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Clinica di Semeiotica Metodologia Medica, University of Ancona, Ospedale Regionale Torrette, Ancona 60020; and Istituto di Medicina Interna e Scienze Endocrine e Metaboliche, University of Perugia, Perugia 06100, Italy
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Tantucci, C., P. Bottini, M. L. Dottorini, E. Puxeddu, G. Casucci, L. Scionti, and C. A. Sorbini. Ventilatory response to
exercise in diabetic subjects with autonomic neuropathy.
J. Appl. Physiol. 81(5):
1978-1986, 1996.
We have used diabetic autonomic neuropathy as a
model of chronic pulmonary denervation to study the ventilatory
response to incremental exercise in 20 diabetic subjects, 10 with
(Dan+) and 10 without (Dan
) autonomic dysfunction, and in 10 normal control subjects. Although both Dan+ and Dan subjects
achieved lower O2 consumption and
CO2 production
(
CO2) than
control subjects at peak of exercise, they attained similar values of
either minute ventilation
(E) or
adjusted ventilation (E/maximal
voluntary ventilation). The increment of respiratory rate with
increasing adjusted ventilation was much higher in Dan+ than in
Dan and control subjects (P < 0.05). The slope of the linear
E/CO2
relationship was 0.032 ± 0.002, 0.027 ± 0.001 (P < 0.05), and 0.025 ± 0.001 (P < 0.001) ml/min in
Dan+, Dan, and control subjects, respectively. Both
neuromuscular and ventilatory outputs in relation to increasing
CO2 were progressively
higher in Dan+ than in Dan and control subjects. At peak of
exercise, end-tidal PCO2 was much
lower in Dan+ (35.9 ± 1.6 Torr) than in Dan (42.1 ± 1.7 Torr; P < 0.02) and control (42.1 ± 0.9 Torr; P < 0.005) subjects.
We conclude that pulmonary autonomic denervation affects ventilatory
response to stressful exercise by excessively increasing respiratory
rate and alveolar ventilation. Reduced neural inhibitory modulation
from sympathetic pulmonary afferents and/or increased
chemosensitivity may be responsible for the higher inspiratory
output.
diabetes; pulmonary denervation; control of breathing; breathing
pattern
INTRODUCTION PREVIOUS EXPERIMENTAL STUDIES in humans on the
role of the pulmonary autonomic nervous system on the modulation of the
breathing pattern during stimulated ventilation were invasive (vagal
blockade) (16, 17) or limited to the trachea and large bronchi (airway anesthesia) (36, 40). Because of these technical limitations, data were
sparse and sometimes conflicting. In investigating heart-lung transplanted patients, some investigators have recently claimed that
pulmonary neurogenic mechanisms essentially influence the level, but
not the pattern, of ventilation during exercise (23), although both
tidal volume (VT) (2, 13) and
respiratory rate (RR) (2, 13, 23) exhibited a steeper increase in these patients compared with normal subjects. Conversely, another study (33)
in similar patients, who were compared only with heart transplant
recipients without a matched group of normal subjects, seems to
indicate that during exercise pulmonary nerves are more important in
regulating the breathing pattern (deeper and slower in heart-lung
transplanted patients) than is the absolute level of ventilation.
Apart from the disruption of bronchial circulation and pulmonary
lymphatics, heart-lung transplanted patients frequently have chronic
muscle deconditioning due to long-term pretransplant debilitation (39)
and may also have a restrictive ventilatory defect (23). Moreover,
despite the indirect evidence provided for the persistence of pulmonary
denervation after transplantation (1, 23), reinnervation several months
from surgery cannot be completely ruled out (12, 26). All of these
findings may be confusing factors when heart-lung transplant recipients
are regarded as a unique model of pulmonary autonomic denervation to be
compared with normal subjects for analysis of the ventilatory response
during exercise.
These patients, however, do not constitute the sole model of pulmonary
autonomic denervation in humans, since a defect of the autonomic
nervous system is not uncommon in diabetes mellitus (15); indeed, in
the study of the ventilatory response to exercise, diabetic patients
with autonomic neuropathy may provide a simple model of chronic
pulmonary autonomic denervation (8, 35).
In the attempt to further investigate the role of the autonomic system
on ventilatory response to exercise, a group of diabetic subjects
suffering from moderate to severe autonomic neuropathy was studied
during stressful exercise.
Our results suggest that diabetic autonomic dysfunction is associated
with a greater ventilatory response to exercise. Although this finding
can be partially explained by the increment of dead space
(VD) ventilation and by a
faster RR, a progressively higher inspiratory activity is likely to be
involved, as indicated by a steeper relationship for mouth occlusion
pressure and alveolar ventilation against exertional
CO2 production
( Possible problems with diabetic neuropathy as a model for pulmonary
denervation are fully considered in
DISCUSSION.
