The Effects of Brain Injury on Heart Rate Variability and the Innate Immune Response in Critically Ill Patients

Abstract

Brain injury and its related increased intracranial pressure (ICP) may lead to increased vagus nerve activity and the subsequent suppression of innate immunity via the cholinergic anti-inflammatory pathway. This may explain the observed increased susceptibility to infection in these patients. In the present study, we investigated the association between brain injury, vagus nerve activity, and innate immunity. We determined heart rate variability (HRV) as a measure of vagus nerve activity, plasma cytokines, and cytokine production of ex vivo lipopolysaccharide-stimulated whole blood in the first 4 days of admission to the neurological intensive care unit (ICU) in 34 patients with various forms of brain damage. HRV, immune parameters, and the correlations between these measures were analyzed in the entire group of patients and in subgroups of patients with conditions associated with high (intracranial hemorrhage [ICH]) and normal ICP (subarachnoid hemorrhage [SAH] with an extraventricular drain alleviating ICP). Healthy volunteers were used for comparison. HRV total spectral power and ex vivo-stimulated cytokine production were severely depressed in patients compared with healthy volunteers (p<0.05). Furthermore, HRV analysis showed that normalized units of high-frequency power (HFnu, corresponding with vagus nerve activity) was higher, and the low-frequency:high-frequency ratio (LF:HF, corresponding with sympathovagal balance) was lower in patients compared to healthy volunteers (p<0.05). HFnu correlated inversely with ex vivo-stimulated tumor necrosis factor-α (TNF-α) production (r=-0.22, p=0.025). The most pronounced suppression of ex vivo-stimulated cytokine production was observed in the ICH group. Furthermore, in ICH patients, HFnu correlated strongly with lower plasma TNF-α levels (r=-0.73, p=0.002). Our data suggest that brain injury, and especially conditions associated with increased ICP, is associated with vagus nerve-mediated immune suppression.