Intraoperative Neuromonitoring of Pelvic Autonomous Nerve Plexus During Total Mesorectal Excision
Phase: NA
Conditions: Rectal Neoplasms
Sponsor: Larissa University Hospital

COVER PAGE
Research Protocol
OFFICIAL  TITLE:  Intraoperative  neuromonitoring  of  pelvic 
autonomous nerve plexus during total mesorectal excision
BRIEF TITLE: Intraoperative neuromonitoring during TME
UNIQUE PROTOCOL ID: PelIONM
DOCUMENT DATE: 29 June 2021 
Principal Investigator:
Konstantinos Perivoliotis, MD
Telephone: 00302413501000
Email: kperi19@gmail.com
Sub-Investigators:
Anastasios Manolakis
Michael Samarinas
Aikaterini Tsiogga
Study Director
Konstantinos Tepetes, Professor of General Surgery
Telephone: 00302413502804
Email: tepetesk@gmail.com
Department of Surgery
University Hospital of Larissa
Mezourlo 41110 Larissa
Greece
1. Introduction

1.1 Literature Review
The introduction of Total Mesorectal Excision (TME) resulted to the improvement of the overall 
survival and local recurrence rates of rectal cancer patients [1]. However, the associated urogenital 
and anorectal functional deficit has a significant effect on the postoperative quality of life of the 
patient [2]. More specifically, the postoperative rates of urogenital and sexual dysfunction that have 
been reported in the various series, are estimated at the levels of 70% and 90%, respectively. 
Additionally, TME is associated with the development of the low anterior syndrome (LARS). 
LARS is characterized by the onset of fecal incontinence, due to injury in the autonomic nerve 
plexuses that innervate the internal anal sphincter (IAS); who in turn is responsible for the 52-85% 
anal resting tone [2]. According to a study by Wallner et al., 38.8% and 33.7% of patients with 
normal preoperative urogenital function, developed postoperative stool and urine incontinence, 
respectively [3].
It becomes apparent that the incidence rates of these complications vary between the various series, 
mainly due to their small sample size, the lack of comparative data, the short follow up period, the 
use of non-validated tools and their retrospective design  [2]. Several predictive factors of these 
adverse events have been suggested in the literature, including old age, tumors located less than 12 
cm from the anal verge, preoperative radiotherapy and injury to the pelvic autonomous nerves [2]. 
The clinical and functional anatomy of the pelvis are quite complex. The inferior hypogastric plexus 
is formed by the parasympathetic pelvic nerves, deriving from the I2-I4 and the sympathetic 
hypogastric nerve. It is a neural anatomic structure that carries organ-specific nerve fibers  [3]. 
Visual identification of the plexus is quite difficult, for various reasons, including the complexity of 
the nerve distribution, the narrow pelvis, the voluminous mesorectum, obesity, previous pelvic 
operations, neoadjuvant radiotherapy, locally advanced tumors, intraoperative bleeding and the 
extensive use of diathermy [4]. According to the current literature, identification of the autonomous 
pelvic plexus is achievable in 72% of cases, whereas partial localization is possible only in 10.7% 
of patients [5]. 
Theoretically, intraoperative neuromonitoring of the pelvic autonomous nerves (pIONM), could 
quantify intraoperative nerve injuries, while in parallel, contribute to the improvement of the 
patients’  postoperative  quality  of  life  [6].  Several  pIONM  techniques  have  been  described, 
including intra-urethral and intra-vesical pressure measurements  [1]. However, it was found that 
intermittent neuromonitoring objectifies the macroscopic integrity assessment of the sacral plexus. 
Recently, a promising technique, based on the simultaneous electromyography of the IAS and 
bladder manometry was developed, with encouraging results. During pIONM, the surgeon delivers 
electric stimuli to the autonomic nerve structures through a hand-held stimulator [7]. At the same 
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time,  electromyogram  changes  of  the  IAS  and  the  external  anal  sphincter  (EAS),  alongside 
intravesical pressure gradients are assessed [7].   
Intraoperative neuromonitoring has been evaluated in several experimental studies. In the study by 
Kneist et al., intraoperative simulation of the inferior hypogastric plexus with a bipolar stimulator 
resulted to the appearance of a measurable and repeatable electromyographic signal from the IAS 
[6]. 
Simultaneous signal processing from the IAS and urinary bladder, improves the, overall, diagnostic 
accuracy of these techniques [8]. Stabilization of the electrodes outside the surgical field, has been, 
also, suggested by some researchers [7, 9]. Additionally, experimental studies evaluated the role of 
pIONM in the minimal invasive TME [10]. 
Moreover, the effectiveness of this technique has been a research subject in multiple clinical trials. 
In the study by Kauff et al., where 85 patients underwent TME, after logistic regression, no use of 
pIONM  and  neoadjuvant  radiotherapy,  were  identified  as  independent  prognostic  factors  of 
postoperative urogenital deficit [2]. Furthermore, the use of pIONM, was associated with a 100% 
sensitivity and a 96% specificity for the postoperative development of urogenital and anorectal 
functional complications [11].
The application of pIONM has been also suggested in the laparoscopic and robotic TME, using 
specially designed stimulators [12–14]. In the study by Zhou et al., preservation of the plexus was 
achieved in 51.7% of patients submitted to a laparoscopic low anterior resection for rectal cancer. 
During  one  year  follow-up,  patients  receiving  pIONM,  displayed  a  superiority  in  terms  of 
postoperative urogenital function, as assessed by the IIEF, IPSS and FSFI questionnaires [15].
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2.  Objective
2.1 Study Aim 
The purpose of this research protocol is the evaluation of the improvement of the anorectal and 
urogenital urinary function, alongside the postoperative quality of life after the application of 
pIONM in patients submitted to TME for rectal cancer. 
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3. Materials and Methods
3.1 Study Sample
The sample of the present study will consist of males and females, 18-90 years old. 
3.2 Pathology
This study will include rectal cancer patients, who will be submitted to TME, regardless of their 
neoadjuvant therapy status
3.3 Inclusion/Exclusion Criteria
The following inclusion criteria will be considered:

Histologically confirmed rectal cancer

Surgical resection with TME

<90 years old

Signed informed consent
The following exclusion criteria will be considered:

Emergency operation

Presence of pacemaker

Partial mesorectal excision

Sepsis or systematic infection

Physical or mental impairment

Pregnancy or nursing

Insufficient preoperative data for the urogenital/ anorectal function

Lack of compliance with the research process
3.4 Interventions
All patients will be submitted to a low anterior resection, depending on the location of the tumor. 
The operations will be performed in an open or laparoscopic approach. TME will be completed by 
the same surgical team, with an adequate experience in colorectal and pelvic operations.
Preservation of the autonomous pelvic nerve plexus will include identification and mapping of the 
superior hypogastric plexus, hypogastric nerves, inferior hypogastric plexus, and pelvic nerves. To 
protect the superior hypogastric plexus, the inferior mesenteric artery will be ligated 1.5cm distal to 
its protrusion. The inferior hypogastric plexus above the aorta, alongside its lateral branches, will be 
5

identified and preserved through sharp dissection of the lateral parietal pelvic fascia. Moreover, 
careful sharp dissection of the Denonvillier fascia will be, also, performed [16].  
3.5 Experimental Arms
This study will include two arms. In the first arm, pIONM will be introduced, for the localization 
and preservation of the pelvic nerve structures. In the second arm, though, no pIONM will be 
applied. 
For the implementation of pIONM, a special device, that allows simultaneous monitoring of 
sphincter  signals  and  bladder  manometry,  will  be  introduced.  This  device  will  employ  the 
placement of a bipolar electrode in the internal and external anal sphincter. Moreover, another 
electrode will be placed on the surrounding tissues. For bladder manometry, the catheter will be 
connected to the pressure sensor, and subsequently to the pIONM monitor [17]. Intraoperatively, 
depending on the approach (open or laparoscopic), the respective bipolar stimulator will be used. As 
soon as the stimulator comes in contact with nerve tissue, an audible signal will be produced. The 
successful nerve stimulation and the increased activity of the respective muscle groups will be, 
automatically detected and recorded [2].
Prior to the initiation of pIONM, urinary bladder will be drained and filled with 200 ml R/L. The 
pIONM  parameters  will  be  the  following:  1-25  mA  current,  30  Hz  frequency  and  200  μs 
monophasic pulses [11]. 
3.6 Anesthesia
All patients will receive general anesthesia, prior to the initiation of the surgical procedure. 
3.7 Primary Endpoint