METHODS Subjects. Twenty male diabetic
patients, 10 without and 10 with diabetic autonomic neuropathy,
henceforth referred to as Dan In the Dan+ group, two patients had preproliferative retinopathy and
one patient had proliferative retinopathy; four of the ten Dan No patient reported respiratory symptoms at the time of the study, and
all had normal physical examination, electrocardiogram, and chest
radiography. None of the patients studied was suffering from anemia or
had signs or symptoms of endocrine or metabolic diseases other than
diabetes. All were normotensive, and none had evidence of ischemic
heart disease or S-T segment depression during previous submaximal or
symptom-limited incremental exercise. To exclude dilated or restrictive
cardiomyopathy and valvular heart disease, all patients underwent a
bidimensional echocardiographic study. Left ventricular systolic or
diastolic dysfunction was not observed at rest, and morphological
and/or functional valvular abnormalities were absent. Despite
the presence of diabetic nephropathy in some patients, none suffered
from renal failure at the time of the study.
Ten male normal subjects recruited from the University staff, matched
for age and weight, were studied as the control group.
Study design. Patients and control
subjects had pulmonary function tests, including determination of
maximal voluntary ventilation (MVV) and measurements of maximal
inspiratory (MIP) and expiratory (MEP) mouth pressures. Spirometry,
flow-volume curves, lung volumes (by the multiple-breath nitrogen
washout technique), single-breath diffusing capacity for carbon
monoxide (DLCO) adjusted for hemoglobin, and
MVV were performed with the subjects in a sitting position while
wearing a noseclip and breathing through a mouthpiece on a Medical
Graphics 1070 computerized system. MVV was measured according to the
standard procedure (breathing as deeply and quickly as possible for 12 s), avoiding RR values of >40 breaths/min.
The predicted values for volumes and flows were those proposed by the
European Community for Coal and Steel (28).
Measurements of MIP and MEP, sustained for The resting ventilatory response to
CO2 was determined in the morning
using the rebreathing method of Read (29).
All three groups performed a submaximal ( The physiological
VD-to-VT
ratio
(VD/VT)
was calculated using estimated arterial
PCO2
(PaCO2) values derived from end-tidal PCO2
(PETCO2) according to
PaCO2 = 5.5 + 0.9 × PETCO2 Effective alveolar ventilation
( The gas-exchange anaerobic threshold (AT)
( Venous blood samples were drawn only from the diabetic subjects to
measure lactate plasma levels at rest and at each minute of exercise.
The samples were immediately placed on ice until centrifugation and
measurements were performed. Analysis was carried out by enzymatic
fluorometric continuous flow assay. For our laboratory, the normal
value (mean and respective range) was 0.68 mmol/l (0.41-1.13 mmol/l). This procedure allowed the detection of the lactate AT (LAT)
( Mouth pressure was monitored at rest and during exercise, and its
value, computed at 100 ms after the beginning of an occluded inspiration (P0.1), was randomly
obtained 4-5 times/min (38). Mouth pressure was measured by a
pressure transducer (143PC03D Microswitch, Honeywell), and the signal,
filtered and digitized with a sampling frequency of 200 Hz, was sent to
an IBM personal computer for calculation of
P0.1. The measurements of
P0.1 were averaged to get a single
value for each 30-s period.
Arterial O2 saturation was
assessed by ear pulse oximeter (model 3700, Omeda Biox) and was
continuously displayed on the computer monitor.
Conventional electrocardiogram monitoring was performed during the
entire exercise test, and a 12-lead electrocardiograph tracing was
printed every minute. The heart rate signal was also sent to the
computer, and the O2 pulse
( Hypoglycemia was carefully prevented in patients in the 24 h before the
study by teaching them to self-administer the premeal and bedtime
insulin doses so as to avoid premeal blood glucose levels of <5
mmol/l, based on capillary blood glucose measurements by chemistrips.
Each exercise test was performed in the afternoon between 5:00 and 5:30
P.M., 5 h after the patients had their prelunch dose of
regular insulin.
Analysis. To provide comparisons among
groups at similar relative levels of physiological function,
The means of lung function, exercise, and ventilatory timing variables
of the three groups were compared by analysis of variance and by
orthogonal comparisons adopting a two-tailed Student's t-test for unpaired data when allowed
by analysis of variance. The linear correlations were calculated by the
least squares method. Comparisons among groups of the mean slopes were
performed according to the above-mentioned procedure. Data are
expressed as mean ± SE. P < 0.05 was considered to be statistically significant.
RESULTS Characteristics and lung function.
Anthropometric and clinical data of diabetic and control subjects are
shown in Table 1. Patients and
control subjects were not significantly different for age, weight, and
smoking habit. The long-term control of hyperglycemia was similar and
satisfactory in both groups of patients.
Table 1.
