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Clinica di 1 Semeiotica e Metodologia Medica and 3 Neurologia e Neuroriabilitazione, University of Ancona, 60020 Ancona; and 2 Dipartimento di Medicina Interna e Scienze Endocrino-Metaboliche, University of Perugia, 06100 Perugia, Italy
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Because abnormalities in
cerebrovascular reactivity (CVR) in subjects with long-term diabetes
could partly be ascribed to autonomic neuropathy and related to central
chemosensitivity, CVR and the respiratory drive output during
progressive hypercapnia were studied in 15 diabetic patients without
(DAN
) and 30 with autonomic neuropathy (DAN+), of whom 15 had
postural hypotension (PH) (DAN+PH+) and 15 did not (DAN+PH), and in
15 control (C) subjects. During CO2 rebreathing,
changes in occlusion pressure and minute ventilation were assessed, and
seven subjects in each group had simultaneous measurements of the
middle cerebral artery mean blood velocity (MCAV) by transcranial
Doppler. The respiratory output to CO2 was greater in
DAN+PH+ than in DAN+PH and DAN (P < 0.01), whereas
a reduced chemosensitivity was found in DAN+PH (P < 0.05 vs. C). MCAV increased linearly with the end-tidal
PCO2 (PETCO2) in
DAN+PH but less than in C and DAN (P < 0.01). In contrast, DAN+PH+ showed an exponential increment in MCAV with PETCO2 mainly >55 Torr. Thus CVR
was lower in DAN+ than in C at PETCO2 <55
Torr (P < 0.01), whereas it was greater in DAN+PH+ than in DAN+PH (P < 0.01) and DAN
(P < 0.05) at PETCO2 >55
Torr. CVR and occlusion pressure during hypercapnia were correlated only in DAN+ (r = 0.91, P < 0.001). We
conclude that, in diabetic patients with autonomic neuropathy, CVR to
CO2 is reduced or increased according to the severity of
dysautonomy and intensity of stimulus and appears to modulate the
hypercapnic respiratory drive.
diabetes; control of breathing
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A HIGHER RATE OF MORTALITY
HAS been extensively reported in diabetic patients with autonomic
neuropathy (DAN+) compared with diabetic patients without dysautonomy
(43). In DAN+, most deaths occur suddenly during stressing
conditions and/or sleep and have often been attributed to
cardiorespiratory events (12, 28, 36). Hence, a number of
studies have investigated the influence of the diabetic dysautonomy on
the control of breathing (19, 24, 35, 42), leading,
however, to controversial results. In fact, whereas a
consistent decrease in hypoxic drive has been found in DAN+, indicating
a reduced peripheral chemosensitivity in these subjects (24, 27,
34, 42), conflicting results have been reported, as far as the
central chemosensitivity was concerned, as increased (27),
normal (34, 35), and decreased (19, 24, 40,
42) responses of the respiratory drive to hypercapnia have been
described in similar populations of DAN+. Recently, by splitting DAN+
into two groups that were characterized, according to the standard
cardiovascular tests (13), by the presence of either
parasympathetic and sympathetic damage with postural hypotension (PH)
(DAN+PH+) or predominant parasympathetic damage without PH (DAN+PH),
we were able to show an increased response of the respiratory centers
to progressive hypercapnia in the former group, whereas the opposite
was found in the latter (38). These findings may suggest a
modulatory effect of the sympathetic arm of the autonomic nervous
system on the CO2 responsiveness of the respiratory centers
that, in fact, is enhanced when the sympathetic activity is markedly
decreased, as in DAN+PH+, and reduced when this is not counterbalanced,
as in DAN+PH. The operating mechanism, however, is unknown. Because
abnormalities in cerebrovascular reactivity (CVR) to different stimuli
have been shown in large subsets of patients with long-lasting
diabetes, many of whom were young and possibly suffering from autonomic
neuropathy (11), we reasoned that, besides a potential
direct mechanism, the sympathetic nervous system could indirectly
influence the respiratory center output by regulating the cerebral
blood flow (CBF) in the presence of effective stimuli. To verify this
hypothesis, the CVR to CO2 was assessed in diabetic
patients with different degrees of dysautonomy, while the ventilatory
and neuromuscular response of the respiratory drive to progressive
hypercapnia was monitored.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects.
Forty-five male diabetic patients, 15 without (DAN) and 30 with
(DAN+) diabetic autonomic neuropathy were recruited from the
Dipartimento di Medicina Interna e Scienze Endocrine e Metaboliche of
University of Perugia and enrolled in the study after they had given
fully informed consent. The protocol was approved by the local ethics
committee and was in accordance with the Helsinki Declaration.
