Background
Community-acquired pneumonia (CAP) represents the first cause of death for infectious diseases in western countries, with a mortality rate that has remained stable since the introduction of antibiotics in the 1940s [
1]. During the past years, several efforts have been focused on exploring new approaches and testing strategies to reduce mortality by reducing complications related to pneumonia. Recent evidence has particularly shown that cardiovascular events (CVE) might occur in up to 30 % of hospitalized patients with CAP leading to an increase short and long-term mortality [
2‐
5]. A better understanding of the physiopathological pathways sustaining the association between CAP and CVE is still needed in order to target interventions to improve patients’ outcomes.
It has been hypothesized that an alteration of cardiac autonomic control (CAC), as assessed by heart rate variability (HRV), may play a key role among the complex interaction of events that may lead to the occurrence of CVE during CAP [
4‐
8]. This alteration is characterized by a reduction of total variability and an altered sympatho-vagal balance. Previous literature reported an alteration of CAC in several cardiovascular diseases, including congestive heart failure and myocardial infarction, and it has shown that it is strongly associated with poor outcomes [
9‐
11]. The impact of infections on CAC has been evaluated so far only in patients with severe sepsis who show a lower total HRV and impaired sympathetic modulation [
12]. No previous experiences have been designed to study CAC in a specific population of patients with CAP.
The aim of this study was to evaluate CAC in hospitalized patients with CAP and particularly the impact of possible autonomic alterations on both disease severity on admission and early clinical outcomes.
Discussion
This pilot study demonstrates that cardiac autonomic profile of CAP patients is characterized by a lower total variability and loss of sympathetic rhythmical component with predominant respiratory modulation in comparison to controls. Among patients with severe CAP, cardiac autonomic control shows a lower sympathetic modulation and predominant parasympathetic oscillatory rhythm. Finally, after adjustment for the severity of the disease on admission, CAP patients showing a delay in reaching clinical stability, had lower total power and lower sympathetic modulation on hospital admission.
Our data seem to be in line with previous experiences performed in septic patients. During sepsis, a lower total variability, which represents the capability of the cardiovascular system of responding to external perturbations and impaired sympathetic modulation characterizes CAC and the lower the total variability, the more severe is sepsis [
12,
24]. So far, no data have been reported on the evaluation of the cardiac autonomic control in a homogenous population of hospitalized patients with pneumonia. A common expectation would be an increase of sympathetic activity, as previously hypothesized [
8]. However, we found a loss of rhythmical properties of sympathetic discharge and a predominant respiratory modulation in CAP patients. These finding suggest that the events that occur during pneumonia, including a systemic inflammatory response and impairment in gas exchange, could affect the central rhythmic organization of autonomic control. This is similar to what occurs in patients with congestive heart failure (CHF). Studies in patients with CHF evaluating muscle sympathetic nerve activity (MSNA) showed a high sympathetic activity, positively correlated with the severity of the disease, but a lower total variability and sympathetic oscillation, with a relative predominance of the parasympathetic oscillation [
25]. In CHF patients, this occurs when central and peripheral reflexes, mediated by respiration, baroreceptors and chemoreceptors, loose their ability to rhythmically inhibits central sympathetic activity. Therefore, a parallel decrease in LFnu modulation and total variability is a marker of an increased sympathetic activity associated with the loss of its physiological rhythmical properties, and this is associated with a poorer prognosis [
11,
19,
25].
Inflammatory reflex, through the activation of
vagus nerve, controls the immune response to injury [
26]. Alterations of CAC we found in CAP patients could be seen as the final consequence of a complex interaction between systemic inflammation, that could trigger the inflammatory reflex, and hypoxia, that could trigger central and peripheral autonomic reflexes. Autonomic alterations in this population, characterized by a lower level of total variability and a reduction of LF components, could be partially related to the activation of the above mentioned excitatory different reflexes and these results were more evident in patients with severe CAP, compared to those without severe CAP on admission. In summary, CAP patients with a more severe disease on admission seem to show a loss of rhythmic sympathetic oscillation, with a predominant respiratory oscillation characterizing HRV. These findings were consistent across different evaluations of the severity of the disease on admission.
Finally, when we evaluated an early clinical outcome in our population, we found that total power and 0V% were significantly lower among those with a delay in reaching clinical stability, as confirmed in the multivariable approach. We already know from previous literature that a reduction of total power is strongly associated with poor outcomes in several cardiovascular diseases, including myocardial infarction, CHF, and major arrhythmias [
10,
11]. Few other studies identified HRV as prognostic factor in patients with sepsis. A reduction of total variability and LF and higher HF are associated with poor in-hospital outcome and poor short-term prognosis in septic patients [
12,
24,
27,
28].
Our results might have important clinical implications in light of the occurrence of cardiovascular events in up to 30 % of hospitalized patients with CAP with an increase in both short and long-term mortality [
2]. Previous literature has showed that a deregulation of the sympatho-vagal balance increases cardiovascular risk in cardiac patients [
9‐
11]. Our results provide important physiopathological elements, which can be used for the risk stratification of CAP patients. We could speculate that a deregulation of CAC characterized by a reduction of total variability and loss of sympathetic rhythmical property could be related and/or predict the onset of cardiovascular events and mortality in CAP patients. Now, we cannot speculate that a specific treatment directed towards alteration of CAC might help in reducing cardiovascular complications in CAP patients. We suggest future ad hoc clinical studies to correlate the autonomic dysfunction to cardiovascular morbidity and mortality in CAP patients as well as interventional studies to restore sympathetic rhythmical discharge are required.
One of the major limitations of our study was the absence of a direct evaluation of the sympathetic activity using MSNA. However, MSNA is an invasive technique that is difficult to apply in acute patients. We decided to evaluate CAC only on admission, while other evaluations during hospitalization or even after hospital discharge could provide information during both treatment and recovery from pneumonia. Biochemical assessments of serum cytokines levels or other markers of systemic inflammation have not been performed. The analysis and interpretation of HRV in CAP patients may be challenging because when breathing is more vigorous, respiratory fluctuations may dominate HRV. Paced breathing could have added additional information in our study. We included CAP patients independently from the presence of cardiovascular comorbidity in order to evaluate a population close to real life. Among them, some were on beta-blockers that might affect CAC. Due to small sample size, we were not able to correct for this important confounder, while we suggest future studies including a larger sample of CAP patients to take into account not only beta-blockers but also other drugs, which could possibly affect CAC. In addition, a sub-group analysis on patients with bacteremia would have been very important, but unfortunately, we had only 3 patients with bacteremia, and we were not able to perform any specific analysis on them. Finally, the small sample size allowed us to investigate neither a specific population of bacteraemic patients nor a possible relationship between CAC and pathogens causing pneumonia.
On the other hand, this was the first pilot experience evaluating the cardiovascular autonomic modulation in hospitalized patients with CAP according to both different markers of the severity of the diseases and early clinical outcome. All the findings were consistent through the evaluation of the severity of the disease on admission and clinical outcomes and our results were strengthened by the use of two different tools, spectral and symbolic analysis, able to provide complementary information on CAC.