Anthropometric and clinical data of subjects and patients
CO2). Increased CO2 chemosensitivity or decreased
autonomic (probably sympathetic) inhibitory influence on the central
drive could represent the main mechanism underlying the abnormally
elevated inspiratory output observed in these patients.
and Dan+, respectively, were
recruited from the Istituto di Medicina Interna e Scienze Endocrine e
Metaboliche, Department of Internal Medicine, University of Perugia and
were enrolled in the study after giving fully informed consent. The
protocol was approved by the local ethics committee and was in
accordance with the Declaration of Helsinki. All patients were on
insulin treatment with four daily insulin injections (regular insulin
before each meal and intermediate-acting insulin at bedtime). No drugs
likely to interfere with the pulmonary or cardiovascular function were
taken by the patients. Autonomic neuropathy was assessed by means of
the standard battery of cardiovascular tests (14); each test was scored
according to the literature (5), and patients were considered positive for autonomic neuropathy if the total score was 
4. Five out of 10 Dan+ patients had severe postural hypotension with upright fall in
systolic blood pressure of >30 mmHg. Postural hypotension is thought
to be the consequence of impaired splanchnic vasoconstriction due to
overt sympathetic damage of the autonomic nervous system.
patients had background retinopathy. Four Dan patients had
microalbuminuria, whereas in the Dan+ group microalbuminuria was
detected in five patients and proteinuria in three. In regard to the
symptoms related to the autonomic dysfunction, only one Dan+ patient
complained of nocturnal watery diarrhea.
1 s, were obtained in
triplicate at functional residual capacity (FRC), by using a
differential pressure transducer (±300
cmH2O, Validyne). The mean of the
two best efforts was considered for analysis. Volume-corrected predicted values for MIP and MEP were those proposed by Cook et al.
(9).
90% of maximum predicted
heart rate) or symptom-limited incremental exercise test, using a
computer-driven electronically braked cycle ergometer (model KEM-3,
Mijnhardt). After resting for 15 min, patients and control subjects
sustained a 2-min period of loadless pedaling and then cycled at 60 revolutions/min with an incremental load of 0.33 W/s (20 W/min
ramping). Exercise time ranged between 8 and 15 min to avoid too short
as well as excessively long efforts. Patients and subjects breathed
through a mouthpiece into a two-way breathing valve of 100 ml of
VD while wearing a noseclip. The expiratory air flow was measured by a pneumotachograph and the expired
volume was obtained integrating for the time while the air was
continuously sampled at the mouth to determine inspiratory and
expiratory (mixed and end-tidal) gas concentrations, which allowed a
breath-by-breath analysis of minute ventilation
(E; BTPS),
O2 consumption
(O2;
STPD),
CO2
(STPD),
E/O2
and E/CO2,
and ventilatory timing parameters: RR,
VT, inspiratory (TI) and expiratory
(TE) times, and mean
inspiratory flow
(VT/TI) (CPX system, Medical Graphics). Predicted values for
exercise parameters were those of Hansen et al. (18) for incremental exercise testing.
0.0021 × VT (18). The
physiological VD was computed by
the product of
VD/VT
and VT.
A) was
derived from
A = E × (1 VD/VT),
and its relationship with
CO2 was used as an index of
ventilatory drive that is independent of individual variations of
VD/VT.
O2 at AT) was determined
by means of the computer-resident algorithm according to the V-slope
method (4) or by eye (as a mean of the measurements made by 2 independent observers) when the automatically detected O2 at AT was clearly
erroneous.
O2 at LAT) by
plotting lactate concentration vs.
O2, according to a
log-log model of data transformation. The intersection between the
linear regression lines of the two-segment analysis of the
transformed data defined the LAT on the
O2 axis (3).
O2/heart rate)
could be obtained for each breath.
E was
normalized as a percentage of MVV
(E/MVV) and
VT as a percentage of
inspiratory capacity (IC)
(VT/IC). These variables are
referred to as adjusted E and
adjusted VT.
Control
Dan
Dan+
Age, yr
35.8 ± 6.2
43.0 ± 10.5
40.3 ± 7.6
Weight, kg
78.3 ± 7.7
70.8 ± 9.6
71.4 ± 11.5
Smoking habit, pack · yr
11.1 ± 10.3
11.6 ± 14.5
19.9 ± 16.3
Duration of
disease, yr
15.5 ± 5.6
20.0 ± 9.7
HbA1c, %
7.1 ± 0.6
7.8 ± 1.9
IDDM/NIDDM, no.