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4. Fifteen of 30 DAN+ patients had predominant parasympathetic involvement of the autonomic nervous system, that is,
an impairment of at least two tests of deep breathing, Valsalva maneuver, and lying down to standing, but a normal increase in diastolic blood pressure to sustained handgrip and lack of PH, and we
referred to them as DAN+PH. The remaining 15 DAN+ exhibited severe
autonomic neuropathy, that is, parasympathetic damage associated with
an overt sympathetic damage as reflected by PH, i.e., an upright fall
of systolic blood pressure >30 mmHg and impaired response to sustained
handgrip, i.e., an increment of diastolic blood pressure <16 mmHg, and
we referred to them as DAN+PH+ (4, 5, 29). One patient in
the DAN group, four in the DAN+PH group, and nine in the DAN+PH+
group had preproliferative retinopathy; two DAN+PH+ patients had
proliferative retinopathy. The remaining patients had no proliferative
or background retinopathy. Two subjects in the DAN group, seven in
the DAN+PH group, and 10 in the DAN+PH+ group had microalbuminuria
(overnight urinary protein excretion of 20-200 µg/min); one
subject in the DAN+PH group and four subjects in the DAN+PH+ group
had proteinuria (<2 g/24 h), but none of them had serum creatinine
>1.5 mg/dl. Two patients in the DAN+PH+ group had symptoms related to
autonomic dysfunction, that is, nocturnal watery diarrhea and gustatory
sweating, respectively.
All patients had to be normotensive, without evidence or history of
ischemic heart and cerebrovascular disease. Duplex scans of the carotid
arteries had to show no or only mild (<30%) stenosis of the internal
carotid artery. None of the patients studied had symptoms or signs of
endocrine or metabolic disease other than diabetes. No respiratory
symptoms were observed or reported at the time of the study. Fifteen
male normal subjects recruited from the University staff were studied
as the control (C) group (Table 1).
Study design.
All patients and C subjects underwent pulmonary function tests
including spirometry, flow/volume curves, determination of lung volumes
(by multiple-breath nitrogen washout technique), and measurements of
maximal inspiratory (MIP) and expiratory mouth pressures (MEP). All
tests were performed with subjects in the sitting position, wearing a
nose clip, and breathing through a mouthpiece connected to a
computerized measuring system (MedGraphics 1070; Medical Graphics, St.
Paul, MN). The predicted values for volumes and flows were those
proposed by the European Community for Coal and Steel
(31). Measurements of MIP and MEP, sustained for at least
1 s, which could not differ by >5%, were obtained in triplicate
at functional residual capacity by a differential pressure transducer
(±300 cmH2O; Validyne, Northridge, CA). Subjects were
comfortably seated, wearing a nose clip, and performed maximal inspiratory and expiratory efforts against an obstructed mouthpiece with a small leak (internal diameter ~2 mm) during inspiration to
prevent the subjects from generating pressures with their facial muscles. The mean of the two best efforts was considered for analysis. Predicted values for MIP and MEP were those proposed by Cook et al.
(7). Minute ventilation (
E), tidal
volume (VT), and respiratory rate (RR) were measured at
rest from the time-integrated flow signal with the subjects breathing
room air in the seated position through a two-way, non-rebreathing,
balloon shutter occlusion valve (Hans-Rudolph, Kansas City, MO).
Randomly, during each four to eight breaths during expiration, the
inspiratory line was silently closed by automatically inflating the
balloon with a computer-supported pneumatic system (respiratory
pressure module MedGraphics, Medical Graphics). The mouth pressure was
measured during the following occluded inspiration at a side port on
the occlusion valve, which was connected to a pressure transducer
(±150 cmH2O; Validyne) through a noncompliant polyethylene
catheter (internal diameter 1.4 mm; length 95 cm). The value of mouth
pressure with occluded airways, calculated 100 ms after the beginning
of the inspiration (P0.1), was displayed by the computer
(respiratory pressure module MedGraphics, Medical Graphics)
(41). Baseline P0.1 was obtained as a mean of
at least eight values of occlusion pressure, after the lowest and the
highest were rejected. CO2 was continuously sampled at the
mouth, and the expiratory end-tidal CO2 partial pressure
(PETCO2) was measured breath by breath by
a rapid infrared CO2 analyzer (gas analyzer module, CPX
MedGraphics, Medical Graphics).
