Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC).

BACKGROUND: The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a prospective observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort, reported persistent benefit of prior intensive therapy on retinopathy and nephropathy in type 1 diabetes mellitus. We evaluated the effects of prior intensive insulin therapy on the prevalence and incidence of cardiac autonomic neuropathy (CAN) in former DCCT intensive and conventional therapy subjects 13 to 14 years after DCCT closeout. METHODS AND RESULTS: DCCT autonomic measures (R-R variation with paced breathing, Valsalva ratio, postural blood pressure changes, and autonomic symptoms) were repeated in 1226 EDIC subjects in EDIC year 13/14. Logistic regression models were used to calculate the odds of incident CAN by DCCT treatment group after adjustment for DCCT baseline covariates, duration in the DCCT, and quantitative autonomic measures at DCCT closeout. In EDIC year 13/14, the prevalence of CAN using the DCCT composite definition was significantly lower in the former intensive group versus the former conventional group (28.9% versus 35.2%; P=0.018). Adjusted R-R variation was significantly greater in the former DCCT intensive versus the former conventional group (29.9 versus 25.9; P<0.001). Prior DCCT intensive therapy reduced the risks of incident CAN by 31% (odds ratio, 0.69; 95% confidence interval, 0.51 to 0.93) and of incident abnormal R-R variation by 30% (odds ratio, 0.70; 95% confidence interval, 0.51 to 0.96) in EDIC year 13/14. CONCLUSIONS: Although CAN prevalence increased in both groups, the incidence was significantly lower in the former intensive group compared with the former conventional group. The benefits of former intensive therapy extend to measures of CAN up to 14 years after DCCT closeout.

Long-term effect of diabetes and its treatment on cognitive function.

BACKGROUND: Long-standing concern about the effects of type 1 diabetes on cognitive ability has increased with the use of therapies designed to bring glucose levels close to the nondiabetic range and the attendant increased risk of severe hypoglycemia. METHODS: A total of 1144 patients with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study were examined on entry to the DCCT (at mean age 27 years) and a mean of 18 years later with the same comprehensive battery of cognitive tests. Glycated hemoglobin levels were measured and the frequency of severe hypoglycemic events leading to coma or seizures was recorded during the follow-up period. We assessed the effects of original DCCT treatment-group assignment, mean glycated hemoglobin values, and frequency of hypoglycemic events on measures of cognitive ability, with adjustment for age at baseline, sex, years of education, length of follow-up, visual acuity, self-reported sensory loss due to peripheral neuropathy, and (to control for the effects of practice) the number of cognitive tests taken in the interval since the start of the DCCT. RESULTS: Forty percent of the cohort reported having had at least one hypoglycemic coma or seizure. Neither frequency of severe hypoglycemia nor previous treatment-group assignment was associated with decline in any cognitive domain. Higher glycated hemoglobin values were associated with moderate declines in motor speed (P=0.001) and psychomotor efficiency (P<0.001), but no other cognitive domain was affected. CONCLUSIONS: No evidence of substantial long-term declines in cognitive function was found in a large group of patients with type 1 diabetes who were carefully followed for an average of 18 years, despite relatively high rates of recurrent severe hypoglycemia. (ClinicalTrials.gov number, NCT00360893.)

DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history.

The DCCT/EDIC (Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications) provides a comprehensive characterization of the natural history of diabetic neuropathy in patients with type 1 diabetes and provides insight into the impact of intensive insulin therapy in disease progression. The lessons learned about the natural history of distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy and the impact of glycemic control on neuropathy are discussed in this review.

Extending the preoxygenation period from 4 to 8 mins in critically ill patients undergoing emergency intubation.

