Follow Your Nose: A Key Clue to Understanding and Treating COVID-19.

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.

Is the heart rate variability monitoring using the analgesia nociception index a predictor of illness severity and mortality in critically ill patients with COVID-19? A pilot study.

INTRODUCTION: The analysis of heart rate variability (HRV) has proven to be an important tool for the management of autonomous nerve system in both surgical and critically ill patients. We conducted this study to show the different spectral frequency and time domain parameters of HRV as a prospective predictor for critically ill patients, and in particular for COVID-19 patients who are on mechanical ventilation. The hypothesis is that most severely ill COVID-19 patients have a depletion of the sympathetic nervous system and a predominance of parasympathetic activity reflecting the remaining compensatory anti-inflammatory response. MATERIALS AND METHODS: A single-center, prospective, observational pilot study which included COVID-19 patients admitted to the Surgical Intensive Care Unit was conducted. The normalized high-frequency component (HFnu), i.e. ANIm, and the standard deviation of RR intervals (SDNN), i.e. Energy, were recorded using the analgesia nociception index monitor (ANI). To estimate the severity and mortality we used the SOFA score and the date of discharge or date of death. RESULTS: A total of fourteen patients were finally included in the study. ANIm were higher in the non-survivor group (p = 0.003) and were correlated with higher IL-6 levels (p = 0.020). Energy was inversely correlated with SOFA (p = 0.039) and fewer survival days (p = 0.046). A limit value at 80 of ANIm, predicted mortalities with a sensitivity of 100% and specificity of 85.7%. In the case of Energy, a limit value of 0.41 ms predicted mortality with all predictive values of 71.4%. CONCLUSION: A low autonomic nervous system activity, i.e. low SDNN or Energy, and a predominance of the parasympathetic system, i.e. low HFnu or ANIm, due to the sympathetic depletion in COVID-19 patients are associated with a worse prognosis, higher mortality, and higher IL-6 levels.

ANI and BIS variations in supine and prone position during closed-tracheal suction in sedated and myorelaxed ICU patients with severe COVID-19: A retrospective study.

The purpose of this study was to assess Analgesia/Nociception Index (ANI) and bispectral index (BIS) variations in supine and prone position during closed-tracheal suction in intensive care unit (ICU) patients with severe COVID-19 pneumonia requiring myorelaxation and prone positioning. We retrospectively reviewed the data of 15 patients hospitalized in ICU for severe COVID-19 pneumonia requiring sedation, myorelaxation and prone positioning. The BIS, instant ANI (ANIi), mean ANI (ANIm), heart rate (HR), systolic blood pressure (SBP) and SpO2 were retrieved in supine and prone position 1 min before tracheal suction then every minute from the beginning of tracheal suction during 4 min and compared using ANOVA for repeated measures (p < 0.05 considered as statistically significant). Both ANIm and ANIi decreased significantly during tracheal suction with no difference between positions, whereas BIS showed no significant variation within time and between groups. The median [Q1-Q3] ANIm value decreased from 87 [68-98] to 79 [63-09] in supine position and from 79 [63-95] to 78 [66-98] in prone position 2 min after the beginning of tracheal suction. The median [Q1-Q3] ANIi value decreased earlier 1 min after the beginning of tracheal suction from 84 [69-98] to 73 [60-90] in supine position and from 84 [60-99] to 71 [51-88] in prone position. Both HR, SBP and SpO2 varied modestly but significantly during tracheal suction with no difference between positions. Monitoring ANI, but not BIS, may be of interest to detect noxious stimuli such as tracheal suction in ICU myorelaxed patients with severe COVID-19 pneumonia requiring prone positioning.