6/4
8/2
DAN
score
0.6 ± 0.6
5.6 ± 1.4
VC, % predicted
112.8 ± 11.6
110.8 ± 12.9
102.1 ± 14.4
IC, % predicted
114.2 ± 7.0
104.1 ± 16.4
101.2 ± 15.1
FRC, % predicted
102.0 ± 23.9
100.6 ± 21.0
98.8 ± 25.7
RV, % predicted
107.5 ± 21.6
95.8 ± 16.7
99.2 ± 27.2
TLC, % predicted
114.2 ± 12.0
102.4 ± 10.8
97.5 ± 15.4
FEV1, % predicted
113.9 ± 10.6
104.7 ± 13.9
99.1 ± 16.8
FEV1/FVC, %
81.0 ± 4.3
82.0 ± 5.2
83.3 ± 4.2
FEF25-75, % predicted
94.3 ± 14.8
92.9 ± 26.9
93.3 ± 27.3
DLCO/VA, % predicted
101.5 ± 15.7
89.9 ± 18.6
91.5 ± 16.9
MVV, % predicted
104.1 ± 12.7
101.8 ± 15.1
102.8 ± 18.3
MIP at FRC, % predicted
101.3 ± 15.5
135.7 ± 33.4
117.2 ± 37.3
MIP at FRC, cmH2O
109.6 ± 17.0
123.1 ± 33.5
108.4 ± 29.5
MEP at FRC, % predicted
129.2 ± 39.2
139.5 ± 43.7
137.6 ± 85.1
MEP at FRC, cmH2O
169.6 ± 34.5
146.2 ± 36.6
136.9 ± 40.3
Values are means ± SE. Dan
, diabetic subjects without
autonomic neuropathy; Dan+, diabetic subjects with autonomic
neuropathy; HbA1c, hemoglobin A1 glycosylate (values in nondiabetic
subjects: 3.8-5.5%); IDDM/NIDDM, insulin-/non-insulin-dependent
diabetes mellitus; DAN, diabetic autonomic neuropathy; VC, vital
capacity; IC, inspiratory capacity; FRC, functional residual capacity;
RV, residual volume; TLC, total lung capacity; FEV, forced expiratory volume; FEF, forced expiratory flow; FEV1, FEV in 1 s;
FEF25-75, 25-75% of FEF;
DLCO, diffusing capacity for carbon monoxide;
VA, alveolar volume; MVV, maximal voluntary ventilation;
MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure.
Lung function tests, including MVV and
DLCO,
expressed as a function of the alveolar volume (VA) were in
the normal range for both Dan and Dan+ subjects and were not
significantly different from those of control subjects. The indexes of
respiratory muscle strength (MIP and MEP), reported both as absolute
values and as percentages of predicted values, were also normal in the
Dan and Dan+ groups and were not dissimilar from those of
control subjects.
Neuromuscular and ventilatory responses to progressive
hypercapnic stimulation, assessed as a relationship of
P0.1 and
E against
PETCO2, respectively, were
not different in Dan+ and control subjects and were 0.50 ± 0.10 vs. 0.46 ± 0.06 cmH2O/Torr for the
P0.1/PETCO2
slope (not significant) and 3.71 ± 0.73 vs. 3.27 ± 0.35 l · min
1 · Torr1
for the
E/PETCO2
slope (not significant).
Exercise performance. The maximum
workload and
O2 at
peak of exercise (here referred to as
DLCO/VA)
(O2 max)
achieved by the three groups are reported in Table
2. At peak of exercise, the workload, as
percentage of predicted value, was not significantly different in the
three groups. Instead,
O2 max was much lower in diabetic than in control subjects, both as absolute value and as
percentage of predicted value. In this respect, although Dan+ subjects
had a lower O2 max as
percentage of predicted value, compared with Dan, the difference
was not statistically significant. As absolute value of
O2, control subjects had the
highest gas- exchange AT (O2
at AT), which, in turn, was not different between the Dan and
Dan+ groups. O2 at AT,
expressed as a percentage of
O2 max, was higher in
the Dan+ group.
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The LAT (O2 at LAT) was
almost identical in the diabetic groups (Table 2). In addition, the
exertional increment of lactate plasma levels was superimposable in the
Dan and the Dan+ subjects, as shown in Fig.
1.
O2) normalized
for respective maximal
(O2 max), is shown for
diabetic subjects with (Dan+) and without (Dan) autonomic
neuropathy. Data are mean ± SE. No differences are observed between
the 2 groups.
At peak of exercise, CO2 was
significantly greater in control than in diabetic subjects but was
similar in Dan and Dan+ subjects.
Two of the Dan+ subjects stopped the exercise test because of leg fatigue. None of the diabetic subjects suffered from hypoglycemia during the exercise.
Exercise ventilation.
E at peak of
exercise was similar in the three groups both in absolute value and as
a percentage of MVV (Table 2). The ventilatory response to increasing
CO2 was linear in all
subjects (r values ranging from 0.98 to 0.99) (Fig. 2A). The
slope of
E/CO2
was 0.032 ± 0.002 ml/min in Dan+ and was steeper than that of both
control (0.025 ± 0.001 ml/min; P < 0.001) and Dan (0.027 ± 0.001 ml/min;
P < 0.05) subjects.