OBJECTIVE: To determine the effectiveness of increasing the preoxygenation period with 100% oxygen in the critically ill patient from 4 to 8 mins in preparation for emergency tracheal intubation. DESIGN: Nonrandomized, controlled trial. SETTING: Large, level one trauma center, tertiary care intensive care unit. PATIENTS: Critically ill patients failing noninvasive respiratory support techniques who required tracheal intubation followed by mechanical ventilation. INTERVENTIONS: A baseline arterial blood gas was obtained on noninvasive passive therapy and at 4, 6, and 8 mins of active preoxygenation efforts with 100% oxygen therapy with a noncollapsing resuscitator bag and mask. Best effort to achieve a tight fitting mask seal was pursued coupled with other mask ventilation maneuvers to optimize noninvasive oxygenation and ventilation. MEASUREMENTS AND MAIN RESULTS: Thirty-four patients consecutively intubated by the author during the 7-month study period were studied. The baseline PaO2 (mean +/- SD) with concurrent noninvasive support was 61.9 +/- 14.6 mm Hg (range: 44-109 mm Hg) and increased a mean of 22 mm Hg to 83.8 +/- 51.5 mm Hg after 4 mins of preoxygenation (p < 0.01). Continued preoxygenation efforts (6 mins) increased the PaO2 to 88.2 mm Hg +/- 48.5 and after 8 mins to 92.7 mm Hg +/- 55.2. At the 8-min mark, 5 of 34 patients achieved > 10% increase in their PaO2 and only two patients increased their 4-min PaO2 by > or = 50 mm Hg after the additional 4 mins of preoxygenation. One quarter of the patients experienced a reduction in their PaO2 from the 4 to the 8-min time period. Nearly, 50% of the patients met the criteria for desaturation during the intubation procedure. CONCLUSIONS: Extending the preoxygenation period from the customary 4 mins to either 6 or 8 min seems to be marginally effective in the majority of patient suffering from cardiopulmonary deterioration and such an extension may jeopardize oxygenation efforts in some patients.

Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion.

OBJECTIVE: To evaluate the impact of prior intensive diabetes therapy on neuropathy among former Diabetes Control and Complications Trial (DCCT) participants. RESEARCH DESIGN AND METHODS: At the conclusion of the DCCT, subjects in the intensive group were encouraged to maintain intensive therapy, and subjects in the conventional group were encouraged to begin intensive therapy. Thereafter, we annually assessed neuropathy as part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Neuropathy was defined using the Michigan Neuropathy Screening Instrument (MNSI). We recorded potential adverse consequences of neuropathy. RESULTS: At the first EDIC examination, 1,257 subjects participated in the neuropathy assessment. Consistent with DCCT results, the former intensive group showed a lower prevalence of neuropathy than the conventional group based on positive questionnaire (1.8 vs. 4.7%; P = 0.003) or examination (17.8 vs. 28.0%; P < 0.0001) results. Despite similar levels of glycemic control, symptoms and signs of neuropathy remained less prevalent among the former intensive group compared with the conventional group. At the beginning of the EDIC study, prior intensive therapy reduced the odds of having symptoms and signs of neuropathy using MNSI criteria by 64% (P = 0.0044) and 45% (P < 0.0001), respectively, with similar odds reductions observed for both neuropathic symptoms (51%, P < 0.0001) and neuropathic signs (43%, P < 0.0001) across 8 years of EDIC follow-up. CONCLUSIONS: The benefits of 6.5 years of intensive therapy on neuropathy status extended for at least 8 years beyond the end of the DCCT, similar to the findings described for diabetic retinopathy and nephropathy.

Vibration perception threshold as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: results from the DCCT/EDIC study.

OBJECTIVE: To describe the sensitivity, specificity, positive predictive value, and negative predictive value of vibration perception threshold (VPT) testing in subjects with type 1 diabetes relative to gold standard assessments of peripheral neuropathy. RESEARCH DESIGN AND METHODS: VPT was determined in 1,177 adults with type 1 diabetes 13-14 years after participating in a study of intensive (INT) versus conventional (CONV) diabetes treatment. Abnormal VPT was defined by values exceeding 2.5 SD above age-specific normal values. Signs and symptoms of peripheral neuropathy were assessed and electrodiagnostic studies were performed to establish definite clinical neuropathy, abnormal nerve conduction, and confirmed clinical neuropathy (the presence of both definite clinical neuropathy and abnormal nerve conduction). RESULTS: Thirty-seven percent of subjects had definite clinical neuropathy, 61% had abnormal nerve conduction, and 30% had confirmed clinical neuropathy. Abnormal VPT was more common among former CONV than among INT subjects (64 vs. 57%, P < 0.05) and was associated with older age. VPT was a sensitive measure of confirmed clinical neuropathy (87%) and of definite clinical neuropathy (80%) and a specific measure of abnormal nerve conduction (62%). Higher VPT cut points improved test sensitivity and lower cut points improved specificity. Areas under the receiver operating characteristic curves ranged from 0.71-0.83 and were higher for older than for younger subjects and highest for those with confirmed clinical neuropathy. CONCLUSIONS: VPT was a sensitive measure of peripheral neuropathy. Future researchers may choose to select VPT cut points for defining abnormality based on the population studied and clinical outcome of interest.

Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study.

