoring of the period after mild hyperventilation. Parts (1) and (2) provided measurements of chemoreflex sensitivity to O2 and CO2, assessed cardiovascular and cerebrovascular changes induced by these maneuvers, and verified if changing the levels of oxygen alone could modify the cardiovascular response. Part (3) was performed to mimic the typical breath holding reported in subjects with FD and to monitor the cardiovascular changes and the conditions that induced and reversed the apnea. Parts (1) and (2) were performed with a rebreathing circuit; part (3) was performed in 11 subjects with FD and in 7 control subjects by breathing for 2 minutes at 15 breaths/minute (i.e., close to the normal breathing rate to limit the extent of hyperventilation), which lowered CO2 levels by approximately 10 mm Hg. Many patients with FD cannot voluntarily control respiratory excursions. Therefore, this test was performed only in those patients with FD capable of sufficient coordination to follow instructions for deep breathing and in a subset of matched control subjects.
The respiratory flow was integrated by software to calculate breath-by-breath tidal volume, minute ventilation, breathing rate, SaO2, and end-tidal carbon dioxide (CO2-et ). The chemoreflex sensitivity to hypoxia or hypercapnia was obtained from the slope of the linear regression of minute ventilation versus SaO2 or CO2-et , respectively (11, 12). Mean values for heart period (RR interval) and systolic BP were obtained during 1 minute before (baseline) and during the last minute of each rebreathing test. The sensitivity of MCFV to CO2-et was calculated by the slope of the linear regression between these two values during hyperoxic progressive hypercapnia.
Data presented here are mean ± SEM. Differences were analyzed by analysis of variance mixed design (repeated measures in two subject groups). If overall significant changes were observed (p < 0.05), then significance was tested by Sheffe's test. Correlation between different variables was evaluated by linear regression analysis.
| RESULTS |
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Resting Ventilation
After correction for BSA, ventilation did not differ significantly between FD and control subject groups. However, the FD subject group had markedly lower oxygen saturation and higher CO2 values than the control group. In addition, the FD group had higher supine BP and lower RR interval than the control group, as well as higher MCFV (Table E1 in the online supplement).
Chemoreflex Responses to Hypoxia and to Hypercapnia
Examples of raw data obtained in one control and in one subject with FD are shown in and .
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Although hyperventilation caused similar CO2 decreases in both groups ( right panel), profound effects were evident in the subjects with FD after termination of hyperventilation . All subjects with FD experienced complete apnea (mean duration: 51.5 ± 9.9 seconds) accompanied by severe desaturation (reaching an average of 75.8 ± 3.5%, ). After hyperventilation, BPs reached values below resting levels, similar to the response seen during progressive hypoxia, whereas RR interval increased to levels greater than baseline values . In both groups, apnea terminated when CO2-et values were 1–2 mm Hg below baseline levels in subjects with FD (38.6 ± 11 mm Hg versus 39.7 ± 1.1 mm Hg; p = NS) and in control subjects (31.6 ± 1.4 versus 33.7 ± 0.6; p = NS). In the control subjects, termination of hyperventilation induced transitory slowing of respiration (with a pause of 11.2 ± 5.5 seconds; p < 0.008 versus subjects with FD) without desaturation , and BP and RR interval returned toward baseline levels at the end of this short period
During apnea, the MCFV increased in all subjects and in both groups it reached values similar to the MCFV baseline levels ( left and right panels), despite the fact that in subjects with FD (but not control subjects) the return to baseline CO2 levels was accompanied by marked oxygen desaturation.
| DISCUSSION |
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| TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES |
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Effect of Hypoxia on Cardiovascular Function: Development of Central Ventilatory Depression
When subjects with FD became hypoxic we observed marked hypotension and bradycardia but no increase in ventilation. Although the primary response to hypoxia is vasodilation, this is normally compensated by sympathetic activation; as such, normal subjects experience tachycardia and a moderate increase in BP, together with hyperventilation resulting from activation of the peripheral chemoreflexes (13). In subjects with FD, our findings indicate the onset of a central depression affecting both respiratory and cardiovascular centers, which further worsens hypoxia and induces a vicious circle. The sympathetic deficit associated with FD (1, 2) cannot compensate for the vasodilation induced by hypoxia and facilitates the induction of central depression. In addition, baroreflex dysfunction in subjects with FD, recently reported by our group (14) also might reduce the sympathetic modulation of the vessels. The sympathetic dysfunction probably enhances the BP decrease observed during hypoxic conditions, and may contribute to the vicious circle by altering cerebral perfusion. In addition, due to the mutual interactions between chemo- and baroreflexes (15), sympathetic dysfunction cannot induce an increase in ventilation in response to a drop in BP, as it typically occurs in patients with orthostatic hypotension when they stand. These perturbations were less evident when patients were in the supine position, due to the frequent occurrence of spine hypertension in the dysautonomic population. However, the lack of appropriate response of BP, heart rate (HR), and cerebral blood flow velocity during hypoxia and apnea indicates that BP and respiratory abnormalities are both present in these patients.