Change in the quality of life of the patient at 3 months postoperatively, based on the SF-36 
questionnaire. Change in the quality of life of the patient, at 3 months postoperatively, 
compared to the respective preoperative measurements, based on the Short Form 36 (SF-36) 
questionnaire [Time Frame: Preoperatively, 3 months postoperatively]. SF-36: Short Form 
Survey. Minimum Value: 0. Maximum Value: 100. Higher scores indicate a better outcome
3.8 Secondary Endpoints

Operative time. The total operative time will be recorded. Measurement unit: minutes [Time 
Frame: Intraoperative period]
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
Intraoperative  bleeding.  The  total  intraoperative  blood  loss  volume  will  be  recorded. 
Measurement unit: mL [Time Frame: Intraoperative period]

Postoperative discharge time. Postoperative time that the patient can be safely discharged. 
Measurement  unit:  hours.  The  patient  will  be  discharged,  when  it  is  ensured  that  is 
medically safe to be released. In particular, as the exit time of the patient, will be regarded 
the time that the patient will fulfil the Clinical Discharge Criteria. More specifically, the 
patient  should  meet  the  following:  steady  vital  signs, be  oriented,  without  nausea  or 
vomiting,  mobilized  with  a  steady  gait,  without  a  significant  bleeding  [Time  Frame: 
Maximum time frame 15 days postoperatively]

Postoperative complications. Occurrence of postoperative complications (based on Clavien 
Dindo classification [18]). If such an episode occurs, then it will be defined as=1 'YES' If 
such an episode does not occur, then it will be defined as=0 'NO' [Time Frame: 1 month 
postoperatively]

Negative resection margin. Occurrence of negative resection margin. If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be 
defined as=0 'NO' [Time Frame: 1 month postoperatively]

Local recurrence. Occurrence of local recurrence. If such an episode occurs, then it will be 
defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' 
[Time Frame: 1 year postoperatively]

Bladder  capacity.  Urodynamic  assessment  [19].  Evaluation  of  bladder  capacity. 
Measurement unit: ml [Time Frame: Preoperatively and 2 months postoperatively]

Bladder  compliance.  Urodynamic  assessment  [19].  Evaluation  of  bladder  compliance. 
Measurement unit: ml/cm H2O [Time Frame: Preoperatively and 2 months postoperatively]

Detrusor pressure at maximum flow. Urodynamic assessment [19]. Evaluation of detrusor 
pressure at maximum flow. Measurement unit: cm H2O [Time Frame: Preoperatively and 2 
months postoperatively]

Maximum urinary flow rate. Urodynamic assessment [19]. Evaluation of maximum urinary 
flow  rate.  Measurement  unit:  ml/s  [Time  Frame:  Preoperatively  and  2  months 
postoperatively]

Voiding volume. Urodynamic assessment [19]. Evaluation of voiding volume. Measurement 
unit: ml [Time Frame: Preoperatively and 2 months postoperatively]

Post-void  residual.  Urodynamic  assessment  [19].  Evaluation  of  post-void  residual. 
Measurement unit: ml [Time Frame: Preoperatively and 2 months postoperatively]
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
Anal canal resting phase pressure. HR-ARM assessment. Evaluation of anal canal resting 
phase pressure. Measurement unit: mmHg [Time Frame: Preoperatively and 2 months 
postoperatively]

Sphincter  zone  length.  HR-ARM  assessment.  Evaluation  of  sphincter  zone  length. 
Measurement unit: cm [Time Frame: Preoperatively and 2 months postoperatively]

Short squeeze test. HR-ARM assessment. Evaluation of short squeeze (5sec) pressure. 
Measurement unit: mmHg [Time Frame: Preoperatively and 2 months postoperatively]

Long squeeze test. HR-ARM assessment. Evaluation of long squeeze (30sec) pressure. 
Measurement unit: mmHg [Time Frame: Preoperatively and 2 months postoperatively]

