530190 research-article2014
SRIXXX10.1177/1553350614530190Surgical InnovationSobocki et al
Innovative Technologies
Laparoscopically Implanted System for Stimulation of the Hypogastric Plexus Induces Colonic Motility, Defecation, and Micturition: Experimental Study
Surgical Innovation 2015, Vol. 22(1) 70–76 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1553350614530190 sri.sagepub.com
Jacek Sobocki, MD1, Michal Nowakowski, MD1, Roman M. Herman, MD1, Piotr Wałęga, MD2, Mariusz Frączek, MD3, Ryszard Tuz, BSc4, Tomasz Schwartz, BSc4, and Maciej Murawski, BSc4
Abstract Background. Modulation of the enteric nervous system seems to be promising in several functional colorectal disorders for which targeted, causal treatment methods do not exist. However, sacral nerve stimulation can induce undesirable muscle contraction or paresthesia. Therefore, we have developed a laparoscopic technique for implanting a neural electrode, placed directly over the pelvic autonomic nerve plexus. The aim of this experimental study was to evaluate the effect of stimulating the hypogastric plexus and pelvic nerves on inducing distal colon contraction, defecation, and micturition. Method. A total of 10 white, male healthy pigs (25-30 kg) were subjected to the laparoscopic implantation of the electrode and the stimulator. In the third and fourth weeks postimplantation, the efficacy of the acute and chronic stimulation to induce defecation was evaluated. Results. The average operative time was 105 minutes (85-150 minutes). In all pigs, acute stimulation activated induced defecation, every second day, every time on demand, with an average delay of 139.7 s. Micturition was induced incidentally. Acute or chronic stimulation did not cause any harm, pain, or suffering to the animals. No adverse effects of the stimulation were observed, and no septic complications or macroscopic fibrosis around the electrodes were found on autopsy. Conclusion. Hypogastric plexus stimulation can be a useful and safe option of distal colon contraction, defecation, and micturition. However, the efficacy of the stimulation was observed for a relatively short period of time, and it is not known if it will be sustained for a longer duration. Keywords colorectal surgery, interventional endoscopy, tissue engineering
Introduction There are several functional colorectal disorders defined by and included in Rome III criteria1 for which targeted, causal treatment methods do not exist (ie, irritable bowel syndrome [IBS]-C1, functional bloating-C2, functional constipation-C3, functional diarrhea-C4, unspecified functional bowel disorder-C5, and functional abdominal pain syndrome-D). For instance, the only radical option for intractable colonic inertia is an ablative surgical procedure, which significantly improves symptoms but has important side effects.2 In other cases, only behavioral, dietary, or pharmacological interventions may bring some improvement, but efficiency of the currently known treatment is limited. The enteric nervous system and its extrinsic connection play a significant role in the pathogenesis of symptoms, as suggested by several publications.3-5 Modulation
of this complex system is an intriguing idea and seems to be promising. Sacral nerve stimulation (SNS) was used in the treatment of constipation with some success.6 However, this technique can induce undesirable stimulation (skeletal muscle contraction, paresthesia, etc), and therefore, more specific stimulation of the pelvic plexus seems to be logical and more appropriate. Superficial/transcutaneous lead 1
St Anna Memorial Hospital, Warsaw, Poland Jagiellonian University, Cracow, Poland 3 Medical University of Warsaw, Warsaw, Poland 4 University of Agriculture, Cracow, Poland 2
Corresponding Author: Jacek Sobocki, Department of General, Oncology and Gastrointestinal Surgery, St Anna Memorial Hospital, ul. Żytnia 7/1, 31-408 Cracow, Poland. Email: [email protected]
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Figure 1. Study flow.
placement is related to a higher risk of lead migration (up to 16%)7 and wound problems (up to 7%).8 Therefore, we have developed a laparoscopic technique for implanting a neural electrode, which we have named the “SPIDER procedure” after the shape of the electrode placed over the pelvic autonomic nerve plexus. The aim of the study was to evaluate the effect of stimulating the hypogastric plexus and pelvic nerves on inducing distal colon contraction, defecation, and micturition.
Methods Ethics The ethics of the study were approved by Jagiellonian University First Local Ethical Committee for Experiments on Animals.
Animals The study was conducted on 10 white male healthy pigs (weighing between 25 and 30 kg). Animals were kept in separate cages. Constant temperature, humidity, and 16:8 hour light-dark cycle were sustained. The standard diet was supplied twice a day. Cages were cleaned twice a week. All experimental procedures were performed with the assistance of a technician who fed and cared for the animals. All procedures were designed to avoid immobilization and minimize stress on the animals. Dimensions
of the cages allowed animals to move freely in all directions. Animals were kept under daily supervision of a veterinarian.
Study Flow Before participating in the study, the animals’ health was examined to determine if they were suffering from any disease (Figure 1). Implantation of the electrode and the stimulator was performed on day 0. No procedures were performed during the next 2 weeks of recovery. In the subsequent 2-week period (acute stimulation trials), the stimulator was turned on for 2 minutes every 2 days to induce defecation (bowel stimulation parameters) and subsequently micturition (urinary stimulation parameters). Continuous stimulation (5 s on, 25 s off) was started on the 28th day post–implantation surgery. The aim of this part of the experiment was to assess adverse effects, undesirable stimulation, and risk of electrode displacement. After 6 weeks, the animals were killed humanely, the stimulating system was assessed and explanted, and the pelvis was examined for any pathologies.
