Noninvasive vagus nerve stimulation to reduce ileus after major colorectal surgery: early development study

Vagus nerve stimulation has emerged as a plausible intervention to reduce ileus after surgery. An early development study was undertaken with the aim of exploring the feasibility of self‐administered, noninvasive vagus nerve stimulation (nVNS) after major colorectal surgery.


INTRODUC TI ON
Ileus occurs in 10%-20% of patients undergoing elective colorectal surgery [1]. It is a distressing condition characterized by abdominal distension, persistent vomiting and delayed faecal elimination after surgery. For patients, this prolongs the length of hospital stay and increases the risk of serious complications such as pneumonia and venous thromboembolic events [2]. For healthcare systems, it increases costs by up to 71%, particularly those associated with nursing care, laboratory investigations and medications [3]. In light of this, ileus is recognized as a research priority by the Association of Coloproctology of Great Britain and Ireland [4].
The mechanism of ileus is multifactorial, with most evidence pointing towards opioid-and inflammatory-induced dysfunction of intestinal transit [5]. In the last 20 years, a number of interventions to prevent ileus and its sequelae have been explored but few have led to meaningful patient benefit. The most promising have included strategies to rationalize opioid-based analgesia (such as mu-receptor antagonists) and to moderate the postoperative inflammatory response (such as enhanced recovery protocols) [6]. Recently, electrical stimulation of the vagus nerve has been proposed as a new intervention. In preclinical models, vagus nerve stimulation accelerates the recovery of bowel function by activating a cholinergic anti-inflammatory pathway in the gut. This inhibits the expression of proinflammatory mediators by intestinal macrophages, which occurs in response to intestinal handling and leads to dysfunction of intestinal smooth muscle [7,8]. This mechanism has been translated into early human studies, where invasive stimulation during surgery has been shown to reduce markers of systemic inflammation [9]. There are a number of challenges for implementing invasive stimulation, however, including increased operative risk and a limited opportunity to perform stimulation during surgery, so a different approach is required.
Noninvasive vagus nerve stimulation (nVNS) involves electrical stimulation of the vagus nerve at its cervical surface landmark. This may reduce the risk of serious complications such as neurovascular injury and may preclude the need for longer procedures with greater risk. The aim of this study was to explore the safety, treatment compliance and usability of nVNS when self-administered by patients before and after major colorectal surgery.

Ethics and governance
Research ethics approval for the study was obtained from the North

Study design
A parallel-group, double-blinded, randomized controlled trial was undertaken between 1 January 2018 and 31 August 2019. This was an IDEAL Stage 2a development study, focussing on safety and early feasibility [11]. Participants were randomized equally to Sham and Active stimulation groups. There were no changes to the study design apart from an extension to the recruitment end date (31 January 2019 extended to 31 August 2019).

Participants
All potential participants were identified from multidisciplinary team meetings and approached in an outpatient setting. Adults with suspected or confirmed colorectal cancer due to undergo elective, minimally invasive (laparoscopic or robotic) colorectal resection were eligible to take part. The following exclusion criteria applied: inflammatory bowel disease, major cardiac disease (including previous myocardial infraction, congestive heart failure, atrial fibrillation/ flutter, second-or third-order atrioventricular block), cerebrovascular disease (previous transient ischaemic attack or cerebrovascular accident), seizures in the last 5 years, previous vagotomy at any location, preoperative therapeutic radiotherapy, or regular prescription of medication known to mediate the normal physiological immune response (such as disease-modifying antirheumatic drugs).

Study setting
The study was undertaken at a single tertiary referral centre (the John Goligher Colorectal Unit, St James's University Hospital, Leeds, UK). Treatment decisions were made by a multidisciplinary team of surgeons, oncologists and radiologists. Participants underwent surgery within a guideline-compliant enhanced recovery programme [12]. Preoperatively, this includes screening for anaemia, prophylactic antibiotics, prevention of nausea and minimal fasting.
Intraoperatively, it includes principles of physiological normalization and short-acting anaesthesia. Anaesthetic protocols were not

What does this paper add to the literature?
Previous evidence identifies vagus nerve stimulation as a plausible intervention to reduce ileus, but previous approaches were invasive and have unclear applicability to clinical practice. This study explores the safety and early feasibility of noninvasive vagus nerve stimulation when self-administered by patients using a hand-held device.
The results support further investigation of this intervention in an adequately powered randomized trial. standardized for the study. Postoperatively, it includes principles of multimodal analgesia, early oral intake and early mobilization.

Interventions
The nVNS was performed using the GammaCore® device (electroCore Inc.). This is a class IIa, noninvasive device which is CE marked for the treatment of gastric motility disorders. The device delivers an electrical impulse via two stainless steel electrodes mounted on a hand-held apparatus. The intensity of stimulation is self-adjustable and can be titrated to user comfort. Active devices deliver a 5 kHz sine wave burst lasting for 1 ms (five sine waves per 200 μs) repeated every 40 ms (peak voltage 24 V, peak output current 60 mA). Sham devices deliver a low-frequency (0.1 Hz) biphasic direct current impulse (amplitude 0-28 V through 15 kΩ ± 10%) that is designed to be perceptible but subtherapeutic for stimulating the vagus nerve [13]. Participants received training from the investigator prior to use. The procedure involved application of conducting gel, self-adjustment of the stimulation intensity to the maximum tolerated level and placement of the device on the surface landmark of the cervical vagus nerve (carotid pulsation).
Twice daily stimulation was performed for 120 s across the landmarks of both vagus nerves for 5 days prior to surgery and 5 days after.

