Influence of Autonomic Neuropathy of Different Severities on the Hypercapnic Drive to Breathing in Diabetic Patients

doi:10.1378/chest.112.1.145

Chest

Volume 112, Issue 1, July 1997, Pages 145-153

https://doi.org/10.1378/chest.112.1.145 Get rights and content

To investigate the effects of the autonomic nervous system on control of breathing, the neuromuscular (mouth occlusion pressure at 0.1 s after onset of inspiration [P_0.1]) and ventilatory (minute ventilation [ $\dot{V}$ E]) response to progressive hyperoxic hypercapnia was assessed in diabetic patients with autonomic dysfunction of different severity. Eighteen diabetics with autonomic neuropathy, nine with parasympathetic damage (DANp), and nine with parasympathetic and sympathetic damage (DANp+s), as indicated by marked postural hypotension, low increment of diastolic BP during sustained handgrip, and lowest resting catecholamine plasma levels, were studied together with a group of 10 diabetic patients without autonomic neuropathy (D) and a group of 10 normal subjects (C). All subjects had pulmonary function tests, including maximal voluntary ventilation and diffusion of carbon monoxide, measurements of respiratory muscle strength as maximal inspiratory mouth pressure (MIP) and maximal expiratory mouth pressure (MEP), and a CO₂ rebreathing test (Read's method). Although in the normal range, lung volumes and FEV₁ and forced expiratory flows were lower in the DANp and DANp+s groups than in the D and C groups, MIP and MEP were similar among C and diabetic groups, as well as resting P_0.1, $\dot{V}$ E, tidal volume (VT), and respiratory rate (RR). The slope of the linear relationship between P_0.1 and end-tidal Pco₂ (PETCO₂) was higher in DANp+s (0.63±0.07 cm H₂O/mm Hg) than in C (0.45±0.06 cm H₂O/mm Hg; p<0.05) and three times greater in DANp+s than in D (0.26±0.03 cm II₂O/mm Hg; p<0.001) and DANp (0.24±0.03 cm H₂O/mm Hg; p< 0.001), who in turn showed a lower ΔP_0.1/ΔPETCO₂ than C. The $\dot{V}$ E increase with increasing PETCO₂ was greater in DANp+s (3.70±0.85 L/min/mm Hg) than in DANp (2.13±0.20 L/min/mm Hg; p<0.05) and D (2.37±0.40 L/min/mm Hg; p=0.07), but not significantly higher from that of C (3.17±0.36 L/min/mm Hg). No differences were found for ΔVT/ΔPETCO₂ among the groups, whereas the ARR/APETCO₂ relationship was steeper in DANp+s than in DANp (p<0.05) and D (p=0.055). These data reflect a depressed CO₂ response both in D and DANp. The presumable decrease of the sympathetic nerve traffic in DANp+s appears to reverse this abnormality. DANp+s, however, exhibit an enhanced CO₂ neuromuscular response even in respect to C, suggesting that the sympathetic nervous system might modulate the output of the respiratory centers to hypercapnic stimulus.

Section snippets

Subjects

Twenty-eight male diabetic patients, 10 without and 18 with diabetic autonomic neuropathy, henceforth referred to as D and DAN, respectively, were recruited from the Istituto di Medicina Interna e Scienze Endocrine e Metaboliche of the Department of Internal Medicine of the University of Perugia and enrolled in the study after they had given fully informed consent. The protocol was approved by the local ethical committee and was in accordance with the Helsinki Declaration.
At the time of the

Characteristics and Lung Function

Anthropometric and clinical characteristics are shown in Table 2 for diabetics and control subjects. Patients and control subjects were not significantly different for age, height, weight, and smoking habit. The long-term control of hyperglycemia was similar and satisfactory for D, DANp, and DANp+s.

Lung volumes, including MW, Dco as function of alveolar volume (Dco/VA), flow/volume curves derived parameters, and MIP and MEP (herein reported also in absolute values) were listed in Table 3.

Vital

Discussion

The main finding of this study is the increased hypercapnic drive in diabetic patients with autonomic neuropathy associated with marked postural hypotension, abnormality of sustained handgrip testing, and lowest resting catecholamine plasma levels (DANp+s). The decrease of the sympathetic nerve traffic, which presumably occurs in these patients, appears to completely reverse the reduced neuromuscular CO₂ response exhibited either by the diabetics without autonomic neuropathy (D) or by the

ACKNOWLEDGMENTS

The technical assistance of Rita Fraboni and Giampiero Cipiciani has been invaluable.

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In diabetes the cardio-respiratory integrated control remains to a large extent to be investigated. Although several studies have tested the hypothesis of altered respiratory or cardiovascular control, the respiratory and cardiovascular reflexes were tested only in small number of subjects and only separately on chemoreflex (hypercapnic only [11], hypoxic only [12], both chemoreflexes [13]) or baroreflex [2,3]. Results were interpreted simply as yet another additional evidence of neuropathy and thus of little novelty.
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Diabetic patients in the Sleep Heart Health Study had a higher incidence of periodic breathing and central apneas than non-diabetic subjects.59 It has been suggested that diabetes-associated autonomic neuropathy alters upper airway reflex responses, peripheral control of upper airway muscles, mechanoreceptor activation thresholds, central ventilatory stability and control, and peripheral response to hypercapnia and hypoxia.93,160 Chronic hyperglycemia, moreover, induces oxidative stress, causing nerve dysfunction and structural damage,161 which could worsen autonomic dysfunction and aggravate sleep disordered breathing, creating a vicious circle.
Epidemiological data suggest that sleep apnea–hypopnea syndrome (SAHS) is independently associated with the development of insulin resistance and glucose intolerance. Moreover, despite significant methodological limitations, some studies report a high prevalence of SAHS in patients with type 2 diabetes mellitus (DM2). A recent meta-analysis shows that moderate–severe SAHS is associated with an increased risk of DM2 (relative risk = 1.63 [09–2.45]), compared to the absence of apneas and hypopneas.
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Supported by a grant from the Ministero del FUniversita e della Ricerca Scientifica e Tecnologica of Italy.

Presented as a poster communication at the American Thoracic Society International Congress, May 1995, Seattle.

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Chest

Clinical Investigations: Control of Breathing: ArticlesInfluence of Autonomic Neuropathy of Different Severities on the Hypercapnic Drive to Breathing in Diabetic Patients

Section snippets

Subjects

Characteristics and Lung Function

Discussion

ACKNOWLEDGMENTS

Respir Physiol

Life Sci

Respir Physiol

Brain Res

Evidence for vasomotor escape from sympathetic stimulation in the rabbit. Brain Res

Natural history of diabetic autonomic neuropathy

Q J Med

Mortality in diabetic autonomic neuropathy

Lancet

Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics

Q J Med

Cardiorespiratory arrest and diabetic autonomic neuropathy

Lancet

Cardiorespiratory arrest in diabetes

Lancet

Cardiac denervation in diabetic neuropathy

Ann Intern Med

Abnormal chemoreceptor response to hypoxia in patients with tabes dorsalis

BMJ

Chemosensitivity in patients with diabetic neuropathy

Clin Sci

Sleep apnea in diabetic patients with autonomic neuropathy

J R Soc Med

Preservation of the hypoxic drive to breathing in diabetic autonomic neuropathy

Clin Sci

Autonomic neuropathy and the ventilatory responses of diabetics to progressive hypoxemia and hypercarbia

Diabetes

Respiratory responses of diabetics to hypoxia, hypercapnia and exercise

Thorax

Ventilatory control in diabetes mellitus

Eur J Respir Dis

Impaired hypoxic ventilatory drive in diabetic patients with autonomic neuropathy

J Clin Endocrinol Metab

Ventilatory and heart rate responses to hypoxia and hypercapnia in patients with diabetes mellitus

Thorax

No effect of naloxone on ventilatory response to progressive hypercapnia in IDDM patients

Diabetes

Clinical Investigations: Control of Breathing: Articles
Influence of Autonomic Neuropathy of Different Severities on the Hypercapnic Drive to Breathing in Diabetic Patients