Cardiac Autonomic Dysfunction in Children and Adolescents with Type 1 Diabetes Mellitus

Introduction: Autonomic neuropathy is less well documented in children with type 1 diabetes mellitus and has received less attention than other diabetic complications. Sudden death and cardio-respiratory arrest in patients with type 1 and type 2 diabetes mellitus have b cardiac autonomic dysfunction. Aim: The aim of this study was to determine the prevalence of autonomic neuropathy in a cohort of children and adolescents with type I diabetes and to examine the relationship between this complication, and duration of diabetes and degree of glycemic control. Material and Methods: Seventy-six type 1 diabetic children and adolescents below age 18 years of age, and 76 non diabetic school children, matched for age and sex, had their cardiac autonomic nerve fun autonomic function tests. Namely the respiratory sinus arrhythmia test ; the Valsalva ratio test; the heart rate response to standing, and the blood pressure response to standing. The first three are tests of parasympathetic funct last one is a sympathetic function test. Results: The diabetic patients had a median age of 12 years and their median duration of diabetes mellitus was 43 months. They showed a significantly higher resting heart rate and a significant drop pressures upon standing compared to the control group. The duration of diabetes mellitus showed linear correlation to the symptoms of autonomic dysfunction. Conclusion: We conclude that cardiac autonomic neuropathy is not duration of illness where glycemic control is less than optimal. Such tests may serve as long in diabetic patients.


Introduction
About 13% of patients with type I diabetes mellitus develop diabetic neuropathy as a damage to peripheral and/or autonomic nerves This complication is usually described in adult patients with type 2 diabetes mellitus after several years of illness and often in the presence of poor metabolic control.It is less well documented i children with type 1 diabetes mellitus who have relatively short duration of disease (<7 years).Because the symptoms of autonomic neuropathy are insidious in onset and difficult to recognize, it has received less attention than other diabetic complications.However, although it is not usually life threatening, diabetic autonomic neuropathy (DAN) may be associated with substantial morbidity [2][3][4] .Sudden death and cardio arrest in patients with type 1 and type 2 diabetes mellitus have been attributed to cardiac tion in Children and Adolescents with Type 1 Diabetes Mellitus Elamin A 1 , Rajesh K 2 , Tuvemo T 3 is less well documented in children with type 1 diabetes on than other diabetic complications.Sudden death and h type 1 and type 2 diabetes mellitus have been attributed to ermine the prevalence of autonomic neuropathy in a cohort I diabetes and to examine the relationship between this and degree of glycemic control.ype 1 diabetic children and adolescents below age 18 years of age, and 76 non age and sex, had their cardiac autonomic nerve fun espiratory sinus arrhythmia test ; the Valsalva ratio test; the heart rate response to nse to standing.The first three are tests of parasympathetic funct median age of 12 years and their median duration of diabetes mellitus was 43 higher resting heart rate and a significant drop in systolic and diastolic blood he control group.The duration of diabetes mellitus showed linear correlation to n.
autonomic neuropathy is not rare in young diabetic patients of relatively short trol is less than optimal.Such tests may serve as longpheral neuropathy, glycemic control, Middle East type I diabetes y as a result of nomic nerves 1 5 .neuropathy in those patients has been considered a sensitive indicator of increased risk of mortality and morbidity 6 .The development of some simple tests of autonomic nerve function have helped in the assessment of patients complaining of cli features that may be attributed to autonomic dysfunction as well as in the assessment of asymptomatic subjects.These tests also have a predictive and prognostic value in the clinical evaluation of such patients.
The aim of this study was to determ prevalence of autonomic neuropathy in a cohort of children and adolescents with type I diabetes and to examine the relationship between this complication, and duration of diabetes and degree of glycemic control.Four autonomic nerve function tests were used.Additional objective was thus to assess which one of these tests was the most predictive and correlates best with the clinical symptoms and signs of autonomic neuropathy.

Subjects and methods
The study is one of a series of studies that address complications in young patients with type 1 diabetes.The patients were seen regularly at the pediatric diabetes outpatient clinic of Sultan Qaboos University Hospital in Muscat, Sultanate of Oman, for clinical evaluation and insulin prescription on monthly basis.The cohort Cardiac autonomic nerve function was assessed by four standard physiologic tests: the respiratory sinus arrhythmia test (RSA); the Valsalva ratio test (VR); the heart rate response to standing (30:15 ratio), and the blood pressure response to standing (Postural BP).The first three are tests of parasympathetic function, while the last one is a sympathetic function test.The patients were left to lie down supine for half an hour of rest before the tests were performed.During this time their medical history was recorded including details of symptoms suggestive of autonomic neuropathy, and a thorough physical examination was performed.None of the patients had clinical evidence of any intrinsic heart or respiratory disease nor were any of them on any medication that might affect their cardiovascular system.

Statistical analysis
Student's t-test was used to compare the mean of each test result between the groups.
Linear and multiple regression analysis were computed using the SPSS statistical software to examine the correlation between the duration of diabetes and the degree of glycemic control, and the presence of autonomic dysfunction.The predictive value of each test in relation to the symptoms and signs of DAN was also tested.Level of statistical significance was set at p<0.05.

