Short communicationPre-surgical heart-rate variability strongly predicts less post-operative pain in patients with epilepsy
Introduction
Though surgery can be life-saving, and helps to cure or minimize diseases, it is also frequently associated with post-operative pain [1]. Clinicians know that most patients undergoing surgery will suffer from post-operative pain, a fact confirmed by many studies worldwide [[2], [3], [4], [5], [6], [7], [8], [9]]. For some surgeries however, pain is underdiagnosed. For example, after craniotomy, post-operative pain may be underdiagnosed, partly because of the common idea that people have no sensation in brain tissue. Yet, 87% of patients experience pain during the first 24 h after craniotomy [10]. More than just being a temporary issue for patient comfort and quality of life, post-operative pain has multiple consequences for health and recovery [11].
Post-operative pain after a craniotomy may be examined in patients who suffer from epilepsy. In fact, epilepsy is one of the most common chronic neurological disorders: More than 50 million patients suffer from active epilepsy, of whom 10 million could be treated with surgery [12]. The latter mostly struggle with drug-resistant epilepsy (DRE). The International League Against Epilepsy (ILAE) defined DRE as failure of adequate trials of two appropriate, well tolerated, antiepileptic medications, to achieve sustained seizure freedom [13]. For those patients, surgery may be one of the only manners for obtaining some relief. Indeed, surgery achieves complete seizure freedom or a meaningful reduction in seizures, risk of seizure associated injury and reduction in medication burden [14]. However, surgery implies craniotomy, and as noted above, post-operative pain as well, which may lead to complications.
Identification of risk factors and predictors of post-operative pain remains unclear despite an increasing interest around this field of research. It appears that although a considerable proportion of patients are anxious prior to surgery, the predictive role of anxiety in post-operative pain is not established because results from studies are inconsistent [15]. Such inconsistency is found with other predictors, for example age may be a predictor of post-operative pain after mastectomy [16] or not [17]. Finally, the only factor that seems to be consistently associated with post-operative pain in the literature is a surgical factor: the type of surgery itself [18,19]. However, as patients have multiple factors which may predict pain such as age, gender, body mass index (BMI), pre-surgical anxiety, depression and social support [16,17,[20], [21], [22]], it may be helpful to find an objective indicator which is related to the whole “patient factor”, in other words a factor associated with both psychosocial and physiological predictors.
Taking an integrative neuroimmunological approach, we focused here on vagal nerve activity due to its role in pain modulation. The vagal nerve is the 10th cranial nerve, which innervates visceral organs and modulates responses of multiple body systems (hormonal, cardiac, immune) [23]. In fact, several potential processes and variables which contribute to pain, also correlate with vagal nerve activity such as age and anxiety [24,25]. De Couck et al. developed an integrative model of vagal nerve pain modulation, which highlights the protective involvement of the vagal nerve in several pain related mechanisms: Inflammation, excessive sympathetic activity, oxidative stress, brain pain modulation and opioid responses [26]. The vagus inhibits oxidative stress and inflammation e.g., 27, inhibits sympathetic activity as the main branch of the parasympathetic nervous system, and it modulates certain aspects of the brain pain matrix [26]. A meta-analysis of 51 studies found that heart-rate variability (HRV), the indirect index of vagal nerve activity, is inversely related to pain [13]. Though HRV reflects levels of efferent vagal input to the heart, due to the very strong correlation between HRV and actual vagal nerve activity of r = 0.88 [36], we refer here to HRV as the indirect index of vagal activity per-see. Concerning the clinical relevance of the vagus to pain, a randomised controlled trial showed that non-invasive vagal nerve stimulation reduced headaches [34]. Based on these converging findings, we thus hypothesized that pre-surgical vagal nerve activity, indexed by HRV, would be negatively correlated with post-operative pain, independent of confounders. While we consider the vagal index of HRV as an integrative biomarker of physiological and psychological correlates of pain, these were not fully measured in the present study, and we mainly aimed to examine the predictive role of HRV in post-operative pain, independent of basic background (e.g., age) and surgical confounders.
Thus, the purpose of this study was to explore whether vagal nerve activity, indirectly indexed by HRV, may predict post-operative pain after stereotactic surgery, independent of other background and surgical predictors and confounders. Such prediction may help to identify in advance patients who may suffer later, in order to prevent their pain, anticipate needed treatments and reduce associated post-operative complications.
Section snippets
Ethical approval
This research was conducted in accordance with the principles of the Helsinki declaration.
Study setting
This study was part of a larger prospective study examining a device for measuring HRV in relation to peri-operative outcomes including post-operative pain. Patients' levels of vagal nerve activity, indexed by HRV, were measured before they underwent stereotactic surgery. Then, patients' post-operative pain was assessed, as described below.
Participants
This study included patients with DRE who were undergoing
General sample characteristics
Thirty patients were eligible for this study. Approximately half the sample were women, and just over half the sample was operated on the left side of the brain. Patients' mean age was approximately 27 years, their mean BMI was below obese, and their mean SDNN levels were approaching 50 msec. Patients' mean post-operative pain levels were clinically significant, on a 1–10 scale. Over three-quarters of the sample (77%) of patients had significant post-operative pain (> 3) at least once during
Discussion
This study demonstrated that pre-surgical vagal nerve activity, indirectly indexed by HRV, was a profound and independent predictor of post-operative pain, among patients with epilepsy undergoing brain surgery. More specifically, the purely vagal parameter of pre-surgical HF-HRV significantly, and surprisingly strongly and inversely correlated with patients' post-operative pain, independent of patients' age, surgical duration, and several surgical anaesthetics. In a hierarchical multiple
Acknowledgements
Prof Gidron thanks the French National Cancer Institute for funding his initial work during the present study, as Chair of psycho-oncology.
Conflict of interest and sources of funding
The authors report no conflict of interest. Regarding funding, Pr. Y. Gidron and Ms. L. Caton had the financial support of the French National Institute Against Cancer (INCA). This project received material support from BioTekna (Venice, Italy) which provided the PPG Stress Flow used for the heart rate variability assessment.
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