Stimulator, Electrodes, Current Parameters, and Programming Protocol Stimulation current was generated by a neurostimulator (model 1097, CCC, Montevideo, Uruguay). It is possible to preprogram the stimulator in a large range of parameters
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Figure 2. Lead construction.
by using a programming wand connected to a PC computer. In accordance with the study protocol, a magnet function was used to turn the stimulation on or off to provide a stress-free environment for the animals. Lead and electrodes were developed based on previous anatomical studies of hypogastric plexus and pelvic nerves (Figure 2). Three electrodes were placed on 3 arms of the lead in a configuration allowing the stimulation of the hypogastric plexus area and the bilateral pelvic nerves. Programming parameters were as follows: amplitude 5 mA, frequency 50 Hz, and pulse width 0.5 ms. Two programs were used: (1) the bowel program used electrodes for predominant plexus stimulation and (2) the urinary bladder program with predominant stimulation of the pelvic nerves.
Anesthesia and Implantation Procedure After an overnight fast, the following protocol was used for the induction of anesthesia: 1 mg atropine intramuscularly, 10 mg ketamine intramuscularly, and 1 mg midazolam intramuscularly to reduce perioperative stress. Amoxicillin (450 mg) was used for prophylaxis of infectious complications. No tracheal intubation was applied. Animals were ventilated with the use of a facial/snout mask and monitored by continuous pulse oximetry. Anesthesia was sustained by continuous halothane supply with intravenous infusion of 0.9% NaCl to maintain fluid balance. Implantation was performed using a laparoscopic technique with pneumoperitoneum pressure of 12 mm Hg. Three trocars were introduced for peritoneal access: 10 mm for the camera located superiorly to the umbilicus and 5 mm and 10 mm as operative trocars, which were also utilized for electrode introduction. The mesenteric root and the bifurcation of the aorta were exposed. The intended area of electrode location was blindly dissected extraperitoneally with the use of the grasper and gentle gas insufflation. Total extraperitoneal introduction of the electrode was performed via a 10-mm left lateral trocar into the prepared area: 1 arm was placed in the cephalic direction for hypogastric plexus stimulation and the other
2 arms in the caudolateral direction, parallel to the pelvic nerves. Next, the electrode was tightly secured with the prepared polypropylene pads. Correct positioning of the electrodes was determined by anatomical landmarks and trial stimulation. The stimulator was implanted into the subfascial pocket of the lumbar region and connected to the electrode. To ensure correct electrode positioning, a plane X ray was taken after the surgery. In general, the animals completely recovered from anesthesia within 90 minutes and were allowed to drink in the evening of the day of the surgery. Postoperative analgesia was maintained for 3 days, and the antibiotic was continued for 48 hours (twice a day). On the first postoperative day, access to standard food (Starter PT 420, Provimi, Warsaw, Poland) was provided ad libitum. No pain or stress reaction was observed. Animals reached their preoperative amount of food intake within 3 days.
Evaluation of Bowel Motility Intraoperative trial stimulation was applied for 30 s. Correct positioning of the electrode was confirmed by inducing bowel contraction and an increase in the intrarectal pressure. For the manometric study, we used a 1-channel balloon sphinctometer (MSM ProMedico GmbH, Alsdorf, Germany). In the third and fourth weeks of the trial, the efficacy of the stimulation to induce defecation was evaluated. The time period between the activation of the stimulator and defecation was measured. Number and consistency of stools were noted. Symptoms of stress, pain, or discomfort were observed and recorded according to the stress and side effects score.
Evaluation of Stress and Side Effects For the estimation of stress, pain, or discomfort, the following parameters were used: dejected, bristled up, cyanotic snout and ears, defense position, and rigid/ curved tail. Every symptom was scored on a scale from 0 to 2 points (0, absent; 1, uncertain; 2, present) with a
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Table 1. Time From the Start of the Stimulation to Defecation (Average From 7 Testing Trials on Each Animal). Pig Average Time to Minimal Time to Maximal Time to Number Defecation (s) Defecation (s) Defecation (s)
Figure 3. Increase in the intrarectal pressure.
1 2 3 4 5 6 7 8 9 10
maximum score of 10 points. Deviation from the growth chart and a decrease in the food intake were noted as well.
Table 2. Time From the Start of the Stimulation to Initiation of Micturition (Average From 7 Testing Trials on Each Animal). Pig Number
Results The average operative time was 105 minutes (85-150 minutes). All wounds healed without complications. No septic complications were observed.
Intraoperative Stimulation Intraoperative stimulation induced intense multisegmental and propulsive activity involving the whole of the large bowel and parts of the small bowel as observed in laparoscopy. The average time from initiation of the stimulation to activation of motility was 35 to 185 s (average 65 s). This phenomenon lasted for 50 to 250 s after stimulation and was accompanied by an increase in the intrarectal pressure by 32.5 mm Hg on average (Figure 3).
Induction of Defecation and Micturition In all pigs, acute bowel program stimulation activated induced defecation, every second day, every time on demand, with an average delay of 139.7 s (Table 1). The earliest defecation was after 15 s and the latest after 250 s. Finally, after 70 activations of the stimulator (7 times in 10 animals), the stimulation/defecation ratio was 1/1 with an effectiveness of 100%. Micturition was induced incidentally in 1 of 3 activations of the stimulator on average (Table 2). After 70 activations of the stimulator (7 times in 10 animals), the stimulation/micturition ratio was 3/1, and the effectiveness was 37.1%. There was no intrasubject correlation between defecation and micturition. Acute or chronic stimulation did not cause any harm, pain, or suffering to the animals, as shown by veterinary examination. The symptoms score during stimulation
132 178 135 109 174 102 136 146 150 135
60 160 100 15 110 35 40 85 75 92
215 220 180 230 250 190 240 245 210 245
Number of Urinations
Average Time to Urination (s)
Range (s)
3 4 4 3 4 0 3 2 2 1
46 57 42 68 73 — 53 47 65 77
35-68 34-90 26-68 54-85 36-120 — 31-76 42-52 65-156 77-77
1 2 3 4 5 6 7 8 9 10
was 0.6 on average (range = 0-3). Animals’ growth did not differ from the norms recorded in the standardized growth charts. Additionally, there were no abnormalities in the food intake.
Side Effects of Chronic Stimulation and Results of Autopsy In 1 pig, loose stools were observed on chronic stimulation. No adverse effects of the stimulation were observed. During veterinary examination, the symptoms score never exceeded 3 points. Analysis of the video recordings showed normal behavior of the animals. Autopsy did not show lead displacement in any of the animals. No septic complications or macroscopic fibrosis around the electrodes were observed.
Discussion Literature data suggest that at least some functional disorders result from lesions or deregulation of the enteral
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nervous system. Previous studies have shown that direct bowel stimulation9-11 as well as SNS4,12,13 may potentially improve colonic motility. Neuromodulation of the hypogastric plexus avoids the risk of undesired somatic stimulation (often present with SNS), covers most of the left colon (slow transit affects the left colon predominantly), and minimizes the risk of bowel injury (electrode migration) as compared with direct bowel stimulation. We also explored the possibility of complementing the procedure with an additional advantage—namely, the ability to control both fecal and urinary disorders with single implantation. To the best of our knowledge, at the time of our investigation, our study was the first to use the transperitoneal, presacral approach for the purposes of neuromodulation for stimulation of colonic motility. Bruninga et al10 showed that colonic motility may be improved by electrical stimulation of the bowel in cats with spinal cord injury. Vaucher et al14 implanted electrodes into the cecal wall of 12 pigs. Colonic transit time was determined by radiopaque markers for each pig before implantation. This assessment was repeated 4 weeks after implantation with sham stimulation and 5 weeks after implantation with electrical stimulation. Aboral sequential trains of 1 ms pulse width (10 V; 120 Hz) were applied twice daily for 6 days using an external battery-operated stimulator. Colonic transit time was reduced, as measured by radiopaque markers.14 Similar results were published by other authors15-18 who showed that stimulation induced strong sequential colonic contractions and significantly accelerated content movement. Liu and Chen19 suggested that the nitrergic pathway is involved in this mechanism. Potential complications of this approach are thought to be associated with the placement and method of implantation. Electrodes implanted directly into the bowel wall act locally and may migrate to its lumen, inducing septic complications. Moreover, intraperitoneal leads may induce bowel strangulation and ileus. A pilot human study with colonic pacing has been performed in a small series of patients with severe IBS who had not responded to medical management.9 In this study, 9 patients had a cardiac pacemaker inserted into a subcutaneous pouch and the leads placed at the colosigmoid junction. Pacing was performed after each meal. Authors observed normalization of EMG activity and improvement in bowel function and pain. In 7 patients, pacing was discontinued after 6 months; however, 9 patients had continued improvement at the 13-month follow-up.9 Shafik et al11,20 showed that colonic pacing may improve some symptoms in IBS-C patients20 and patients with colonic inertia.11 It is believed that the electrical stimulation influences the enteric nervous system.21 Thus, stimulation of its extrinsic connections may be more efficient.
The inferior mesenteric plexus is a mixed autonomic plexus, which accompanies the inferior mesenteric artery. It receives the sympathetic postganglionic fibers from paravertebral sympathetic chain ganglia through the sacral splanchnic nerves and probably preganglionic sympathetic fibers from cell bodies located in the L1-L3 segments of the spinal cord, which enter the plexus through the lumbar splanchnic nerves.22,23 SNS has been used for patients with urinary frequency, urinary urge incontinence, and interstitial cystitis with good results. Kenefick at al6 used SNS in patients with chronic, severe constipation. SNS was also used for slow transit constipation.12,13 Although the numbers of patients are small, preliminary results seem promising. No randomized studies of IBS patients have been published so far, but the use of sacral neuromodulation in IBS seems logical. The results of Kenefick et al6 showed increased colonic motility, similar to our study. Moreover, hypogastric plexus stimulation in our study induced defecation “on request” (every time, in all pigs, and with a delay of only 15-250 s), which may suggest a higher efficacy of the presacral approach (SPIDER system) compared with SNS. It is likely that the incidence of side effects, electrode displacement, and undesirable stimulation will be much lower in our approach. Nevertheless, it is beyond the scope of the current article to discuss whether retroperitoneal implantation of the electrode is more complex, requiring laparoscopic surgery experience, but justified by the long period of stimulation and improved efficacy. Explantation of the system, if necessary, is more complicated as well. Possover24 described the LION procedure (Laparoscopic Implantation of Neuroprothesis) for the treatment of neurogenic bladder dysfunctions in patients who failed SNS. In this approach, multipolar electrodes are implanted into the presacral region, in a manner similar to our study. It must be noted, however, that there are differences between our technique and the LION procedure with respect to lead shape and positioning of the electrodes. In LION, the electrode is fixed proximally and distally with a monofilament nonresorbable 5.0 suture, whereas the cable is passed strictly retroperitoneally, laterally to the iliac vessels.24 In our study, self-fixation pads were used. Possover24 reported using parameters that were similar to those used by us— namely, 15 to 30 Hz, 0.25 ms, and 0.5 to 4 V as compared with 50 Hz, 0.5 ms, and fixed amplitude of 5 mA in our procedure. Furthermore, this author published excellent results with regard to his experience in 21 consecutive patients.25 All procedures were performed successfully by laparoscopy (transperitoneal approach, similar to our study) without any complications. The mean operative time for such a procedure was 34 minutes compared with 105 minutes in our study; this may be a result of the complex shape of our electrode, intended to stimulate the plexus and nerves bilaterally and also a result of test
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Sobocki et al stimulation performed as part of the study protocol. In 2 patients of the series, postoperative neuromodulation failed. In all other 19 patients, with the follow-up varying between 3 months and 3 years, neuromodulation was successful. The author suggests that the presacral, as opposed to the percutaneous, approach is more effective because it permits implanting the electrode under direct visual control in a manner that allows direct contact with the nerves. Additionally, the author emphasizes that in the classical percutaneous transforaminal technique of implantation, only 1 sacral nerve root can be reached by 1 implanted electrode, whereas in the presacral procedure, as the electrode is placed perpendicular to the sacral plexus, all the involved sacral nerve roots (S2-S4/5) are reached by the electrical field of the electrode.25 This suggests a lesser risk of lead migration and septic complications because the cable and the electrode are placed in a safe position deep in the pelvis, optimally protected by the pelvic bone, and in an area where transposition caused by movement does not usually occur. Despite important findings, our study also has a number of potential limitations. The study was performed on pigs, which have defecation habits different from that of humans. Animals were healthy and, therefore, not consistent with the experimental model of constipation. Other authors, including Vaucher et al,14 have addressed the adequacy of the porcine model for the study of colonic transit and similarities to human physiology. It must be noted, however, that although the results of our study are encouraging, the effect of stimulation on the colon affected by inertia is unknown. The efficacy of the stimulation was observed for a relatively short period of time, and it is not known if it will be sustained for a longer duration. Acknowledgments We appreciate the support of Karl-Storz Endoscopies, who supplied laparoscopic equipment.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was financed by European grant within Healthy Aims consortium by the Sixth Framework Program of European Committee. The study was supported by Grant No. IST 2002-1001837 Sixth Framework Program of European Committee.
Authors’ Note This article was presented at the oral session, DDW 2008; May 17-22; San Diego, California.
References 1 Rome III criteria. Gastroenterology. 2006;130:1459-1537. 2 FitzHarris GP, Garcia-Aguilar J, Parker SC, et al. Quality of life after subtotal colectomy for slow-transit constipation: both quality and quantity count. Dis Colon Rectum. 2003;46:433-440. 3 Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol. 2005;39(5, suppl 3):S184-S193. 4 Ohman L, Simren M. New insights into the pathogenesis and pathophysiology of irritable bowel syndrome. Dig Liver Dis. 2007;39:201-215. 5 Wedel T, Roblick U, Gleiss J, et al. Disorders of intestinal innervation as a possible cause for chronic constipation [in German]. Zentralbl Chir. 1999;124:796-803. 6 Kenefick NJ, Vaizey CJ, Cohen CR, Nicholls RJ, Kamm MA. Double-blind placebo-controlled crossover study of sacral nerve stimulation for idiopathic constipation. Br J Surg. 2002;89:1570-1571. 7 Symons S, Barnecott J, Harrison S. Sacral nerve stimulation (neuromodulation) for the treatment of lower urinary tract symptoms in adult patients. ACNR. 2005;5:35-37. 8 Pannek J, Grigoleit U, Hinkel A. Bacterial contamination of test stimulation leads during percutaneous nerve stimulation. Urology. 2005;65:1096-1098. 9 Bassotti G, Chistolini F, Marinozzi G, Morelli A. Abnormal colonic propagated activity in patients with slow transit constipation and constipation-predominant irritable bowel syndrome. Digestion. 2003;68:178-183. 10 Bruninga K, Riedy L, Keshavarzian A, Walter J. The effect of electrical stimulation on colonic transit following spinal cord injury in cats. Spinal Cord. 1998;36:847-853. 11 Shafik A, Shafik AA, El-Sibai O, Ahmed I. Colonic pacing: a therapeutic option for the treatment of constipation due to total colonic inertia. Arch Surg. 2004;139: 775-779. 12 Holzer B, Rosen HR, Novi G, et al. Sacral nerve stimulation in patients with severe constipation. Dis Colon Rectum. 2008;51:524-530. 13 Malouf AJ, Wiesel PH, Nicholls T, Nicholls RJ, Kamm MA. Short-term effects of sacral nerve stimulation for idiopathic slow transit constipation. World J Surg. 2002;26: 166-170. 14 Vaucher J, Cerantola Y, Gie O, et al. Electrical colonic stimulation reduces mean transit time in a porcine model. Neurogastroenterol Motil. 2010;22:88-92. 15 Aellen S, Wiesel PH, Gardaz JP, et al. Electrical stimulation induces propagated colonic contractions in an experimental model. Br J Surg. 2009;96:214-220. 16 Amaris MA, Rashev PZ, Mintchev MP, Bowes KL. Microprocessor controlled movement of solid colonic content using sequential neural electrical stimulation. Gut. 2002;50:475-479. 17 Sanmiguel CP, Casillas S, Senagore A, Mintchev MP, Soffer EE. Neural gastrointestinal electrical stimulation enhances colonic motility in a chronic canine model of delayed colonic transit. Neurogastroenterol Motil. 2006;18:647-653.
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18 Sevcencu C, Rijkhoff NJ, Gregersen H, Sinkjaer T. Propulsive activity induced by sequential electrical stimulation in the descending colon of the pig. Neurogastroenterol Motil. 2005;17:376-387. 19 Liu S, Chen JD. Colonic electrical stimulation regulates colonic transit via the nitrergic pathway in rats. Dig Dis Sci. 2006;51:502-505. 20 Shafik A, El-Sibai O, Shafik AA, Ahmed I. Colonic pacing in the treatment of patients with irritable bowel syndrome: technique and results. Front Biosci. 2003;8:b1-b5. 21 Li C, Liu S, Guan Y, Qian W, du F, Hou X. Long pulse gastric electrical stimulation induces regeneration of myenteric plexus synaptic vesicles in diabetic rats. Neurogastroenterol Motil. 2010;22:453-461.
22 Baader B, Herrmann M. Topography of the pelvic autonomic nervous system and its potential impact on surgical intervention in the pelvis. Clin Anat. 2003;16:119-130. 23 Pearl RK, Monsen H, Abcarian H. Surgical anatomy of the pelvic autonomic nerves: a practical approach. Am Surg. 1986;52:236-237. 24 Possover M. Laparoscopic exposure and electrostimulation of the somatic and autonomous pelvic nerves: a new method for implantation of neuroprothesis in paralyzed patients? Gynecol Surg. 2004;1:87-90. 25 Possover M. The laparoscopic implantation of neuroprothesis to the sacral plexus for therapy of neurogenic bladder dysfunctions after failure of percutaneous sacral nerve stimulation. Neuromodulation. 2010;13:141-144.
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SRIXXX10.1177/1553350614530190Surgical InnovationSobocki et al
Innovative Technologies
Laparoscopically Implanted System for Stimulation of the Hypogastric Plexus Induces Colonic Motility, Defecation, and Micturition: Experimental Study
Surgical Innovation 2015, Vol. 22(1) 70–76 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1553350614530190 sri.sagepub.com
Jacek Sobocki, MD1, Michal Nowakowski, MD1, Roman M. Herman, MD1, Piotr Wałęga, MD2, Mariusz Frączek, MD3, Ryszard Tuz, BSc4, Tomasz Schwartz, BSc4, and Maciej Murawski, BSc4
Abstract Background. Modulation of the enteric nervous system seems to be promising in several functional colorectal disorders for which targeted, causal treatment methods do not exist. However, sacral nerve stimulation can induce undesirable muscle contraction or paresthesia. Therefore, we have developed a laparoscopic technique for implanting a neural electrode, placed directly over the pelvic autonomic nerve plexus. The aim of this experimental study was to evaluate the effect of stimulating the hypogastric plexus and pelvic nerves on inducing distal colon contraction, defecation, and micturition. Method. A total of 10 white, male healthy pigs (25-30 kg) were subjected to the laparoscopic implantation of the electrode and the stimulator. In the third and fourth weeks postimplantation, the efficacy of the acute and chronic stimulation to induce defecation was evaluated. Results. The average operative time was 105 minutes (85-150 minutes). In all pigs, acute stimulation activated induced defecation, every second day, every time on demand, with an average delay of 139.7 s. Micturition was induced incidentally. Acute or chronic stimulation did not cause any harm, pain, or suffering to the animals. No adverse effects of the stimulation were observed, and no septic complications or macroscopic fibrosis around the electrodes were found on autopsy. Conclusion. Hypogastric plexus stimulation can be a useful and safe option of distal colon contraction, defecation, and micturition. However, the efficacy of the stimulation was observed for a relatively short period of time, and it is not known if it will be sustained for a longer duration. Keywords colorectal surgery, interventional endoscopy, tissue engineering
Introduction There are several functional colorectal disorders defined by and included in Rome III criteria1 for which targeted, causal treatment methods do not exist (ie, irritable bowel syndrome [IBS]-C1, functional bloating-C2, functional constipation-C3, functional diarrhea-C4, unspecified functional bowel disorder-C5, and functional abdominal pain syndrome-D). For instance, the only radical option for intractable colonic inertia is an ablative surgical procedure, which significantly improves symptoms but has important side effects.2 In other cases, only behavioral, dietary, or pharmacological interventions may bring some improvement, but efficiency of the currently known treatment is limited. The enteric nervous system and its extrinsic connection play a significant role in the pathogenesis of symptoms, as suggested by several publications.3-5 Modulation
of this complex system is an intriguing idea and seems to be promising. Sacral nerve stimulation (SNS) was used in the treatment of constipation with some success.6 However, this technique can induce undesirable stimulation (skeletal muscle contraction, paresthesia, etc), and therefore, more specific stimulation of the pelvic plexus seems to be logical and more appropriate. Superficial/transcutaneous lead 1
St Anna Memorial Hospital, Warsaw, Poland Jagiellonian University, Cracow, Poland 3 Medical University of Warsaw, Warsaw, Poland 4 University of Agriculture, Cracow, Poland 2
Corresponding Author: Jacek Sobocki, Department of General, Oncology and Gastrointestinal Surgery, St Anna Memorial Hospital, ul. Żytnia 7/1, 31-408 Cracow, Poland. Email: [email protected]
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Figure 1. Study flow.
placement is related to a higher risk of lead migration (up to 16%)7 and wound problems (up to 7%).8 Therefore, we have developed a laparoscopic technique for implanting a neural electrode, which we have named the “SPIDER procedure” after the shape of the electrode placed over the pelvic autonomic nerve plexus. The aim of the study was to evaluate the effect of stimulating the hypogastric plexus and pelvic nerves on inducing distal colon contraction, defecation, and micturition.
Methods Ethics The ethics of the study were approved by Jagiellonian University First Local Ethical Committee for Experiments on Animals.
Animals The study was conducted on 10 white male healthy pigs (weighing between 25 and 30 kg). Animals were kept in separate cages. Constant temperature, humidity, and 16:8 hour light-dark cycle were sustained. The standard diet was supplied twice a day. Cages were cleaned twice a week. All experimental procedures were performed with the assistance of a technician who fed and cared for the animals. All procedures were designed to avoid immobilization and minimize stress on the animals. Dimensions
of the cages allowed animals to move freely in all directions. Animals were kept under daily supervision of a veterinarian.
Study Flow Before participating in the study, the animals’ health was examined to determine if they were suffering from any disease (Figure 1). Implantation of the electrode and the stimulator was performed on day 0. No procedures were performed during the next 2 weeks of recovery. In the subsequent 2-week period (acute stimulation trials), the stimulator was turned on for 2 minutes every 2 days to induce defecation (bowel stimulation parameters) and subsequently micturition (urinary stimulation parameters). Continuous stimulation (5 s on, 25 s off) was started on the 28th day post–implantation surgery. The aim of this part of the experiment was to assess adverse effects, undesirable stimulation, and risk of electrode displacement. After 6 weeks, the animals were killed humanely, the stimulating system was assessed and explanted, and the pelvis was examined for any pathologies.
Stimulator, Electrodes, Current Parameters, and Programming Protocol Stimulation current was generated by a neurostimulator (model 1097, CCC, Montevideo, Uruguay). It is possible to preprogram the stimulator in a large range of parameters
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Surgical Innovation 22(1)
Figure 2. Lead construction.
by using a programming wand connected to a PC computer. In accordance with the study protocol, a magnet function was used to turn the stimulation on or off to provide a stress-free environment for the animals. Lead and electrodes were developed based on previous anatomical studies of hypogastric plexus and pelvic nerves (Figure 2). Three electrodes were placed on 3 arms of the lead in a configuration allowing the stimulation of the hypogastric plexus area and the bilateral pelvic nerves. Programming parameters were as follows: amplitude 5 mA, frequency 50 Hz, and pulse width 0.5 ms. Two programs were used: (1) the bowel program used electrodes for predominant plexus stimulation and (2) the urinary bladder program with predominant stimulation of the pelvic nerves.
Anesthesia and Implantation Procedure After an overnight fast, the following protocol was used for the induction of anesthesia: 1 mg atropine intramuscularly, 10 mg ketamine intramuscularly, and 1 mg midazolam intramuscularly to reduce perioperative stress. Amoxicillin (450 mg) was used for prophylaxis of infectious complications. No tracheal intubation was applied. Animals were ventilated with the use of a facial/snout mask and monitored by continuous pulse oximetry. Anesthesia was sustained by continuous halothane supply with intravenous infusion of 0.9% NaCl to maintain fluid balance. Implantation was performed using a laparoscopic technique with pneumoperitoneum pressure of 12 mm Hg. Three trocars were introduced for peritoneal access: 10 mm for the camera located superiorly to the umbilicus and 5 mm and 10 mm as operative trocars, which were also utilized for electrode introduction. The mesenteric root and the bifurcation of the aorta were exposed. The intended area of electrode location was blindly dissected extraperitoneally with the use of the grasper and gentle gas insufflation. Total extraperitoneal introduction of the electrode was performed via a 10-mm left lateral trocar into the prepared area: 1 arm was placed in the cephalic direction for hypogastric plexus stimulation and the other
2 arms in the caudolateral direction, parallel to the pelvic nerves. Next, the electrode was tightly secured with the prepared polypropylene pads. Correct positioning of the electrodes was determined by anatomical landmarks and trial stimulation. The stimulator was implanted into the subfascial pocket of the lumbar region and connected to the electrode. To ensure correct electrode positioning, a plane X ray was taken after the surgery. In general, the animals completely recovered from anesthesia within 90 minutes and were allowed to drink in the evening of the day of the surgery. Postoperative analgesia was maintained for 3 days, and the antibiotic was continued for 48 hours (twice a day). On the first postoperative day, access to standard food (Starter PT 420, Provimi, Warsaw, Poland) was provided ad libitum. No pain or stress reaction was observed. Animals reached their preoperative amount of food intake within 3 days.
Evaluation of Bowel Motility Intraoperative trial stimulation was applied for 30 s. Correct positioning of the electrode was confirmed by inducing bowel contraction and an increase in the intrarectal pressure. For the manometric study, we used a 1-channel balloon sphinctometer (MSM ProMedico GmbH, Alsdorf, Germany). In the third and fourth weeks of the trial, the efficacy of the stimulation to induce defecation was evaluated. The time period between the activation of the stimulator and defecation was measured. Number and consistency of stools were noted. Symptoms of stress, pain, or discomfort were observed and recorded according to the stress and side effects score.
Evaluation of Stress and Side Effects For the estimation of stress, pain, or discomfort, the following parameters were used: dejected, bristled up, cyanotic snout and ears, defense position, and rigid/ curved tail. Every symptom was scored on a scale from 0 to 2 points (0, absent; 1, uncertain; 2, present) with a
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Table 1. Time From the Start of the Stimulation to Defecation (Average From 7 Testing Trials on Each Animal). Pig Average Time to Minimal Time to Maximal Time to Number Defecation (s) Defecation (s) Defecation (s)
Figure 3. Increase in the intrarectal pressure.
1 2 3 4 5 6 7 8 9 10
maximum score of 10 points. Deviation from the growth chart and a decrease in the food intake were noted as well.
Table 2. Time From the Start of the Stimulation to Initiation of Micturition (Average From 7 Testing Trials on Each Animal). Pig Number
Results The average operative time was 105 minutes (85-150 minutes). All wounds healed without complications. No septic complications were observed.
Intraoperative Stimulation Intraoperative stimulation induced intense multisegmental and propulsive activity involving the whole of the large bowel and parts of the small bowel as observed in laparoscopy. The average time from initiation of the stimulation to activation of motility was 35 to 185 s (average 65 s). This phenomenon lasted for 50 to 250 s after stimulation and was accompanied by an increase in the intrarectal pressure by 32.5 mm Hg on average (Figure 3).
Induction of Defecation and Micturition In all pigs, acute bowel program stimulation activated induced defecation, every second day, every time on demand, with an average delay of 139.7 s (Table 1). The earliest defecation was after 15 s and the latest after 250 s. Finally, after 70 activations of the stimulator (7 times in 10 animals), the stimulation/defecation ratio was 1/1 with an effectiveness of 100%. Micturition was induced incidentally in 1 of 3 activations of the stimulator on average (Table 2). After 70 activations of the stimulator (7 times in 10 animals), the stimulation/micturition ratio was 3/1, and the effectiveness was 37.1%. There was no intrasubject correlation between defecation and micturition. Acute or chronic stimulation did not cause any harm, pain, or suffering to the animals, as shown by veterinary examination. The symptoms score during stimulation
132 178 135 109 174 102 136 146 150 135
60 160 100 15 110 35 40 85 75 92
215 220 180 230 250 190 240 245 210 245
Number of Urinations
Average Time to Urination (s)
Range (s)
3 4 4 3 4 0 3 2 2 1
46 57 42 68 73 — 53 47 65 77
35-68 34-90 26-68 54-85 36-120 — 31-76 42-52 65-156 77-77
1 2 3 4 5 6 7 8 9 10
was 0.6 on average (range = 0-3). Animals’ growth did not differ from the norms recorded in the standardized growth charts. Additionally, there were no abnormalities in the food intake.
Side Effects of Chronic Stimulation and Results of Autopsy In 1 pig, loose stools were observed on chronic stimulation. No adverse effects of the stimulation were observed. During veterinary examination, the symptoms score never exceeded 3 points. Analysis of the video recordings showed normal behavior of the animals. Autopsy did not show lead displacement in any of the animals. No septic complications or macroscopic fibrosis around the electrodes were observed.
Discussion Literature data suggest that at least some functional disorders result from lesions or deregulation of the enteral
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nervous system. Previous studies have shown that direct bowel stimulation9-11 as well as SNS4,12,13 may potentially improve colonic motility. Neuromodulation of the hypogastric plexus avoids the risk of undesired somatic stimulation (often present with SNS), covers most of the left colon (slow transit affects the left colon predominantly), and minimizes the risk of bowel injury (electrode migration) as compared with direct bowel stimulation. We also explored the possibility of complementing the procedure with an additional advantage—namely, the ability to control both fecal and urinary disorders with single implantation. To the best of our knowledge, at the time of our investigation, our study was the first to use the transperitoneal, presacral approach for the purposes of neuromodulation for stimulation of colonic motility. Bruninga et al10 showed that colonic motility may be improved by electrical stimulation of the bowel in cats with spinal cord injury. Vaucher et al14 implanted electrodes into the cecal wall of 12 pigs. Colonic transit time was determined by radiopaque markers for each pig before implantation. This assessment was repeated 4 weeks after implantation with sham stimulation and 5 weeks after implantation with electrical stimulation. Aboral sequential trains of 1 ms pulse width (10 V; 120 Hz) were applied twice daily for 6 days using an external battery-operated stimulator. Colonic transit time was reduced, as measured by radiopaque markers.14 Similar results were published by other authors15-18 who showed that stimulation induced strong sequential colonic contractions and significantly accelerated content movement. Liu and Chen19 suggested that the nitrergic pathway is involved in this mechanism. Potential complications of this approach are thought to be associated with the placement and method of implantation. Electrodes implanted directly into the bowel wall act locally and may migrate to its lumen, inducing septic complications. Moreover, intraperitoneal leads may induce bowel strangulation and ileus. A pilot human study with colonic pacing has been performed in a small series of patients with severe IBS who had not responded to medical management.9 In this study, 9 patients had a cardiac pacemaker inserted into a subcutaneous pouch and the leads placed at the colosigmoid junction. Pacing was performed after each meal. Authors observed normalization of EMG activity and improvement in bowel function and pain. In 7 patients, pacing was discontinued after 6 months; however, 9 patients had continued improvement at the 13-month follow-up.9 Shafik et al11,20 showed that colonic pacing may improve some symptoms in IBS-C patients20 and patients with colonic inertia.11 It is believed that the electrical stimulation influences the enteric nervous system.21 Thus, stimulation of its extrinsic connections may be more efficient.
The inferior mesenteric plexus is a mixed autonomic plexus, which accompanies the inferior mesenteric artery. It receives the sympathetic postganglionic fibers from paravertebral sympathetic chain ganglia through the sacral splanchnic nerves and probably preganglionic sympathetic fibers from cell bodies located in the L1-L3 segments of the spinal cord, which enter the plexus through the lumbar splanchnic nerves.22,23 SNS has been used for patients with urinary frequency, urinary urge incontinence, and interstitial cystitis with good results. Kenefick at al6 used SNS in patients with chronic, severe constipation. SNS was also used for slow transit constipation.12,13 Although the numbers of patients are small, preliminary results seem promising. No randomized studies of IBS patients have been published so far, but the use of sacral neuromodulation in IBS seems logical. The results of Kenefick et al6 showed increased colonic motility, similar to our study. Moreover, hypogastric plexus stimulation in our study induced defecation “on request” (every time, in all pigs, and with a delay of only 15-250 s), which may suggest a higher efficacy of the presacral approach (SPIDER system) compared with SNS. It is likely that the incidence of side effects, electrode displacement, and undesirable stimulation will be much lower in our approach. Nevertheless, it is beyond the scope of the current article to discuss whether retroperitoneal implantation of the electrode is more complex, requiring laparoscopic surgery experience, but justified by the long period of stimulation and improved efficacy. Explantation of the system, if necessary, is more complicated as well. Possover24 described the LION procedure (Laparoscopic Implantation of Neuroprothesis) for the treatment of neurogenic bladder dysfunctions in patients who failed SNS. In this approach, multipolar electrodes are implanted into the presacral region, in a manner similar to our study. It must be noted, however, that there are differences between our technique and the LION procedure with respect to lead shape and positioning of the electrodes. In LION, the electrode is fixed proximally and distally with a monofilament nonresorbable 5.0 suture, whereas the cable is passed strictly retroperitoneally, laterally to the iliac vessels.24 In our study, self-fixation pads were used. Possover24 reported using parameters that were similar to those used by us— namely, 15 to 30 Hz, 0.25 ms, and 0.5 to 4 V as compared with 50 Hz, 0.5 ms, and fixed amplitude of 5 mA in our procedure. Furthermore, this author published excellent results with regard to his experience in 21 consecutive patients.25 All procedures were performed successfully by laparoscopy (transperitoneal approach, similar to our study) without any complications. The mean operative time for such a procedure was 34 minutes compared with 105 minutes in our study; this may be a result of the complex shape of our electrode, intended to stimulate the plexus and nerves bilaterally and also a result of test
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Sobocki et al stimulation performed as part of the study protocol. In 2 patients of the series, postoperative neuromodulation failed. In all other 19 patients, with the follow-up varying between 3 months and 3 years, neuromodulation was successful. The author suggests that the presacral, as opposed to the percutaneous, approach is more effective because it permits implanting the electrode under direct visual control in a manner that allows direct contact with the nerves. Additionally, the author emphasizes that in the classical percutaneous transforaminal technique of implantation, only 1 sacral nerve root can be reached by 1 implanted electrode, whereas in the presacral procedure, as the electrode is placed perpendicular to the sacral plexus, all the involved sacral nerve roots (S2-S4/5) are reached by the electrical field of the electrode.25 This suggests a lesser risk of lead migration and septic complications because the cable and the electrode are placed in a safe position deep in the pelvis, optimally protected by the pelvic bone, and in an area where transposition caused by movement does not usually occur. Despite important findings, our study also has a number of potential limitations. The study was performed on pigs, which have defecation habits different from that of humans. Animals were healthy and, therefore, not consistent with the experimental model of constipation. Other authors, including Vaucher et al,14 have addressed the adequacy of the porcine model for the study of colonic transit and similarities to human physiology. It must be noted, however, that although the results of our study are encouraging, the effect of stimulation on the colon affected by inertia is unknown. The efficacy of the stimulation was observed for a relatively short period of time, and it is not known if it will be sustained for a longer duration. Acknowledgments We appreciate the support of Karl-Storz Endoscopies, who supplied laparoscopic equipment.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was financed by European grant within Healthy Aims consortium by the Sixth Framework Program of European Committee. The study was supported by Grant No. IST 2002-1001837 Sixth Framework Program of European Committee.
Authors’ Note This article was presented at the oral session, DDW 2008; May 17-22; San Diego, California.
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