E, VT, and RR were calculated from the
data averaged from the four breaths preceding each occlusion. For each
rebreathing test, E and P0.1 were
plotted against PETCO2, and data were
fitted according to the least squares method. The slopes and intercepts
of the linear regression were computed. The coefficient of correlation
was >0.97 in all subjects. At a flow rate of 1 l/s, the resistance of
the rebreathing circuit was 1.1 cmH2O · l
1 · s.
Baseline HR and arterial hemoglobin oxygen saturation were obtained by
means of an ear pulse oximeter (Biox 3700, Ohmeda, Boulder, CO), and
systolic and diastolic arterial blood pressures were obtained by using
a sphygmomanometer in all subjects when they were sitting.
In each diabetic group, seven subjects with similar clinical and
functional characteristics and seven matched C subjects underwent measurements of mean blood velocity in the middle cerebral artery (MCAV) by ultrasound transcranial Doppler using a Multidop (ESAOTE, Firenze, Italy), both in basal conditions and during rebreathing. After
the middle cerebral artery was insonated at a depth of 50 mm, on the
temporal window, by using a hand-held 2-MHz probe, MCAV was
continuously assessed and measured at each occlusion maneuver for the
analysis. The CVR, which is the increase in MCAV expressed as a
percentage of baseline MCAV (14), was also computed at
different values of PETCO2 (45, 50, 55, and 60 Torr) and at peak.
In all instances, positioning of the probe and MCAV measurements were
made by the same operator (C. Fiorani).
Simultaneously, in these subjects, HR, arterial blood pressure, and,
only in diabetic patients in the morning, venous blood samples to
measure catecholamine plasma levels were obtained under basal
conditions and during the rebreathing test at 55 Torr and at peak value
of PETCO2.
Blood samples for determination of the plasma epinephrine and
norepinephrine, drawn throughout an 18-gauge Teflon catheter inserted
into a superficial vein of the forearm, were immediately placed on ice
until centrifugation and storage of plasma at 20°C could be
performed. Later analysis was carried out by using the HPLC method
(18).
Plasma glucose concentration was measured at baseline and at the end of
the rebreathing test in all diabetic patients by means of a Beckman
glucose analyzer (Beckman Instruments, Palo Alto, CA). The rebreathing
test and ultrasound transcranial Doppler were performed twice, in the
morning between 1100 and 1130 and in the afternoon between 1600 and
1630. The values of MCAV, CVR, and slopes of the linear relationship of
P0.1 against PETCO2
(
P0.1/PETCO2) and of
E against PETCO2
(E/PETCO2)
averaged from the two tests were considered for the analysis.
Statistical analysis. Comparison of the four groups was performed by using the ANOVA, and orthogonal comparisons were done by adopting the two-tailed unpaired Student's t-test, corrected according to Bonferroni, when allowed by ANOVA. If no assumption about the scatter of the data could be made, the groups were compared by adopting the Kruskal-Wallis test, and, when a significant difference was found, multiple comparisons were performed to compute the difference of the rank's means. Linear correlations were calculated by means of the least squares method. A P value < 0.05 was considered as significant. Data are expressed as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pulmonary function tests.
Lung volumes, indexes derived from the flow/volume curve, MIP, and MEP
are listed in Table 2. The pulmonary
function parameters were within the normal range in all the groups.
Vital capacity was higher in C and DAN than in both DAN+ groups
(P < 0.05). Total lung capacity, inspiratory capacity,
and forced expiratory volume in the first second were higher in C than
in both DAN+ groups (P < 0.01), and inspiratory
capacity and forced expiratory volume in the first second were higher
in DAN than in DAN+PH+ (P < 0.05). Total lung
capacity was higher in DAN than in DAN+PH (P < 0.05). The other parameters of lung function did not differ between C
and diabetic patients. MIP and MEP were not significantly different
among the groups, both as absolute value and as percentage of
predicted. Baseline PETCO2 and arterial
hemoglobin oxygen saturation were normal and nearly identical in all
groups (Table 2).
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Control of breathing.
The baseline values of P0.1, E,
VT, and RR were similar in all groups (Table
3). At the end of the rebreathing test,
the peak value of PETCO2 was not different
among the groups, amounting to 65 ± 1 Torr for the C subjects and
65 ± 1, 64 ± 1, and 62 ± 1 Torr for DAN, DAN+PH,
and DAN+PH+, respectively. The slope of the linear relationship of
P0.1/PETCO2, which was
0.45 ± 0.04 cmH2O/Torr in C subjects, was
significantly higher in DAN+PH+ (0.62 ± 0.05 cmH2O/Torr) than in DAN (0.36 ± 0.04 cmH2O/Torr; P < 0.01) and DAN+PH
(0.28 ± 0.03 cmH2O/Torr; P < 0.01).