Outcomes and measures
Safety outcomes included the incidence of complications within 30 days after surgery measured using the Clavien-Dindo scale (minor, grades I-II; major, grades III-V) and the incidence of treatment-related adverse events [14]. Each participant was assigned a single grade corresponding to the highest recorded complication. Early feasibility outcomes included self-reported compliance to the stimulation schedule and device usability measured using the modified System Usability Scale (SUS) [15]. The overall output of the SUS generates an arbitrary score out of 100, where 0-64 is considered 'not acceptable', 65-84 'acceptable', and 85-100 'excellent' (Appendix S1 in the Supporting Information). Clinical outcomes were days until first flatus, stool and tolerance of solid diet. These were expressed individually and then collapsed into composite measures of GI-2 (time to first stool and tolerance of solid diet) and GI-3 (time to first flatus or stool, and tolerance of solid diet), as reported previously [16]. The need for nasogastric tube intubation, parenteral nutrition and postoperative morphine consumption between days 0 and 3 (expressed as oral morphine equivalent values) were explored descriptively.

Randomization and blinding
Participants were randomized equally (1:1) to Sham and Active device groups, stratified by type of surgery (right-sided and left-sided).
An independent statistician generated the randomization list with random permuted blocks. Randomization was performed by a research assistant who was not involved in confirming eligibility or consent. The same assistant prepared devices for allocation to participants by the investigator. Participants and the investigator (outcome assessor) were blinded to the allocation until completion of the study. All devices were identical in appearance, weight, visual feedback and user application.

Sample size and statistics
As an early development study, no formal hypothesis testing across the study groups was planned. A sample of 40 participants was considered sufficient to explore safety and early feasibility in order to justify and provide direction for future research. Data were expressed as means with standard deviation, medians with interquartile ranges

Public involvement
A patient representative joined the study management team to help guide its design and delivery. In particular, their involvement helped to shape the design of patient-facing materials and training activities relating to the device. They continue to be involved in the conduct and interpretation of findings within a wider programme of research.  Table 2.

Device safety
In Treatment-related adverse events were infrequent and nonserious, with a single case of stimulation-site pain recorded in both Sham and Active groups. In both cases, this required no further intervention (Table 3). Note: Data are reported as n (%) or as mean ± standard deviation unless stated otherwise.

TA B L E 1 Participant characteristics
Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index; COPD, chronic obstructive pulmonary disease.
aData are reported as median (interquartile range).

Device compliance
In the feasibility population, compliance with the preoperative stim-

Device usability
In the feasibility population, the median SUS output was 80/100 were minimal and are shown in Figure S1.

Bowel recovery outcomes
In the feasibility population, the most prominent differences  Table 4.

DISCUSS ION
This early development study supports the feasibility of self-  [13,18]. In preclinical studies, it increases intestinal transit and prevents both systematic and intestinal inflammation [19,20]. Interestingly, some evidence suggests that activation of the cholinergic anti-inflammatory pathway (using prucalopride) is more efficacious when done before surgery [21]. This is being explored further in a wider body of research [22] and is why patients performed pre-and postoperative stimulation in the present study.
This study provides constructive data to inform the ongoing translation of nVNS in the setting of major colorectal surgery.
Firstly, overall compliance to the intervention was good but a small decrease was noted on the first and last postoperative days.
It is speculated that the initial decrease may reflect difficulty in self-administering the device immediately after surgery, whilst the latter may reflect a lack of motivation once bowel function has returned. Secondly, the usability of the device was considered acceptable and approached the level considered to be excellent. This is promising in the current population since a number of challenges to self-administration exist in the perioperative period, including drowsiness, reduced mobility and pain. Whilst the current population comprised patients being treated for bowel cancer, it is proposed that these usability findings are generalizable across similar In summary, this early development study supports the safety, compliance and usability of self-administered nVNS after major colorectal surgery. Ongoing work will explore the feasibility of a definitive clinical trial, including considerations of recruitment, blinding, training activities and follow up. Importantly, it will also explore patient perspectives on the treatment schedule and will seek to identify residual barriers to compliance [22]. To support the selection of outcomes in a definitive trial and other similar research, a core outcome set for bowel recovery is under development by an international collaboration of patients and healthcare providers [24]. This will provide an agreed set of outcomes relevant to ileus after major abdominal surgery and will rationalize the variation in outcome reporting identified previously [25]. The role of patients and other stakeholder groups will be essential during this work to ensure that any positive findings are readily implementable in practice.

CO N FLI C T O F I NTE R E S T S
No competing interests. This was an investigator-initiated, industrysupported study. Its design and analysis were performed independently of the industry partner.

AUTH O R CO NTR I B UTI O N S
SJC and DGJ conceptualized the study and its design. MN provided patient and public insight into the design and delivery of the study.
SJC and JAH performed study activities and collected data. TC and NC provided statistical support. NC is the statistical guarantor and DGJ is the overall study guarantor.

DATA AVA I L A B I L I T Y S TAT E M E N T
Proposals for further analyses may be forwarded to the corresponding author. These shall be reviewed by the study team, including a TA B L E 4 Bowel function outcomes n Sham device n trained statistician, and if deemed to be feasible will be performed collaboratively between the authors and proposer.

T WIT TER
Stephen J. Chapman @SJ_Chapman