Autonomic dysfunction in COVID-19 patients receiving mechanical ventilation: A cross-sectional study

ABSTRACT BACKGROUND: Coronavirus disease 2019 (COVID-19) can damage cardiac tissue by increasing troponin levels and inducing arrhythmias, myocarditis, and acute coronary syndrome. OBJECTIVES: To analyze the impact of COVID-19 on cardiac autonomic control in mechanically ventilated intensive care unit (ICU) patients. DESIGN AND SETTING: This cross-sectional analytical study of ICU patients of both sexes receiving mechanical ventilation was conducted in a tertiary hospital. METHODS: Patients were divided into COVID-19-positive (COVID(+)) and COVID-19-negative (COVID(-)) groups. Clinical data were collected and heart rate variability (HRV) records obtained using a heart rate monitor. RESULTS: The study sample comprised 82 subjects: 36 (44%) in the COVID(-) group (58.3% female; median age, 64.5 years) and 46 (56%) in the COVID(+) group (39.1% females; median age, 57.5 years). The HRV indices were lower than the reference values. An intergroup comparison identified no statistically significant differences in the mean normal-to-normal (NN) interval, standard deviation of the NN interval, or root mean square of successive differences in NN intervals. The COVID(+) group had an increased low frequency (P = 0.05), reduced high frequency (P = 0.045), and increased low frequency/high frequency (LF/HF) ratio (P = 0.048). There was a weak positive correlation between LF/HF and length of stay in the COVID(+) group. CONCLUSION: Patients who received mechanical ventilation had lower overall HRV indices. COVID(+) patients who received mechanical ventilation had lower vagal HRV components. These findings likely indicate clinical applicability, as autonomic control impairments are associated with a greater risk of cardiac death.


INTRODUCTION
Breathing difficulties with severe hypoxemia, caused by infection with the severe acute respiratory syndrome (SARS) virus, is the most important manifestation of coronavirus disease 2019 . 1 In addition to the possibility of a pulmonary lesion, COVID-19 may directly cause heart damage in the form of myocarditis, heart failure, cardiogenic shock, acute coronary syndrome, and cardiac arrhythmias. Clinical manifestations are also accompanied by increased cardiac biomarker levels. The mechanisms that cause these cardiovascular disorders are not yet clear; however, they are believed to be related to excessive inflammatory responses, hypoxemia, thromboembolic phenomena, and endothelial dysfunction. 2,3 The severity of infection increases simultaneously with the activation of the inflammatory pathways that trigger cytokine storm. 4 Cardiac autonomic control can be studied through heart rate variability (HRV), which is the physiological phenomenon of variation in the time interval between heartbeats. 5,6 Decreased HRV is a sign of abnormal and insufficient adaptation of the autonomic nervous system (ANS) and may indicate physiological malfunctioning in some clinical conditions. 7-10 Autonomic dysfunction is common in various disorders that occur in patients with critical conditions, such as multiple organ dysfunction syndrome, sepsis, myocardial infarction, decompensated heart failure, and severe brain injury. [11][12][13][14] Furthermore, depressed parasympathetic activity has been implicated in the pathogenesis of diseases associated with excessive inflammatory responses. 15 These changes may be clarified by the inflammatory reflex theory -i.e., activation of the vagus nerve and consequently reduced inflammatory responses in septic and aseptic inflammation models. 16 Reduced HRV may be an independent predictive factor of 30-day all-cause mortality in intensive care unit (ICU) patients. 15

Study design
This cross-sectional analytical study was conducted between

RESULTS
The study comprised 82 individuals divided into two groups 18 (39.1%) were female. The groups were homogeneous, and the sample characterization data are presented in Table 1.
No difference in vital signs was observed between the two groups, except for SpO 2 , which was significantly lower in the COVID(+) than COVID(-) group (95.5% versus 97.0%; P = 0.035).
Nonetheless, both values were normal. Among the ventilatory parameters, the FiO 2 used was higher in the COVID(+) group  Table 2).
The indices in the frequency domain that showed a significant difference in the COVID(+) group were subjected to linear regression to analyze possible confounding factors, and a weak positive correlation was observed between LF/HF and days spent in the ICU (P = 0.01; r2 = 0.14) (Figure 1).

DISCUSSION
This study observed changes in cardiac autonomic control interactions in ICU patients receiving invasive MV, whose RT-PCR test was positive for COVID-19. These patients had lower vagal activity and sympathetic hyperactivity in the frequency domain than non-infected patients.
Strong hyperimmune reactions due to COVID-19 produce a large adrenergic release, which is mainly modulated by the sympathetic nervous system. 2,3 Consequently, a modulated compensatory response occurs via the cholinergic anti-inflammatory pathway of the parasympathetic nervous system. 4,5 Thus, the ANS participates in regulating this inflammatory reflex, and its balance is essential for maintaining physiological homeostasis. 11,12 The vagus nerve is an important neuroimmunomodulator of the anti-inflammatory pathway. 22 When working properly, this regulatory anti-inflammatory response limits viral infection dissemination and is vital for controlling and treating COVID-19.
However, when vagal activity is reduced, the inflammatory response may get out of control, contributing to hyperinflammation -the so-called cytokine storm. 23      inverse correlation between LF and LF/HF and C-reactive protein levels. 25 Previous studies examining the role of HRV in COVID-19 found that a reduction in HRV preceded an increase in inflammatory markers. However, these studies used small sample sizes and did not statistically adjust for important confounders such as age and comorbidities. 27,28 One of the first studies examining the potential role of HRV as HRV reductions have been associated with disease severity and increased mortality in ICU patients. 11 Papaioannou et al.
observed that less clinically stable patients have a lower LF/HF ratio and decreased overall variance; they also pointed out that patients recovered from such reduction as they improved and were discharged from the ICU. 25 Likewise, LF/HF values in the present study were lower in both groups, demonstrating that the sample patients were in a severe condition.
The average length of stay for the COVID(+) group was 9 days. It is known that in the first two weeks of infection, the defense mechanisms are deregulated and the severity of the disease increases as the cytokine storm is activated. 4 the first symptoms and death was a mean 9 (range, 5-13) days. 33 Thus, the weak positive correlation between LF/HF and days spent in the ICU observed in the COVID(+) group may be related to the greater dysregulation of the anti-inflammatory reflex observed in the initial 10 days of the disease.

Limitations
This study has some limitations. The pandemic period and difficulty in obtaining an interruption-free HRV record due to elec-