Subjects with FD frequently have elevated supine BP and impaired cerebral autoregulation (16, 17). Elevated supine BP may play a compensatory role during hypoxia by preventing an excessive reduction in cerebral perfusion. This hypothesis was supported by our observation that MCFV failed to increase in subjects with FD during hypoxia but remained adequate despite decreases in both systolic and diastolic BP's. This suggests that despite directionally unfavorable responses of BP and HR to progressive hypoxia, the subject with FD can maintain relatively compensated cerebral blood flow that may limit the extent of cerebral hypoxia during the posthyperventilatory apnea. A substantial proportion of our subjects with FD (12/22) had a gastrostomy to compensate for oral incoordination so that fluid requirements could be met. Thus, the improved fluid balance of our subjects with FD may have contributed to limiting the deleterious cardiovascular effects previously seen during hypoxia (8).
Is the Response to Hypercapnia Normal in Subjects with FD?
The alterations seen during maneuvers inducing hypoxia were absent during progressive hypercapnia even though the subjects with FD were starting from higher CO2 levels and thus reached higher CO2 levels at the end of rebreathing. The most obvious explanation is that we conducted progressive hypercapnia under administration of oxygen. Therefore, although both hypoxia and hypercapnia may theoretically induce central depression, the present study demonstrates that subjects with FD are relatively insensitive to the deleterious effects of excessive hypercapnia, as long as blood oxygenation is maintained. Our observations are consistent with the findings of Edelman and coworkers (7), who noted that BP and HR responded normally to progressive hypercapnia if PaO2 was maintained within normal levels; but when progressive hypercapnia was accompanied by hypoxia, the response was abnormal and consistent with central depression.
Effect of Apnea on Cardiorespiratory Regulation
Moderate hyperventilation normally elicits hypocapnia, with resulting hypoventilation or apnea, until CO2 reaches levels that stimulate ventilation (9, 18). After our control subjects hyperventilated, CO2 levels returned to normal before oxygen saturation started to decrease and SaO2 remained slightly higher than resting values. However, in our subjects with FD, even moderate hyperventilation induced prolonged apnea with profound oxygen desaturation and progressive BP fall, even below baseline levels .
The progressive increase in CO2 in subjects with FD caused an increase of MCFV, suggesting cerebral vasodilation (and). This cerebral vasodilatation, together with higher baseline BP levels, limited or delayed the extent of cerebral hypoxemia and central depression and allowed the subjects to reach a threshold sufficient to stimulate breathing. Because the first breath after apnea generated a CO2 level that was just below the resting CO2 level, it is likely that that termination of apnea was due to stimulation of the central (CO2) chemoreflex (18). The relationship between MCFV and CO2 was not changed by apnea in subjects with FD and remained similar to that of control subjects and to that obtained during hyperoxic hypercapnia, despite the fact that subjects with FD developed a profound hypoxemia. This confirmed that cerebral blood flow in subjects with FD was not sensitive to hypoxia. Thus, blunted hypoxic MCFV may contribute to central depression during hypoxia.
The rapid development of hypoxemia during apnea or during breathing in hypoxia likely results from a combination of factors. The subject with FD has a smaller thorax and vital capacity due to a physically smaller body habitus and limited chest wall expansion caused by kyphoscoliosis. In addition, oxygen carrying capacity is decreased by the common presence of anemia (Table E1 in the online supplement). These factors may contribute to prolonged apnea after hyperventilation, as well as poor tolerance of environments with low partial pressure of oxygen, such as pressurized airplane cabins and high altitudes.