Moreover, the
P0.1/PETCO2 exhibited by
DAN+PH was significantly lower than that shown by C subjects
(P < 0.05) (Table 3).
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E/PETCO2 amounted
to 3.49 ± 0.51 l · min1 · Torr1 in the
DAN+PH+ group and was higher than that in the DAN+PH (2.01 ± 0.18 l · min1 · Torr1;
P < 0.05) and DAN groups (2.43 ± 0.26 l · min1 · Torr1; not
significant).
E/PETCO2
was 3.31 ± 0.21 l · min1 · Torr1 in the C
group and was significantly higher (P < 0.01)
than that in the DAN+PH group (Table 3). The individual values of the P0.1/PETCO2 and
E/PETCO2 slopes
are shown for the diabetic groups and C subjects in Fig.
1. The correlation coefficient of the
identity scatterplot of the
P0.1/PETCO2 slope values
between the two CO2 rebreathing tests was 0.91 (P < 0.001).
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MCAV and CVR.
Baseline MCAV did not differ among the groups, amounting to 60.3 ± 4.2 cm/s in DAN, 58.1 ± 4.8 cm/s in DAN+PH, 63.4 ± 2.4 cm/s in DAN+PH+, and 67.3 ± 2.7 cm/s in C, although it was
slightly lower in diabetic patients than in C subjects. The increment
in MCAV due to progressively increasing hypercapnia was different among
the groups (P < 0.001). In fact, at
PETCO2 of 50 Torr, MCAV was higher in C
(87.6 ± 4.5 cm/s) than in DAN, DAN+PH, and DAN+PH+ (72.6 ± 3.4 cm/s, P < 0.05; 67.2 ± 6.2 cm/s,
P < 0.01; and 73.7 ± 3.4 cm/s, P < 0.05, respectively), whereas at PETCO2
of 60 Torr MCAV was higher in DAN+PH+ (137.8 ± 10.7 cm/s) than in
DAN (96.4 ± 5.8 cm/s; P < 0.01) and DAN+PH
(84.9 ± 9.0 cm/s; P < 0.01). At this value of
PETCO2, MCAV in DAN+PH was significantly
lower than in C (111.0 ± 3.8 cm/s, P < 0.05;
Fig. 2).
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, DAN+PH, and C was exponential in DAN+PH+ because of the progressively greater increase in MCAV at
PETCO2 values of >55 Torr (Fig. 2).
As a result, at PETCO2 of 50 Torr, CVR was
higher in C (32.6 ± 1.4%) than in DAN, DAN+PH, and DAN+PH+
(21.9 ± 5.6%, P < 0.05; 15.4 ± 1.3%,
P < 0.01; and 16.9 ± 3.7%, P < 0.01, respectively). Conversely, at
PETCO2 of 60 Torr, CVR
was higher in DAN+PH+ (111.2 ± 17.7%) compared with
DAN (59.6 ± 5.1%; P < 0.05), DAN+PH
(44.7 ± 5.1%; P < 0.01), and, although not
significantly, also C (64.0 ± 5.1%; P = 0.09)
(Fig. 3).
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Catecholamines, HR, and arterial blood pressure.
The values of plasma norepinephrine and epinephrine, HR, and mean
arterial blood pressure in basal conditions and at the end of the
rebreathing test for those diabetic patients and C subjects who
performed ultrasound transcranial Doppler are listed in Table 4. The HR was unchanged in DAN+PH and
DAN+PH+, and a smaller increase in mean blood pressure was found in
these two groups at the end of the rebreathing test. DAN+PH+ exhibited
the lowest increment in plasma catecholamines, and the final level of
plasma norepinephrine was significantly lower (P < 0.01), compared with DAN.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of the study are that 1) diabetic
patients have an impaired CVR (less increase in CBF) with respect to C subjects at PETCO2 of
<55 Torr (i.e., facing with mild-to-moderate vasodilating
stimuli), especially in the presence of dysautonomy; 2)
DAN+PH+ exhibit a greater CVR (greater increase in CBF) than DAN+PH
and DAN at PETCO2
levels of >55 Torr (i.e., facing with stronger vasodilating
stimuli); 3) DAN+PH+ show an increased hypercapnic respiratory drive that is greater than that observed in DAN+PH and
DAN; 4) DAN+PH are characterized by the lowest CVR and
gain of the respiratory center output in response to CO2.