E) and
CO2 production
(CO2) is steeper in Dan+ than
in Dan and control subjects (C). During exercise, E at
corresponding CO2 values is
significantly greater in Dan+ than in Dan
(* P < 0.05) and C
(° P < 0.01) subjects.
B: linear relationship between
inspiratory neuromuscular drive
(P0.1) and
CO2 is markedly increased in
both diabetic groups with respect to C. During exercise,
P0.1 at corresponding
CO2 values is significantly higher in Dan+ (** P < 0.01)
and Dan (* P < 0.05)
than in C.
The
P0.1/CO2
relationship was essentially linear in patients and control subjects
during exercise (r values ranging from 0.90 to 0.99) and had a mean slope of 0.0031 ± 0.0002, 0.0049 ± 0.0005, and 0.0061 ± 0.0007 cmH2O · ml1 · min1
in control, Dan (P < 0.05),
and Dan+ (P < 0.002) subjects,
respectively. Thus at corresponding exertional values of
CO2,
P0.1 was progressively greater in
the two groups of patients than in the control group (Fig.
2B).
The
P0.1/E
relationship, which reflects the impedance of the respiratory system,
is illustrated throughout the exercise in Fig.
3 for patients and control subjects.
E is
depicted for Dan+, Dan, and C during exercise. For corresponding E values,
P0.1 appears significantly lower
in control (** P < 0.01) than
in Dan+ subjects, whereas Dan subjects show an intermediate behavior. Symbols closest to origin represent resting values and symbols farthest from origin represent highest values reached at peak
of exercise.
Even though the computed physiological
VD/VT
value was not significantly different at rest in the three groups,
during exercise the rate of decrease of the physiological
VD/VT
in relation to adjusted ventilation was substantially lower both in
Dan+ (0.0030 ± 0.0017%/%) and Dan (0.0037 ± 0.0017%/%) compared with control (0.0050 ± 0.0023%/%) subjects
(P < 0.05). The physiological
VD/VT was significantly greater in both groups of patients than in the control group at progressively higher values of
E/MVV (Fig. 4A).
This was mainly due to an abnormal exertional increase in physiological
VD in the diabetic patients
(Fig. 4B).
E
(E/maximal
voluntary ventilation), VD/VT
is significantly higher in Dan+
(** P < 0.02) and Dan
(* P < 0.05) than in C
(A). In this respect, physiological
VD becomes progressively more
elevated in diabetic subjects during exercise (* P < 0.05;
** P < 0.01)
(B), whereas no significant
differences are observed in increment of adjusted
VT
[VT/inspiratory capacity (IC)]
during exercise and in VT/IC at
corresponding
E/MVV values among the 3 groups (C). Conversely,
increase in respiratory rate (RR) during exercise is greater in Dan+
than in Dan and C, and RR, at corresponding
E/MVV values,
is significantly higher in Dan+
(* P < 0.05) compared with
both Dan and C (D). br,
Breaths.
The relationship between computed
A and
metabolic CO2 during exercise
increased progressively more in Dan+ subjects, whereas it remained
almost identical at a lower level for the Dan and control groups
(Fig. 5). The slope of this relationship
was 0.027 ± 0.001 l · min1 · mmHg1
in the Dan+ group and 0.023 ± 0.001 l · min1 · mmHg1
in both the control and Dan groups
(P < 0.01).
A) and
CO2 is steeper in Dan+
than in Dan and C. For corresponding
CO2 values,
A is
significantly greater in Dan+
(* P < 0.05), whereas
Dan and C have superimposable levels of
A throughout
effort. Symbols closest to origin represent resting values, and symbols
farthest from origin represent highest values reached at peak of
exercise.
At rest, PETCO2 was similar
in all groups, amounting to 37.4 ± 0.7, 38.9 ± 0.7, and 38.0 ± 1.2 Torr in the control, Dan, and Dan+
groups, respectively. The corresponding values of estimated
PaCO2 were 37.5 ± 0.7, 38.8 ± 0.8, 38.1 ± 1.1 Torr in the control, Dan, and Dan+ groups,
respectively. Conversely, at peak of exercise
PETCO2 was
significantly lower in Dan+ than in control
(P < 0.005) and Dan
(P < 0.02) subjects, amounting to
35.9 ± 1.6, 42.1 ± 0.9, and 42.1 ± 1.7 Torr in Dan+, control, and Dan groups, respectively. The corresponding values of estimated PaCO2 were 33.5 ± 1.4, 37.6 ± 1.0, and 38.6 ± 1.7 Torr in Dan+, control
(P < 0.005), and
Dan (P < 0.02) groups, respectively.
The resting hemoglobin O2
saturation was normal in the Dan, Dan+, and control subjects
(97.9 ± 1.5, 97.7 ± 1.6, and 98.5 ± 1.2%,
respectively); O2 desaturation did
not occur in any subject during the exercise.
Pattern of breathing. The rate of exponential increase of adjusted VT (VT/IC) during exercise was similar in the three groups (Fig. 4C).