Prolonged Apnea May Predispose to Arrhythmias in Patients with FD
The effects of hypoxia on the sympathetic nervous system are even more evident during apnea. In normal subjects, apnea induces a marked potentiation of the sympathetic vasoconstrictor response to hypoxia (19) due to the lack of inhibitory influence of the pulmonary receptors (20). In addition, peripheral chemoreflex activation in the absence of breathing simultaneously increases cardiac vagal activity causing bradycardia (21, 22). In patients with FD, the vasoconstrictor response to hypoxia was lost and bradycardia was markedly evident . Therefore, bradycardia could result from unopposed vagal stimulation and/or from a central depression. Finally, the increase in ventilation in response to hypoxia is also a primary stimulus to coronary vasodilatation. When the increase in ventilation is prevented, coronary vasodilation is also prevented (23, 24). This could potentially predispose patients to arrhythmias and death during prolonged apneic episodes. If this is the case, it would seem that subjects with FD, although unable to mount an appropriate response to hypoxia, still maintain some afferent information from peripheral chemoreceptors.
The clearly abnormal responses to hypoxia in patients with FD speak to the importance of the autonomic nervous system in facilitating an appropriate physiologic response. The attenuation of this sympathetic vasoconstriction in the setting of FD is an important aspect of understanding what is happening in these patients, particularly during apnea, when the sympathetic vasoconstriction should be most marked. The relevance of these data are further emphasized by the fact that during both hypoxia and apnea the direct vasodilatory effects of hypoxia (13) are less opposed by sympathetic vasoconstriction, hence predisposing patients to hypotension during hypoxia and especially during apnea.
Autonomic Dysfunction Is Totally Organic—or Is It Also Functional?
Sympathetic lesions are well described in subjects with FD, and the abnormal vascular responses are attributed to sympathetic insufficiency (25). Our study suggests that some of the vascular and respiratory abnormalities seen in subjects with FD may be secondary to an abnormal autonomic response, and are worsened by an abnormal response to hypoxia. With a lesion in the sympathetic outflow tract, one would expect decreased BP and HR changes with both progressive hypoxia and progressive hypercapnia. In our subjects with FD, there was no increase in BP (or HR) during progressive hypoxia, but there was an increase in both parameters with progressive hypercapnia. In fact, when subjects with FD were challenged with progressive hypercapnia but kept hyperoxic, they exhibited greater than normal BP and HR responses.
Study Limitations
The method of transcranial Doppler probing is widely used to monitor cerebral blood flow velocity. However, the extent to which this is also an indication of blood flow is dependent upon a number of factors that cannot easily be assessed (e.g., vessel diameter and stability of the ultrasonic signal, anatomic conditions and functional status of the vascular tree downward the site of monitoring). Therefore, although we have found a clear indication of insensitivity of cerebral blood flow velocity to hypoxia, a similar alteration in cerebral blood flow can only be proposed as hypothesis.
Conclusion
Our data indicate that the prime abnormalities in the respiratory control of subjects with FD are a reduced sensitivity to hypoxia and a tendency to develop rapid central depression with relatively mild hypoxia. Patients with FD have greater than normal BP and HR responses to hypercapnia despite their known deficit in autonomic control. A high supine BP is commonly found in patients with different types of dysautonomia. This results from an impaired baroreflex control and, in fact, BP drops markedly on standing. So the increased level of BP in supine position also reflect the inability of the baroreflex to reduce BP. Alternatively, the exaggerated BP and HR responses may be examples of denervation hypersensitivity.
Hyperventilation can be dangerous in subjects with FD because the resulting apnea can provoke rapid hypoxemia and cardiorespiratory depression. If there is an insufficient compensation by hypoxia-induced cerebral vasodilation, or if hypotension develops, then irreversible cardiovascular changes and even death might occur. Coronary flow abnormalities induced by hypoxia and hypoventilation may also contribute to or overlap with these mechanisms. Administration of oxygen at low flow, and assurance of adequate hydration, appear to be beneficial; in addition, techniques increasing the sensitivity to hypoxia (26) appear worth testing. The results of this study have relevance not only for the case of FD but can also extend to other more common pathologies. The occurrence of central depression during hypoxia is frequent in patients with cardiovascular disorders and those with diabetes, as well as in patients with other types of autonomic neuropathies. This condition is probably due to an impairment of cerebrovascular responsiveness to various stimuli, of which hypoxemia may be a common condition, precipitating cardiovascular accidents.
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| TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES |
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