To assess CVR to hypercapnia, we measured blood flow velocity in large cerebral arteries by means of ultrasound transcranial Doppler. This method has been widely adopted (14, 20, 22) instead of determination of regional CBF by single-photon emission computerized tomography or by positron emission tomography to evaluate cerebral vasoreactivity or detect abnormalities of cerebral hemodynamics (9, 10, 37). In fact, changes in velocity and regional CBF have been shown to correlate closely when transcranial Doppler was used simultaneously with these more expensive and technically complex methods.
In the present study, transcranial Doppler ultrasonography was used during progressive hypercapnia, assuming that changes in blood velocity parallel changes in CBF under these conditions also. Because, in normal subjects, the cross-sectional surface area of the basal cerebral arteries is not affected by changes in arterial PCO2 (1), this assumption is valid for C, but we are not aware of whether this has been demonstrated in DAN+. However, if the increment in arterial PCO2, which is a powerful vasodilating stimulus, had increased the cross-sectional surface area of the middle cerebral artery, especially in DAN+PH+, then the increase in MCAV that we recorded in these subjects could have only underestimated the increase in their CBF.
Although some studies performed with the single-photon emission computerized tomography technique have suggested a reduced resting CBF in diabetic patients compared with age-matched C subjects, the lack of significant difference in baseline MCAV between our diabetic and C groups does agree with that reported in several previous works, showing, on average, no reduction either in resting MCAV (14) or in basal global and regional CBF in diabetic patients compared with C subjects (11, 25, 33).
The reduced CVR found in our diabetic patients is in line with the earlier reports showing less increase in CBF after the administration of either intravenous acetazolamide or a given, relatively low percentage of inspiratory CO2 (5%) in general populations of patients with long-term diabetes (11, 14).
Our data, however, show that autonomic neuropathy might play a role in
further decreasing CVR in diabetic patients. Indeed, the average slope
of the MCAV/PETCO2 linear relationship,
computed between 45- and 55-Torr PETCO2 to
avoid the dog-leg phenomenon exhibited by these subjects (Fig. 2), is
lower in DAN+PH (1.84 ± 0.17 cm · s1 · Torr1;
P < 0.01) and also in DAN+PH+ (1.92 ± 0.19 cm · s1 · Torr1;
P < 0.05) than in DAN (2.76 ± 0.29 cm · s1 · Torr1). Although
this difference was not large enough to induce a significantly lesser
CVR in DAN+ than in DAN at 50-Torr
PETCO2 (Fig. 3), nevertheless, it may
suggest a cerebral vasoregulatory action of the autonomic nervous
system, possibly cholinergic, which is altered in DAN+. Therefore,
besides microangiopathic changes of the brain resistance arterioles,
hemorheological changes (14, 23), and presence of
vasoactive substances (14, 23), autonomic neuropathy could be another cause of reduced reactivity of the cerebral vessels to
physiological stimuli in diabetes.
At the same time, a subset of DAN+, namely the DAN+PH group,
exhibited a reduced, neuromuscular, and ventilatory output of the
respiratory drive in response to progressive hypercapnia, reflecting a
significantly decreased central chemosensitivity.
However, compared with DAN+PH and DAN, and even with C, DAN+PH+
showed a markedly greater increase in MCAV at higher values of
PETCO2 (Fig. 2) and an enhanced
hypercapnic respiratory drive (Fig. 1). This late, paradoxical increase
in CVR does imply an exaggerated vasodilation to severe hypercapnia in
diabetic patients with advanced dysautonomy, strongly supporting the
idea that, in the presence of stressing stimuli, the sympathetic
nervous system may play a role in limiting the increase of the CBF, as well as in modulating the output of the respiratory centers to hypercapnia.
Because physiological activation or electrical stimulation of sympathetic nerves in animals has been shown to induce moderate cerebral vasoconstriction and regulate CBF variations (16, 17, 30), direct inhibitory action of the sympathetic nervous system on the cerebral vascular bed in the face of strong vasodilating stimuli may actually be envisaged in humans. Moreover, alterations of adrenergic and cholinergic innervation of brain arterioles have been described in experimental diabetes (14).