Cough test. HR-ARM assessment. Evaluation of cough test (0 and 50 ml). If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be 
defined as=0 'NO'[Time Frame: Preoperatively and 2 months postoperatively]

Push test. HR-ARM assessment. Evaluation of push test (0 and 50 ml). If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be 
defined as=0 'NO' [Time Frame: Preoperatively and 2 months postoperatively]

RAIR test. HR-ARM assessment. Evaluation of rectoanal inhibitory reflex test (20 and 50 
ml). If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not 
occur,  then  it  will be defined  as=0 'NO'  [Time  Frame:  Preoperatively  and  2 months 
postoperatively]

Difference in the quality of life of the patient, based on the SF-36 questionnaire  [20]. 
Difference in the quality of life of the patient, at 6, 12, 24 months postoperatively, compared 
to  the  respective  preoperative  measurements,  based  on  the  Short  Form  36  (SF-36) 
questionnaire [Time Frame: Preoperatively, 6, 12, 24 months postoperatively] SF-36: Short 
Form Survey. Minimum Value: 0. Maximum Value: 100. Higher scores indicate a better 
outcome

Difference in the erectile function of the patient, based on the IIEF questionnaire [21, 22]. 
Difference in the erectile function of the patient, at 3, 6, 12, 24 months postoperatively, 
compared to the respective preoperative measurements, based on the International Index of 
Erectile Function (IIEF) questionnaire [Time Frame: Preoperatively, 3, 6, 12, 24 months 
postoperatively]  IIEF:  International  Index  of  Erectile  Function.  Minimum  Value:  0. 
Maximum Value: 5. Higher scores indicate a better outcome.

Difference in the sexual function of the patient, based on the FSFI questionnaire [23, 24]. 
Difference in the sexual function of the patient, at 3, 6, 12, 24 months postoperatively, 
compared  to  the  respective  preoperative  measurements,  based  on  the  Female  Sexual 
8

Function Index (FSFI) questionnaire [Time Frame: Preoperatively, 3, 6, 12, 24 months 
postoperatively]  FSFI:  Female  Sexual  Function  Index.  Minimum  Value:  2.  Maximum 
Value: 36. Higher scores indicate a better outcome.

Difference in the prostate symptoms of the patient, based on the IPSS questionnaire [25, 26]. 
Difference in the prostate symptoms of the patient, at 3, 6, 12, 24 months postoperatively, 
compared to the respective preoperative measurements, based on the International Prostate 
Symptom Score (IPSS) questionnaire [Time Frame: Preoperatively, 3, 6, 12, 24 months 
postoperatively]  IPSS:  International  Prostate  Symptom  Score.  Minimum  Value:  0. 
Maximum Value: 35. Higher scores indicate a worse outcome

Difference in the low anterior syndrome symptoms of the patient, based on the LARS 
questionnaire [27, 28]. Difference in the low anterior syndrome symptoms of the patient, at 
3, 6, 12, 24 months postoperatively, compared to the respective preoperative measurements, 
based on the  Low  Anterior  Resection  Syndrome  (LARS) questionnaire  [Time  Frame: 
Preoperatively,  3,  6,  12,  24  months  postoperatively]  LARS:  Low  Anterior  Resection 
Syndrome. Minimum  Value: 0. Maximum  Value: 42. Higher scores  indicate  a worse 
outcome.
3.9 Estimation of Study Sample Size
Sample size estimation was based on the primary endpoint. Based on the current literature, Physical 
Functioning levels at 3 months after low anterior resection, were estimated at 72(26)  [29]. The 
application of pIONM resulted to a significant reduction of urogenital functional deficits (20% 
versus 51%, and 56% versus 90%, respectively) [2].
Therefore, for the design of a comparative study, with alpha=5%, beta=80%, and a 30% anticipated 
increase in PF, the estimated sample in each group is 22 patients. Therefore, the required total 
sample size is 44.
3.10 Randomization
The randomization  of the patients  will be performed using a dedicated  software with a 1:1 
allocation ratio. Furthermore, the allocation group will be concealed with opaque envelopes, who 
will be opened preoperatively upon the entry of the patient into the surgical room.
9