On the contrary, the rate of RR linear increase during exercise was
significantly higher in the Dan+ compared with the control and
Dan groups (P < 0.05),
amounting to 0.52 ± 0.16 vs. 0.39 ± 0.14 and 0.36 ± 0.14 breaths/min, respectively (Fig.
4D). RR was similar at rest among
the groups but faster at peak of exercise in the Dan+ patients (Table
3). Although
TI and
TE were significantly shorter at
peak of exercise in Dan+ compared with Dan and control subjects
(Table 3), the rate of TI and
TE decrease during exercise was
not different among the groups.
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There were no significant differences among control, Dan, and
Dan+ subjects in the rate of increase of mean inspiratory flow (VT/TI),
which displayed similar values at rest and peak of exercise for the
three groups (Table 3).
DISCUSSION
Before the results of the study are discussed, some problems with diabetic autonomic neuropathy as a model of pulmonary autonomic denervation should be pointed out.
It is implicit that the extent of the autonomic neuropathy and related pulmonary autonomic denervation cannot be exactly determined in patients in vivo.
Diabetic autonomic neuropathy is by definition a symmetric and distal neuropathy and produces diverse and somewhat selective neural alterations, both in the parasympathetic and sympathetic nervous systems (25). Their expression in diabetic subjects is inherently variable and supports the pathological findings of a frequently partial process. Therefore, our patients are expected to have an incomplete degree of autonomic denervation with differential effects on myelinated and unmyelinated fibers.
Autoptic findings in diabetic subjects with severe dysautonomy, however, have consistenly shown the presence of remarkable pathological alterations in the sympathetic ganglia and either in the vagus or sympathetic nerves, with predominant loss of myelinated fibers (11). In this respect, our patients were suffering from marked autonomic neuropathy, as demonstrated by the quantitative analysis of the reflex cardiovascular responses, the only widely accepted and standardized criteria to clinically assess the extent of the dysautonomy (5, 15).
Concerning the pulmonary involvement, it has been repeatedly observed that diabetic patients exhibit almost invariably some degree of functional impairment reflecting a specific damage to the airways autonomic innervation (8, 10, 19, 30, 35). In these patients, a significant correlation has also been found between cardiac and pulmonary (airways) indexes of autonomic neuropathy (8).
Thus we are aware that this model cannot assume complete pulmonary autonomic denervation but a wide clinical spectrum of autonomic dysfunction, with an inevitable heterogeneity within Dan+ patients regarding the prevalence of cholinergic or sympathoadrenergic damage of the autonomic nervous system in the whole body, including the lungs. On the other hand, this is a quite common clinical condition where a chronic, although incomplete, autonomic neuropathy is well recognized. In this context, we attempted to categorize our diabetic subjects and to score their autonomic neuropathy by state-of-the-art methods to select patients with a high degree of dysautonomy in whom previous reports predict an involvement of the pulmonary autonomic innervation (8, 10, 19, 30, 35).
The results of this study show that during stressful exercise
E increased
progressively much more in diabetic subjects with autonomic neuropathy
than in normal subjects, whereas diabetic subjects without autonomic
neuropathy exhibited an intermediate behavior. The greater increase in
E in the Dan+
subjects was associated with an abnormally high increment of RR,
without differences in the rise of the adjusted
VT. Hence, Dan+ subjects had
more elevated
E at
corresponding CO2 and faster
RR values and comparable adjusted
VT values at similar relative
levels of ventilatory response. In addition, both groups of patients
displayed a significantly lesser decrease in
VD/VT
throughout the effort than control subjects and consequently higher
VD/VT
values at similar relative levels of ventilatory response.
In line with studies performed in heart-lung transplanted patients (23,
31, 34), there were no differences in
E levels or
indexes of breathing pattern at rest in Dan+ compared with Dan
and control subjects, which suggests that pulmonary neurogenic mechanisms are not important in determining the resting ventilatory pattern in humans.
O2 max in both diabetic
groups was significantly lower than in the control group. This is
believed to reflect the interaction between the impaired cardiac
performance and the skeletal muscle deconditioning observed in diabetes
(20). Despite lower
O2 max and maximal
CO2 than in control subjects,
at peak of exercise Dan and Dan+ subjects attained similar
O2 and
CO2 values and had comparable
levels of both
E and
E/MVV with
respect to the control group.
As mentioned in RESULTS, the two diabetic groups, which had
almost identical LAT values, achieved the gas-exchange AT at a lower
absolute O2 value than did
the control group but at a similar or even higher percentage of
O2 max. Moreover, the
changes in lactate plasma levels overlapped in the Dan and the
Dan+ groups throughout the exercise, as shown in Fig. 1. Therefore,
exertional metabolic acidosis did not seem to occur earlier
and/or to progress differently in our diabetic groups, and an
increasingly larger accumulation of acids cannot account for the
steeper relationship between
E (and
P0.1) and
CO2 observed in Dan+ compared
with Dan subjects.
