Considering the current evidence, it was clear that COVID-19 patients in a critical state who present with low autonomic nervous system tone, i.e., a lower energy value, suffer from a higher severity of illness and have a worse prognosis according to the predictive SOFA score. A depletion of sympathetic tone and proportionally greater vagal tone, in other words, a high ANIm, is associated with higher IL-6 levels and higher mortality.
In our patient sample, a high ANIm value above 80 and a low energy value below 0.41, especially in more sedated patients (RASS -4/-5), predicted mortality with very high sensitivity and specificity.
According to the available literature, this is the first study to analyze HRV in critically ill patients suffering from SARS-COV-2 who are on mechanical ventilation. It is also the only one so far that shows that COVID-19 patients with the worst prognosis and highest mortality present significant depletion of the ANS and a predominance of vagal tone, due to depletion of the sympathetic nervous system.
Our study is consistent with the other research findings that have also analyzed HRV in critically ill patients [10-13]. Most of these studies carried out especially in septic patients conclude that those with lower HRV, a decrease in the total energy of the ANS (total power), a reduction of the sympathetic component (LF) and a predominance of the parasympathetic component (HF) presented increased severity according to the APACHE II score and predicted which patients had the highest risk of developing multiple organ dysfunction syndromes (MODS) [12, 13, 18, 19].
Another study by Chen-WL et al.  showed that monitoring HRV at the time of admission to the emergency room for patients resuscitated after the myocardial infarction could predict 24-hour mortality. Those with the worst prognosis presented depletion of the sympathetic component (LF) and low autonomic tone (HF), which was very similar to what happened in patients suffering from severe septic shock [13, 21].
Also, Huang CT et al.  concluded that spectral analysis of HRV in 101 patients admitted to the intensive care unit undergoing mechanical ventilation could predict the success or failure of removal of said support and that patients extubated with a lower HRV and a lower TP had a higher risk of reintubation after 72 hours. Chen IC et al.  demonstrated, as in our study, that lower energy (total power) and higher vagal tone (HF) were independent predictors of mortality in patients with adult respiratory distress syndrome (ARDS).
Finally, a recent meta-analysis of 51 studies  that linked HRV and inflammation concluded that spectral analysis serves to monitor the autonomic activity that controls inflammatory processes in humans. In general, these studies have shown a strong association among inflammatory parameters, mainly IL-6 and CRP, and a higher high-frequency band (HF), and a low total power of the ANS, as was also demonstrated in our study.
As Siddiqi HK et al.  suggest, there are three stages in the COVID-19 disease. There is the first stage of viral replication, the second stage of lung involvement, with the development of severe pneumonia and ARDS caused by SARS-COV-2 , and the third stage with a predominance of a hyper-immune response, with severe multi-organ dysfunction.
What happens in the third stage is severe inflammatory response syndrome (SIRS), extreme macrophage activation, with a significant increase in inflammatory cytokines and other acute-phase reactants (IL-6, ferritin, CRP, D-dimer) .
When faced with any infectious or nociceptive stimulus or tissue injury, there is a first proinflammatory response, which is mainly modulated by the sympathetic nervous system [25,26]. This response produces a strong hyper-immune reaction with a large adrenergic release and significant macrophage activation. This macrophage activation syndrome or SIRS is in turn balanced by a compensatory anti-inflammatory response (CARS). This compensatory response is mostly modulated by the parasympathetic nervous system and by the anti-inflammatory cholinergic pathway. When SIRS subsides and CARS is active for some time, without returning to a state of homeostasis, a state of immunodeficiency or anergy is frequently produced, which triggers an increase in viral replication and bacterial superinfection and can ultimately lead to a fatal outcome for the patient [25-28].
This decreased activity of the ANS, along with the increase in the high-frequency parasympathetic component, seen in patients with COVID-19 and in critically ill patients in general, would represent what happens in the late phase when there is significant autonomic dysregulation, with large-scale sympathetic adrenergic depletion, and a slight predominance of parasympathetic tone as a reflection of the compensatory response .
A recent study  shows that most of the latest clinical trials on COVID-19 patients have focused primarily on "anti-viral" and "anti-inflammatory" therapeutic strategies. However, it suggests that perhaps a new therapeutic approach for more severely ill patients could be the stimulation of this innate inflammatory response.
There is a nucleus in the brain stem that directs the inflammatory reflex when any injury, infection, or nociceptive stimulus occurs, activating the autonomic nociceptive circuit described by Brown EN et al. [31,32]. This is the nucleus of the solitary tract (NTS), which, through the vagus nerve (VN) and the activation of the different nuclei of the central nervous system, modulates both the sympathetic and parasympathetic nervous systems. The NTS activates the anti-inflammatory cholinergic chain through the VN. The VN is a powerful anti-inflammatory element, as it releases acetylcholine, which inhibits macrophage release of cytokines by binding to its specific membrane receptor, the nicotinic alpha 7 receptor.
In turn, the NTS produces activation of the entire sympathetic chain through the rostral ventromedial medulla (RVM), activates the locus coeruleus (LC) nucleus that regulates the “fight or flight” response through noradrenergic release, and activates the hypothalamic-pituitary-adrenal system by releasing adrenocorticotropic hormone (ACTH) following the activation of the paraventricular (PV) nucleus of the hypothalamus [5,6,26,30].
Therefore, activation of this nucleus, both pharmacologically, by activating the alpha 7 nicotinic receptors, and electrically, through vagus nerve stimulation (VNS), appear to be promising therapeutic strategies to balance the ANS and produce a balanced autonomic response [33-35]. Several studies have already tested VNS in patients with immune system disorders, sepsis and COVID-19 with promising results [36,37], and some clinical trials have started over the last few months [38,39].
This is the first study carried out with certain real-life limitations during the pandemic. Its main limitation is the small sample of patients used. For this reason, further research studies are needed for longer periods with larger sample sizes. In future studies, we will attempt to monitor and record neuromuscular blocking data using acceleromyograph, and record the degree of sedoanalgesia, using sedation scales and EEG monitors which include spectrogram analysis.