Also, the responsiveness of the central drive to CO2 could
be directly modulated by the sympathetic nervous system. Indeed, pulmonary sympathetic afferents have been found in dogs and monkeys, and the stimulation of nerves carrying these fibers was able to inhibit
the phrenic discharge in these anesthetized animals (21). In addition, in the absence of catecholamine-mediated peripheral effect, central release of norepinephrine at respiratory-related units
in the central nervous system has been shown to inhibit ventilatory
output through an 
-receptor-mediated action (3, 6).
Accordingly, greater CVR and enhanced hypercapnic respiratory drive
shown by DAN+PH+ could be seen as independent, different expressions of
the same phenomenon represented by the defective central modulation of
the sympathetic autonomic nervous system, whereas the opposite could be
invoked in DAN+PH.
However, a close, direct correlation between CVR, reflecting the
increment of CBF, and the P0.1 values (or the
P0.1/PETCO2 slope),
reflecting the response of the respiratory centers, is present during
progressive hypercapnia in DAN+ (Fig. 4).
Such a strong relationship tends to suggest a causal link between these two phenomena, possibly indicating that a greater or lesser
CO2 load carried out on the central chemoreceptors as a
consequence of an excessive or reduced vasodilation in the presence of
increasing circulatory CO2 levels can markedly influence
the output of the respiratory centers to CO2. In other
words, the hypercapnic central inspiratory drive, enhanced in DAN+PH+
and depressed in DAN+PH, would be an expected, normal response toward
a different acidotic stimulus and would be relatively increased in
DAN+PH+ or reduced in DAN+PH, due, in both instances, to an impaired
CVR.
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No correlation was found between CVR and the
P0.1/PETCO2
slope or the P0.1 values during CO2 rebreathing
in DAN and C.
It should be noted, however, that the vascular responses to progressive hypercapnia were assessed in the forebrain circulation (middle cerebral artery) rather than in the hindbrain circulation, where, because of the lesser sympathetic innervation to blood vessels, the changes in CVR could be quantitatively different and more crucial in influencing the activity of the central chemoreceptors, especially in these subjects.
The results of the present study differ to some extent from those of other investigations carried out in patients with long-term diabetes and also in diabetic patients with disturbed autonomic innervation, in whom a preserved or slightly impaired CVR to administration of acetazolamide (33), CO2 inhalation (15), or blood pressure changes (8) was found, suggesting a minor role of the autonomic neuropathy in the cerebrovascular dysregulation in diabetes. Selection of patients, different techniques, and stimuli could explain the discrepancies. In fact, in obvious contrast to the aforementioned reports, in the present study the diabetic patients were carefully matched and categorized according to the presence and severity of the autonomic neuropathy, and their change in MCAV to hypercapnia was explored at different levels of CO2 by progressively increasing the magnitude of the stimulus.
These findings are clinically relevant because diabetic patients with dysautonomy might be at particular risk for developing cerebrovascular disease. Both the response to hypotension and the ability to increase CBF to cope with increasing metabolic demand could be further affected if the cerebral vasodilating response is further compromised by the presence of autonomic neuropathy. Moreover, in diabetic patients with more advanced dysautonomy, the excessive CVR after intense vasodilating stimuli might also be a negative event. For instance, in the presence of cerebral transient ischemia, it could allow an increased luxury flow in collaterally perfused vascular territories and thus divert blood flow from the ischemic area, thus accelerating the course of cerebral ischemia. This phenomenon might contribute to the greater prevalence of thrombotic stroke than transient ischemic attack in patients with diabetes, compared with the general population (23).
Finally, a possible explanation of the controversial results on the
control of breathing in diabetic patients with autonomic neuropathy is
given. In fact, a double response of the respiratory drive to
hypercapnia is clearly shown by DAN+, depressed in DAN+PH, and
enhanced in DAN+PH+. This finding suggests a modulatory effect, likely
mediated through the CBF regulation and exerted by the sympathetic
nervous system on the central chemosensitivity, which, consequently, is
either reduced or augmented in these patients.
In conclusion, the presence and severity of autonomic neuropathy does affect the CVR to CO2 and influence the hypercapnic drive to breathing in diabetic patients.
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ACKNOWLEDGEMENTS |
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We thank Rita Fraboni for invaluable technical assistance.
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FOOTNOTES |
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C. Tantucci is supported by a grant from Ministero Universita' Ricerca Scientifica e Tecnologica of Italy.
Address for reprint requests and other correspondence: C. Tantucci, Clinica di Semeiotica Medica, Ospedale Regionale Torrette, 60020 Ancona, Italy.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 28 December 1999; accepted in final form 28 August 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05; DAN+PH+ vs.
DAN+PH
P < 0.01.