Lactate concentrations during exercise were not measured in our control
subjects. It is conceivable, however, that exertional metabolic
acidosis began later in this group, as suggested by the higher
gas-exchange AT, and perhaps increased less rapidly. Thus we cannot
exclude that the higher
E (and
P0.1) values recorded at
corresponding CO2 levels in
diabetic subjects compared with control subjects could in
part be induced by metabolic acidosis. Despite a similar degree of
metabolic acidosis in both groups of patients, however,
E was
significantly greater in the Dan+ group, whereas it was only slightly
higher in the Dan than in the control group. Indeed, considering
the higher
VD/VT
value in the Dan than the control group, the contribution, if
any, of acidosis on
E in diabetic
subjects should be modest.
In fact, three mechanisms could better account for the higher
ventilatory output for a given
CO2 observed during
incremental exercise in diabetic patients affected by autonomic
neuropathy: 1) the smaller reduction
in
VD/VT,
2) the greater increment of the RR,
and possibly 3) an increased neural
drive.
The relative increase in
VD/VT
in Dan+, at rest or during exercise, could be ascribed to the
alterations in the bronchomotor tone resulting from bronchial
cholinergic denervation (8), with an augmentation of the anatomic and,
through ventilation-perfusion mismatch, alveolar
VD. In our population, however,
a similar lesser reduction in
VD/VT
during exercise occurred in both groups of patients, and therefore
appears to be linked more to diabetes per se than to the autonomic
dysfunction. An impaired cardiovascular response to exercise,
irrespective of the presence of autonomic dysfunction, has been
recently shown in diabetic patients and can be sustained by factors
other than overt autonomic neuropathy, such as diabetic cardiomyopathy
(6). Thus a reduced exertional increase in cardiac output, as suggested
by the depressed
O2/work relationship found in both Dan and Dan+ subjects during
incremental effort (5), could impair the total lung perfusion and the
distribution of pulmonary blood flow, inducing a lesser uniformity of
the regional ventilation-perfusion relationships and a smaller
reduction in the physiological
VD and
VD/VT.
The greater increment of RR observed in Dan+ compared with Dan
and control subjects could reflect the influence of the pulmonary autonomic (essentially cholinergic) nerve dysfunction on the
ventilatory pattern, at least during stressful exercise. In this
respect, our results contrast with those obtained in experimental
animals, where vagotomy leads to an increase in
VT and a decrease in RR, while
maintaining
TI/TT
and
VT/TI
unchanged, both at rest and during exercise (7, 27). The suppression of
the Hering-Breuer inflation reflex due to the lack of inputs from lung
stretch receptors has been invoked as the main underlying mechanism. It
is well known, however, that in humans the Hering-Breuer inflation
reflex is rather weak and demonstrable only at high inflation volumes (17); hence, a smaller influence, if any, on the breathing pattern during stimulated ventilation would be expected in humans after a
cholinergic nervous system damage in the lungs.
Several investigators have recently studied the effects of pulmonary denervation in heart-lung transplanted patients compared with matched control subjects (2, 23) or heart-transplanted patients (33). In general, these studies have shown that during exercise the RR, and sometimes also the VT, tend to increase more rapidly after the assumed severance of cholinergic lung innervation, in contrast with the slower and deeper breathing pattern observed in classic experiments in animals (2, 13, 23). Despite the completely different model of pulmonary denervation used in the present study, our results are in line with previous observations of abnormal increments of RR associated with relatively normal increases in VT in Dan+ patients during submaximal incremental exercise. Very similar findings have been reported by Kimoff et al. (23) in four heart-lung transplanted patients, although these investigators stressed that in normal humans autonomic pulmonary innervation has a more important role on the level of ventilation rather than on the ventilatory pattern and timing during exercise.
Pulmonary congestion can affect the breathing pattern both by reducing
VT and by increasing RR. We
cannot rule out pulmonary congestion as a cause of the observed
tachypnea in Dan+ during exercise. In this situation, however, the
effect on the RR should occur mainly in the last part of the exercise,
together with a brisk reduction in
VT. This was not the case in our
Dan+ patients and, anyway, it would hardly have contributed to explain
the different breathing frequency of Dan+ and Dan patients, who
showed similar impairment of the cardiovascular response to exercise
(6).
Also, a higher respiratory drive could induce by itself an increased ventilatory output during exercise in Dan+ patients.
The progressively greater P0.1
recorded in these patients during exercise could be entirely explained
by the need for a progressively larger
E, due to
higher
VD/VT
and RR, and for a greater neuromuscular support for any given
E, as shown by
the
P0.1/E
relationship (Fig. 3). In fact, this relationship is slightly steeper
and mostly shifted upward in Dan+ and even in Dan compared with
control subjects, probably because of minor mechanical constraints in diabetic subjects that do not alter lung function at rest while becoming crucial in the presence of larger ventilatory requirements (32).