3.11 Blinding
The patient will be blinded regarding the allocation group. Blinding will not exist at the level of the 
surgeon, the anesthesiologist, and the investigator responsible for the data recording. 
3.12 Urodynamic Examination
Urinary bladder function of all patients will be evaluated by urodynamic examination. Urodynamic 
evaluation  will  be  performed  preoperatively  and  at  two  months  postoperatively.  Assessment 
parameters will include bladder capacity (mL), bladder sensation, detrusor activity during bladder 
filling,  bladder  compliance  (mL/cm  H2O),  detrusor  pressure  at  maximum  flow  (cm  H2O), 
maximum urinary flow rate (ml/s), voiding volume (ml) and post-void residual (ml). Urodynamic 
evaluation will be performed according to the International Continence Society Good Urodynamic 
Practices and Terms, by a specialized urologic team in General Hospital of Larissa [19]. 
3.13 Anorectal Manometry
HR-ARM evaluation will be performed in a specialized outpatient office of the Gastroenterology 
Department, in the University Hospital of Larissa. HR-ARM interpretation will be based on the 
International Anorectal Physiology Working Group (IAPWG) guidelines [31]. Two hours prior the 
examination, the patient will receive a fleet enema. Upon arrival, the HR-ARM transducer will be 
prepared and calibrated (Manoscan AR High-resolution catheter, Medtronic, USA). The patient will 
be placed in a lateral position and the catheter will be introduced in the anus. HR-ARM recording 
(Manoscan Acquisition Software, Medtronic, USA) will include the following parameters: anal 
canal resting phase pressures and sphincter zone length, short squeeze test (5 sec x 3), long squeeze 
test (30 sec x 1), cough and push test (0 and 50 ml balloon) and rectoanal inhibitory reflex test 
(RAIR test at 20 and 50 ml). 
3.14 Discharge Criteria
The patient will be discharged when it is ensured that is medically safe to be released. The exit time 
will be regarded as the time that the patient will fulfill the Clinical Discharge Criteria. More 
specifically, the patient should display the following: steady vital signs, fully oriented, without 
nausea or vomiting, mobilized with a steady gait and without a notable bleeding [32].
10

3.15 Follow up
Postoperative  complications  will be evaluated  at one month,  postoperatively.  In parallel,  the 
histopathology  report  and  the  adjuvant  therapy  schedule  will  be  recorded.  At  two  months, 
postoperatively, urogenital, and anorectal functional evaluation will be completed. Additionally, at 
3, 6, 12 and 24 months, the patient will complete quality of life questionnaires (SF36, IIEF, IPSS, 
LARS). Local recurrence will be evaluated at one year.
3.16 Perioperative Treatment
A standardized perioperative treatment protocol will be applied. ERAS protocol will be, also, 
introduced [33]. The patient will receive antibiotic chemoprophylaxis, 60 minutes preoperatively. 
Additionally, mechanical and antibiotic bowel preparation will be administered the previous day. 
Moreover, 6 and 2 hours solid and liquid food fasting, respectively, will be applied. Nasogastric 
tube will be removed postoperatively and will be reinserted only in cases of ileus. A multimodal 
analgesia will be employed, including analgesics (paracetamol, lornoxicam), and spinal or epidural 
analgesia. Opioid administration will be avoided. Nausea and vomiting prophylaxis will be based 
on granisetron 3mg/3ml IV. Mechanical and low molecular weight heparin thromboprophylaxis (28 
postoperative days) will be introduced. A zero-balance fluid approach will be employed. Fluid 
losses will be replenished by crystalloids (Ringer’s lactate). Urinary catheter will be removed at the 
3rd postoperative day. Mobilization will be initiated from the 1st postoperative day. Systematic 
medication and per-os feeding will be started upon recovery of bowel function.
3.17 Study Group
All participating members have years of experience in their field and have, therefore, completed the 
learning curve for the required techniques. Data collection and recording will be carried out by an 
independent, third party, researcher.
3.18 Trial
The study will be conducted in the Department of Surgery of University Hospital of Larissa in 
collaboration with the Gastroenterology Department of University Hospital of Larissa and the 
Urology Department of General Hospital of Larissa. Patient data will be recorded both in the patient 
charts and in an electronic database. The required laboratory examinations will be defrayed by the 
patient insurance funds.
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