OBJECTIVE: To evaluate the impact of former intensive versus conventional insulin treatment on neuropathy in Diabetes Control and Complications Trial (DCCT) intensive and conventional treatment subjects with type 1 diabetes 13-14 years after DCCT closeout, during which time the two groups had achieved similar A1C levels. RESEARCH DESIGN AND METHODS: Clinical and nerve conduction studies (NCSs) performed during the DCCT were repeated during the Epidemiology of Diabetes Interventions and Complications (EDIC) study by examiners masked to treatment status on 603 former intensive and 583 former conventional treatment subjects. Clinical neuropathy was defined by symptoms, sensory signs, or reflex changes consistent with distal polyneuropathy and confirmed with NCS abnormalities involving two or more nerves among the median, peroneal, and sural nerves. RESULTS: The prevalence of neuropathy increased 13-14 years after DCCT closeout from 9 to 25% in former intensive and from 17 to 35% in former conventional treatment groups, but the difference between groups remained significant (P < 0.001), and the incidence of neuropathy remained lower among former intensive (22%) than former conventional (28%) treatment subjects (P = 0.0125). Analytic models of incident neuropathy that adjusted for differences in NCS results at DCCT closeout showed no significant risk reduction associated with former intensive treatment during follow-up (odds ratio 1.17 [95% CI 0.84-1.63]). However, a significant persistent treatment group effect was observed for several NCS measures. Longitudinal analyses of overall glycemic control showed a significant association between mean A1C and measures of incident and prevalent neuropathy. CONCLUSIONS: The benefits of former intensive insulin treatment persisted for 13-14 years after DCCT closeout and provide evidence of a durable effect of prior intensive treatment on neuropathy.

Impact of diabetes and its treatment on cognitive function among adolescents who participated in the Diabetes Control and Complications Trial.

OBJECTIVE: The purpose of this study was to evaluate whether severe hypoglycemia or intensive therapy affects cognitive performance over time in a subgroup of patients who were aged 13-19 years at entry in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: This was a longitudinal study involving 249 patients with type 1 diabetes who were between 13 and 19 years old when they were randomly assigned in the DCCT. Scores on a comprehensive battery of cognitive tests obtained during the Epidemiology of Diabetes Interventions and Complications follow-up study, approximately 18 years later, were compared with baseline performance. We assessed the effects of the original DCCT treatment group assignment, mean A1C values, and frequency of severe hypoglycemic events on eight domains of cognition. RESULTS: There were a total of 294 reported episodes of coma or seizure. Neither frequency of hypoglycemia nor previous treatment group was associated with decline on any cognitive domain. As in a previous analysis of the entire study cohort, higher A1C values were associated with declines in the psychomotor and mental efficiency domain (P < 0.01); however, the previous finding of improved motor speed with lower A1C values was not replicated in this subgroup analysis. CONCLUSIONS: Despite relatively high rates of severe hypoglycemia, cognitive function did not decline over an extended period of time in the youngest cohort of patients with type 1 diabetes.

Subclinical neuropathy among Diabetes Control and Complications Trial participants without diagnosable neuropathy at trial completion: possible predictors of incident neuropathy?

OBJECTIVE: We sought to evaluate the prevalence of subclinical neuropathy in intensive and conventional treatment groups at completion of the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: We assessed neuropathy using nerve conduction results obtained at DCCT completion after stratifying the DCCT cohort to exclude subjects with progressively less severe degrees of diagnosable neuropathy. We began with those who had confirmed clinical neuropathy (the primary DCCT end point) and eventually excluded all subjects with any clinical or electrodiagnostic evidence of neuropathy. RESULTS: After excluding subjects with confirmed clinical neuropathy at DCCT completion, 8 of 10 nerve conduction measures (including all lower-extremity measures) were significantly improved in the intensive treatment group (O'Brien rank-sum test across all nerve conduction measures, P < 0.0001). Conduction velocity group differences were substantial, and the peroneal conduction velocity averaged 3.1 m/s faster in the intensive compared with the conventional treatment group (45.1 vs. 42.0 m/s, P < 0.0001). Numerous significant differences in median and peroneal motor conduction velocities favoring the intensive treatment group persisted, regardless of the exclusion criteria applied. CONCLUSIONS: Intensive and conventional treatment group subjects without diagnosable neuropathy at DCCT completion had significant differences in electrophysiologic measurements favoring the intensive treatment group. Differences in subsequent incident neuropathy between the original treatment groups may reflect, in part, their levels of subclinical neuropathy at DCCT completion, rather than persistent metabolic effects.