**3. RMSSD**

RMSSD is the root-mean-square of successive differences between adjacent normal RR intervals in a time interval, expressed in millisseconds, and is the primary time domain measure used to assess parasympathetic sources of HRV [4].

Several studies have shown a reduction in RMSSD values in the presence of disease or aging, reflecting a reduction in heart rate variability. Maurer CW et al., in 2016 [9], evaluated the behavior of the autonomic nervous system in 35 patients with functional movement disorders (FMD) compared to 38 healthy controls. They found a significant reduction in RMSSD in patients with FMD (P = 0.02), as well as an increased mean heart rate (P = 0.03), concluding that decreased vagal tone may reflect increased stress vulnerability in patients with FMD.

DeGiorgio, CM et al. [10], studied 19 subjects with intractable partial seizures, at least three per month, in a randomized clinical trial of omega-3 fatty acids in epilepsy. They looked for whether or not there was a correlation between heart rate variability and the estimated risk of Sudden Unexplained Death in Epilepsy, quantified by the SUDEP-7 Inventory. They found that the RMSSD was inversely correlated with the SUDEP-7 score, r = −0.64, p = 0.004. Subjects with higher SUDEP-7 scores had reduced levels of HRV (RMSSD). Other time-dependent measures of HRV (SDNN, SDANN) were not significantly correlated with SUDEP risk scores.

In another study, Maheshwari A et al. [11] evaluated a large group of 12,543 individuals from the general population, participating in The Atherosclerosis Risk in Communities Study. They were looking for a relationship between low HRV and sudden cardiac death (SCD). During a median follow-up of 13 years, 215 SCDs were identified. In the group in which sudden deaths occurred, there was a statistically significant difference in heart rate (70.3 ± 13.8 bpm versus 67.7 ± 10.3 bpm; P = 0.008) and in HF power ms2 (1.6 ± 1.5 Ln versus 2.1 ± 1.3 Ln; P < 0.0001). As for the RMSSD, there was no statistically significant difference between the groups, but in both conditions, the values were below the ideal values for normality (27.3 ± 28.3 ms versus 29.2 ± 23.3 ms; P = 0.25).

Based on the knowledge that sepsis is associated with marked alterations in hemodynamic responses, autonomic dysfunction and impaired vascular function, Bongiorno Junior et al. [12], explored the prognostic utility of cardiac output (CO), stroke volume (SV), indices of vagal modulation (RMSSD and SD1), total heart rate variability (HRV) and flow-mediated dilation (FMD) of the brachial artery (%FMD) in 60 patients recruited at an intensive care unit. They found that in the group of 39 patients who did not survive, HR was higher (105 ± 27 bpm versus 84 ± 15 bpm; P = 0.02) and it was observed that the RMSSD and SD1 indices could be predictors of endothelial function and RMSSD could predict the risk of death in these patients.

The ROC Curve of RMSSD was useful in predicting 28-day mortality in patients with sepsis. The area under the curve was 0.784 (0.656–0.881). The value of 10.8 ms was chosen as the cut-off point for RMSSD (sensitivity of 77.1%, specificity of 73.9%, the positive likelihood ratio of 2.96 and negative likelihood ratio of 0.31. With RMSSD ≤10.8 ms, the mean survival time was 23.1 days and with RMSSD>10.8 ms, the mean survival time was 23.1 days).