Results
Fifty-one patients (67.1%) had no symptoms i.e. asymptomatic diabetic (AD), ten patients (13.2%) reported symptoms of diabetic peripheral neuropathy (DPN), eight patients (10.5%) had symptoms of diabetic autonomic neuropathy (DAN), and seven patients (9.2%) showed symptoms and signs of both peripheral and autonomic diabetic neuropathy (DPAN).The most common symptoms of peripheral neuropathy reported were numbness and tingling sensation mainly in the feet together with pain described as pins and needles that were persistent.For the possibly autonomic neuropathy, the most common symptoms reported in order of frequency were: postural dizziness, sweating abnormalities, nausea, nocturnal diarrhea, epigastric fullness, gustatory sweating, vomiting and constipation.All were reported to be persistent and somewhat troublesome.None of the patients showed any gross neurological signs.
There was no significant statistical difference between the diabetic patients and the control subjects regarding median age, mean weight, mean height, and the average supine blood pressure (table 1).However, in the group of diabetic patients 23 subjects (30%) were below the third percentile for weight, and 19 subjects (25%) were below the third percentile for height, according to Tanner standards 7 .In the control group 11 subjects (14.5%) were below the third percentile for weight and 9 subjects (11.8%) were below the third percentile for height.The resting heart rate of the diabetic children was significantly higher than that of the control group (P < 0.05).Table 2  VR) showed insignificant differences between the diabetic and the control groups (p = 0.5).
There was a positive correlation between duration of diabetes mellitus and prevalence of neuropathy in this group of patients (r = 0.84 p <0.001).The mean duration of diabetes in months ± standard deviation was 17 ± 16 for the A.D., 23 ± 17 for D.A.N., 32 ± 33 for the D.P.N. and 67 ± 30 for the D.P.A.N. group.The number of autonomic neuropathy symptoms reported in each patient correlated significantly only with the duration of his diabetes mellitus (r =0.56).Also the systolic drop in blood pressure was significantly correlated to the diastolic drop in the postural B.P. test (r =0.623).

Discussion
Although autonomic neuropathy is a result of multi-system pathology, the usage of cardiovascular reflex tests has been shown to correlate well with all symptoms of autonomic neuropathy 8 .An elevated resting heart rate in our diabetics compared to the control is in agreement with findings by Storstein and Jervell 11 .This reflects parasympathetic cardiac nerve involvement, as during quiet non-stressed supine position there is little cardiac sympathetic activity 12 .Cardiac parasympathetic activity may be diminished in diabetes even before clinical symptoms of autonomic neuropathy are evident.An association between objectively defined diabetic neuropathy and elevated resting heart rate has been observed 13 .The resting heart rate was not significantly elevated in the D.P.N. and D.P.A.N. groups compared to the control.This may reflect the natural history of cardiac autonomic neuropathy in which an early parasympathetic impairment may elevate the heart rate, but as the duration of the diabetes increases, as in the two groups above mentioned, sympathetic involvement occurs that may relatively slow the heart rate 14 .The heart rate elevation to standing (30:15 ratio) depends upon an intact parasympathetic supply to the heart.Loss of the ability to increase heart rate upon standing was observed to occur even within one year of diagnosing diabetes 15 .The fact that heart rate failed to increase in DPAN groups although they suffered from postural hypotension in comparison to the control and they had greater blood pressure fall may indicate a defect in the baroreceptor reflex arch as suggested by Hilsted 16 .Postural hypotension is the most significant clinical expression of autonomic neuropathy to affect the cardio-vascular system.The postural BP test may be significantly altered even in asymptomatic diabetics 17 .In our study the commonest symptom of autonomic neuropathy reported was postural hypotension.The asymptomatic diabetic (AD) group had significantly altered postural BP test compared to the control P<0.005.Sympathetic activity impairment failing to increase the total peripheral resistance appears to be the primary cause since parasympathetic outflow to the heart is not required for normal postural adaptation 18 .The duration of diabetes mellitus correlated well with autonomic symptoms.This is in agreement with Weinberg and Pfiefer who showed resting heart rate and duration of diabetes were predictive of having symptoms of autonomic neuropathy 19 .
We may conclude that the resting heart rate, in addition to the heart rate response to standing, and the blood pressure response to standing autonomic function tests are easy to perform even on children.They require minimal cooperation by the subjects as compared to the other tests.Even in asymptomatic diabetics and with relatively short duration of diabetes autonomic neuropathy could be diagnosed by these tests and they gave an idea about the severity of autonomic dysfunction.It may be possible for any clinician to perform them as they may help in the assessment and management of his diabetic patients.

Table 1 :
compares the results of the autonomic function tests between the different groups.It illustrates significant differences between the two groups in the heart rate response to standing (30:15 ratio), and postural B.P tests.The details of the results of the autonomic function tests are shown in table3.There was a significant lowering of both systolic and diastolic blood pressures upon standing (P < 0.01) in the postural B.P. test.The other two tests (RSA and Characteristics of the control and diabetic subjects

Table 3 :
Statistical comparison of the results of the autonomic function between the different groups . . .