Effect of Transcutaneous Electrical Auricular Stimulation of the Vagus Nerve in Kidney Transplant Recipients

Vagus Nerve Stimulation

Vagus Nerve, Stimulation, Immune System

Kidney transplantation entails the implantation of a live or deceased organ into a recipient. As a result of this event, there is an inflammatory response in the recipient elicited by the transplanted organ. At the present time, immunosuppressive treatments are routinely used to avoid rejection of the transplanted organ. Although effective in this goal, there is currently an unmet need to develop new strategies to control the innate inflammatory responses and to reduce the injury caused to the organs being transplanted. The investigators propose a novel approach to the management of this inflammatory response. The investigators will explore the cholinergic anti-inflammatory pathway as a potential target, a pathway first characterized in the basic science laboratories of the Feinstein Institute for Medical Research. In short, the vagus nerve activates the splenic nerve which activates choline acetyltransferase expressing T cells in the spleen. Stimulation of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) on macrophages by acetylcholine reduces production of multiple pro-inflammatory cytokines. Currently, vagus nerve stimulation is used to treat a number of human diseases, including epilepsy, depression and migraine headaches. Many of these treatments activate the vagus nerve non-invasively by stimulating a branch of the vagus that innervates the ear. In this study, the investigators will stimulate this branch of the vagus nerve, and look for changes in inflammatory markers in the blood of kidney transplant recipients of both live and deceased donors. Successful completion of this study will allow for future studies in organ transplant recipients.

Intervention and comparators: Patients will receive transcutaneous stimulation of the auricular branch of the left vagus nerve for 5 minutes in the OR already under anesthesia. Subjects will be blinded to their treatment arm. The device to be used will include a handheld electrical pulse generator and a pair of electrodes to be placed at the ear for stimulation. The specific target at the ear will be the auricular branch of the vagus nerve which innervates the skin overlying the cymba conchae of the ear canal. Anatomical landmarks and cutaneous innervation of the external ear. Three nerves contribute to the cutaneous innervation of the lateral aspect of the ear: the auricular branch of the vagus nerve (ABVN), the auriculotemporal nerve (ATN) and the great auricular nerve (GAN). There is a variable degree of overlap in the distribution of these cutaneous nerves. Electrodes will be placed near/at the entrance to the canal of the ear to provide stimulation to the auricular branch. The handheld electrical pulse generator (e.g. Roscoe Medical, TENS 7000) will be programmed to deliver stimulation pulses to the electrodes. The electrodes will be made of conductive material facilitating trans-cutaneous electrical stimulation. All subjects will be told that they may or may not sense the stimulation. Attempts to diminish pain associated with blood drawing will be made by performing whenever possible the phlebotomy coincident with other blood drawing requirements or while the patient is under anesthesia. The investigators will administer transcutaneous electrical stimulation to the left ears for 5 minutes. Subjects receiving auricular stimulation will receive stimulation using the following parameters: 0.300 milliseconds (msec) stimulus peaks at a frequency of 30 Hz for five (5) minutes, with peak current pulse amplitude set to 1.5 milliamps (mA). Research subjects will receive hemodynamic monitoring and heart rate variability monitoring while undergoing vagal stimulation as a routine part of the underlying care for organ procurement or anesthesia management. Transcutaneous electrical stimulation Electrical auricular stimulation is accomplished using a Roscoe Medical TENS 7000 that delivers a programmable electrical current density, frequency, and pulse width. The TENS 7000 will be connected to ear clip (or hand held) electrodes to transcutaneously stimulate the cymba conchae of the ear to activate the auricular branch of the vagus nerve (diagram above), also known as Arnold's nerve, which provides sensory innervation to the skin surrounding the ear canal. Through a neural reflex arc, activation of this sensory nerve sends a neural signal to the brainstem that then activates the efferent vagus nerve through the nucleus of the solitary tract (NTS). This is a well-described and clinically accepted neuromodulatory pathway, as transcutaneous electrical auricular stimulation has been studied to treat seizures, similarly to how invasive electrical vagus nerve stimulation has been approved by the FDA for the past two decades for the same indication. Currently, transcutaneous electrical auricular stimulation is approved in Europe for the treatment of seizures. The scientific basis for these specific choices comes from more than 10 years of experience performing experimental vagus nerve stimulation in animals to control bleeding at The Feinstein Institute for Medical Research. The frequency of stimulus peaks will be 30 Hz. The pulse width of the individual stimulus peaks will be 0.300 milliseconds (msec). The total duration of stimulation will be five (5) minutes. For the remaining stimulation parameter, which is the peak current pulse amplitude, the investigators will use 1.5 milliamps (mA). These stimulation parameters are very similar to parameters previously demonstrated to be safe in two separate tinnitus studies (6, 7). A portable, battery-powered oscilloscope will be used to confirm peak current. Safety procedures Recent assessments of cardiac safety following transcutaneous electrical stimulation of the auricular branch of the vagus nerve have revealed no indication of arrhythmic effects of tVNS (6, 7). In the exceedingly rare instance that a research subject develops a symptomatic bradyarrhythmia, qualified personnel anesthesiologists/surgeons/residents/CRNA) will be immediately available to administer any therapies (intravenous fluid, anti-arrhythmic medications, cardioversion) to treat the bradyarrhythmia and its associated symptoms.

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