On the other hand, when
A was computed
in relation to increasing CO2
during incremental effort to eliminate the confusing effects of the
above-mentioned variables, a progressively larger amount of
A was found in
Dan+ compared with both Dan and control subjects, who, in turn,
had identical
A/CO2
relationships (Fig. 5).
The difference between the peak values of
PETCO2 (and estimated
PaCO2), which were significantly lower
in Dan+ and very similar in Dan and control subjects, is in line
with a disproportionate increase in alveolar ventilation in Dan+
subjects. An excellent correlation has been found between
PaCO2 and
PETCO2 during exercise in
normal subjects (37). Because all subjects had a normal resting
ventilatory function, as shown by the pulmonary function
tests, PETCO2 probably
reflects well the PaCO2 values
throughout the effort also in diabetic subjects, suggesting that Dan+
subjects were indeed hyperventilating in relation to their
exertional CO2.
An earlier and perhaps greater metabolic acidosis cannot be responsible
of the higher
A and lower
PETCO2 observed in Dan+ than
in control subjects. If this had been the case, the peak
PETCO2 value and the
A/CO2
relationship would have been similar in Dan+ and Dan
subjects, who showed almost identical AT values and overlapping lactate
concentrations during exercise (Table 2, Fig. 1).
In our opinion, this hyperventilation could reflect, although
indirectly, an excessive respiratory drive, which could in part be
responsible for the higher P0.1
and E observed
in Dan+ subjects during exercise.
This phenomenon can be regarded as the expression of an altered control of breathing, possibly due to chronic lung autonomic denervation and/or to increased chemosensitivity.
The presence of pulmonary sympathetic afferents has been demonstrated in dogs and monkeys (24), and the stimulation of nerves carrying pulmonary sympathetic afferents has been proven to inhibit the phrenic nerve discharge in these anesthetized animals (24). Although there are no data on the influence of these nervous pathways on the control of breathing in humans, it can be hypothesized that in Dan+ subjects a loss or reduction of sympathetic inhibition following autonomic (sympathetic) neuropathy could lead to an excessive increase in the respiratory drive and contribute to the augmentation of the ventilatory output, at least during exercise.
In this respect, five Dan+ subjects had overt signs of sympathetic
dysautonomy, i.e., significant postural hypotension. Splitting the
exercise response in terms of the
A/CO2
relationship into two subsets of Dan+ subjects with and without
postural hypotension, the highest
A is
substantially exhibited by Dan+ subjects with postural hypotension,
which supports the hypothesis that in Dan+ subjects, respiratory
control is altered mainly in the presence of sympathetic damage of the
autonomic nervous system (Fig. 6).
A
and CO2 in Dan+ was split
into 2 subsets, according to absence (Dan+ PH) or presence
(Dan+ PH+) of postural hypotension. Dan+ PH+ showed
steepest
A/CO2
relationship. In Dan+ PH+,
A at corresponding CO2 values,
although not different from those in Dan+ PH, were
significantly greater than in Dan and C
(* P < 0.05).
Alterations in central or peripheral chemosensitivity could also
explain an increasing respiratory drive. We did not measure the carotid
body response in our patients, but the neuromuscular and ventilatory
responses to CO2 rebreathing were
not different between Dan+ subjects as a group and in control subjects.
Nevertheless, when the
P0.1/PETCO2
and
E/PETCO2
slopes of the five Dan+ subjects with postural hypotension were
computed, their values, amounting to 0.77 ± 0.05 cmH2O/Torr and 4.95 ± 1.27 l · min1 · Torr1,
respectively, were much higher than those recorded in the five Dan+
subjects without postural hypotension and the control subjects (P < 0.01). Hence, a significant
increase in central chemosensitivity can be suspected, at least in
diabetic subjects with more severe autonomic neuropathy involving the
sympathetic nerves.
In conclusion, our results suggest that chronic lung denervation, as occurring in severe diabetic dysautonomy, can induce alterations of the ventilatory response to exercise by influencing the breathing pattern and possibly by determining an abnormally high inspiratory drive through mechanisms still unclear, which appear to involve a damage to the sympathetic autonomic nervous system. In this context, an increased chemosensitivity may actually contribute to sustain the greater central inspiratory activity, leading to an excessively high ventilatory output during heavy exercise. It follows that pulmonary autonomic innervation seems to play a nontrivial role in modulating both the pattern and the level of stimulated ventilation in normal humans.
ACKNOWLEDGEMENTS
The technical assistance of Rita Fraboni and Gianpiero Cipiciani has been invaluable.
FOOTNOTES
Address for reprint requests: C. Tantucci, Clinica di Semeiotica e Metodologia Medica, Ospedale Regionale Torrette, Ancona 60020, Italy.
Received 30 March 1995; accepted in final form 10 January 1996.
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