Autonomic pain responses during sleep: a study of heart rate variability

The autonomic nervous system (ANS) reacts to nociceptive stimulation during sleep, but whether this reaction is contingent to cortical arousal, and whether one of the autonomic arms (sympathetic/parasympathetic) predominates over the other remains unknown. We assessed ANS reactivity to nociceptive stimulation during all sleep stages through heart rate variability, and correlated the results with the presence of cortical arousal measured in concomitant 32-channel EEG. Fourteen healthy volunteers underwent whole-night polysomnography during which nociceptive laser stimuli were applied over the hand. RR intervals (RR) and spectral analysis by wavelet transform were performed to assess parasympathetic (HF(WV)) and sympathetic (LF(WV) and LF(WV)/HF(WV) ratio) reactivity. During all sleep stages, RR significantly decreased in reaction to nociceptive stimulations, reaching a level similar to that of wakefulness, at the 3rd beat post-stimulus and returning to baseline after seven beats. This RR decrease was associated with an increase in sympathetic LF(WV) and LF(WV)/HF(WV) ratio without any parasympathetic HF(WV) change. Albeit RR decrease existed even in the absence of arousals, it was significantly higher when an arousal followed the noxious stimulus. These results suggest that the sympathetic-dependent cardiac activation induced by nociceptive stimuli is modulated by a sleep dependent phenomenon related to cortical activation and not by sleep itself, since it reaches a same intensity whatever the state of vigilance

Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

ObjectiveTo determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.Research design and methodsFrom 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively.ResultsOver a median of 21 years (interquartile range 20-21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52]), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28]), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81]) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality.ConclusionsCancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates