A ganglionic intestinointestinal reflex activated by acute noxious challenge.

To investigate noxious stimulation-responsive neural circuits that could influence the gut, we recorded from intestinally directed (efferent) nerve filaments dissected from mesenteric nerves close to the small intestine in anesthetized rats. These exhibited baseline multiunit activity that was almost unaffected by vagotomy (VagX) and reduced only slightly by cutting the splanchnic nerves. The activity was halved by hexamethonium (Hex) treatment. When an adjacent gut segment received an intraluminal stimulus 2,4,6-trinitrobenzenesulfonate (TNBS) in 30% ethanol, mesenteric efferent nerve activity increased for more than 1 h. The increased activity was almost unaffected by bilateral vagotomy or splanchnic nerve section, indicating a lack of central nervous involvement, but it was 60% reduced by hexamethonium. Spike sorting discriminated efferent single and predominantly single-unit spike trains that responded to TNBS, were unaffected by splachnectomy but were silenced by hexamethonium. After noxious stimulation of one segment, the adjacent segment showed no evidence of suppression of gut motility or vasoconstriction. We conclude that luminal application of a noxious stimulus to the small intestine activates an entirely peripheral, intestinointestinal reflex pathway. This pathway involves enteric intestinofugal neurons that excite postganglionic sympathetic neurons via a nicotinic synapse. We suggest that the final sympathetic efferent neurons that respond to a tissue damaging stimulus are distinct from vasoconstrictor, secretomotor, and motility inhibiting neurons.NEW & NOTEWORTHY An intraluminal noxious chemical stimulus applied to one segment of small intestine increased mesenteric efferent nerve activity to an adjacent segment. This was identified as a peripheral ganglionic reflex that did not require vagal or spinal connections. Hexamethonium blocked most, but not all, ongoing and reflex mesenteric efferent activity. The prevertebral sympathetic efferent neurons that are activated likely affect inflammatory and immune functions of other gut segments.

Endovascular Ablation of the Right Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: Rationale, Design and Lead-in Phase Results of the REBALANCE-HF Trial.

OBJECTIVE: Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants. METHODS: REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up. RESULTS: The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n = 44 SAVM; n = 46 sham) has completed enrollment, and follow-up is ongoing. CONCLUSION: REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. TRIAL REGISTRATION: NCT04592445.

Acute Inhibition of Inflammation Mediated by Sympathetic Nerves: The Inflammatory Reflex.

In this review, we will try to convince the readers that the immune system is controlled by an endogenous neural reflex, termed inflammatory reflex, that inhibits the acute immune response during the course of a systemic immune challenge. We will analyse here the contribution of different sympathetic nerves as possible efferent arms of the inflammatory reflex. We will discuss the evidence that demonstrates that neither the splenic sympathetic nerves nor the hepatic sympathetic nerves are necessary for the endogenous neural reflex inhibition of inflammation. We will discuss the contribution of the adrenal glands to the reflex control of inflammation, noting that the neurally mediated release of catecholamines in the systemic circulation is responsible for the enhancement of the anti-inflammatory cytokine interleukin 10 (IL-10) but not of the inhibition of the pro-inflammatory cytokine tumour necrosis factor α (TNF). We will conclude by reviewing the evidence that demonstrates that the splanchnic anti-inflammatory pathway, composed by preganglionic and postganglionic sympathetic splanchnic fibres with different target organs, including the spleen and the adrenal glands, is the efferent arm of the inflammatory reflex. During the course of a systemic immune challenge, the splanchnic anti-inflammatory pathway is endogenously activated to inhibit the TNF and enhance the IL-10 response, independently, presumably acting on separate populations of leukocytes.

Percutaneous splanchnic nerve neurolysis analgesic efficacy and safety for cancer-related pain: a systematic review and meta-analysis.

PURPOSE: To perform a systematic review and meta-analysis of publications to evaluate the analgesic efficacy and safety of percutaneous splanchnic nerve neurolysis (SNN) for cancer-related pain. METHODS: We searched PubMed, Cochrane Library, and Ichushi-Web for English or Japanese articles published up to July 2022 and reporting patients who underwent percutaneous SNN for cancer-related pain. The outcome measures assessed in the systematic review and meta-analysis were the pain measurement scales and morphine equivalents daily dose (MEDD) before and after the intervention and the rate of complications. RESULTS: Pooled pain measurement scores at pre-intervention, 1-2 weeks, and at 1, 2, 3, and 6 months post-intervention were 6.65 (95% confidence interval [CI], 5.77-7.67, I2 = 97%), 2.79 (95% CI, 2.00-3.88, I2 = 88%), 2.82 (95% CI, 2.49-3.20, I2 = 55%), 2.86 (95% CI, 2.64-3.10, I2 = 0%), 2.99 (95% CI, 2.56-3.46, I2 = 82%), and 3.09 (95% CI, 1.44-6.65, I2 = 70%), respectively. Mean MEDD was described in 8 of the 11 included articles. In all 8 articles, MEDD decreased up to 3 months post-intervention. The pooled minor complication rates for diarrhea and hypotension were 28% (95% CI, 13-49%, I2 = 85%) and 31% (95% CI, 16-51%, I2 = 80%), respectively. The pooled major complication rate was 2% (95% CI, 1-2%, I2 = 0%). CONCLUSIONS: Analysis indicates that percutaneous SNN for cancer-related pain can be performed safely with sustained reduction of pain measurement scales while reducing the administration of opioids.

Divergent splanchnic sympathetic efferent nerve pathways regulate interleukin-10 and tumour necrosis factor-α responses to endotoxaemia.

The efferent branches of the splanchnic sympathetic nerves that enhance interleukin-10 (IL-10) and suppress tumour necrosis factor-α (TNF) levels in the reflex response to systemic immune challenge were investigated in anaesthetized, ventilated rats. Plasma levels of TNF and IL-10 were measured 90 min after intravenous lipopolysaccharide (LPS, 60 µg/kg). Splanchnic nerve section, ganglionic blockade with pentolinium tartrate or ß2 adrenoreceptor antagonism with ICI 118551 all blocked IL-10 responses. Restoring plasma adrenaline after splanchnic denervation rescued IL-10 responses. TNF responses were disinhibited by splanchnic denervation or pentolinium treatment, but not by ICI 118551. Splanchnic nerve branches were cut individually or in combination in vagotomized rats, ruling out any vagal influence on results. Distal splanchnic denervation, sparing the adrenal nerves, disinhibited TNF but did not reduce IL-10 responses. Selective adrenal denervation depressed IL-10 but did not disinhibit TNF responses. Selective denervation of either spleen or liver did not affect IL-10 or TNF responses, but combined splenic and adrenal denervation did so. Finally, combined section of the cervical and lumbar sympathetic nerves did not affect cytokine responses to LPS. Together, these results show that the endogenous anti-inflammatory reflex is mediated by sympathetic efferent fibres that run in the splanchnic, but not other sympathetic nerves, nor the vagus. Within the splanchnic nerves, divergent pathways control these two cytokine responses: neurally driven adrenaline, acting via ß2 adrenoreceptors, regulates IL-10, while TNF is restrained by sympathetic nerves to abdominal organs including the spleen, where non-ß2 adrenoreceptor mechanisms are dominant. KEY POINTS: An endogenous neural reflex, mediated by the splanchnic, but not other sympathetic nerves, moderates the cytokine response to systemic inflammatory challenge. This reflex suppresses the pro-inflammatory cytokine tumour necrosis factor-α (TNF), while enhancing levels of the anti-inflammatory cytokine interleukin-10 (IL-10). The reflex enhancement of IL-10 depends on the splanchnic nerve supply to the adrenal gland and on ß2 adrenoreceptors, consistent with mediation by circulating adrenaline. After splanchnic nerve section it can be rescued by restoring circulating adrenaline. The reflex suppression of TNF depends on splanchnic nerve branches that innervate abdominal tissues including, but not restricted to, spleen: it is not blocked by adrenal denervation or ß2 adrenoreceptor antagonism. Distinct sympathetic efferent pathways are thus responsible for pro- and anti-inflammatory cytokine components of the reflex regulating inflammation.

Opioid withdrawal symptoms after neurolytic splanchnic nerve block in cancer patients.

PURPOSE: Few reports on opioid withdrawal (OW) due to opioid tapering in cancer patients have been published. The incidence of and risk factors for OW after neurolytic splanchnic nerve block (NSNB) are unknown. This study aimed to elucidate the incidence of and risk factors for OW among cancer patients who could have reduced opioid doses after NSNB. METHODS: This was a multicenter, retrospective, observational study. We reviewed the medical charts of patients who underwent NSNB for intractable cancer pain at four tertiary hospitals in Yokohama City from April 2005 to October 2020. We included patients whose opioid dose was reduced by > 5 mg/day (equivalent oral morphine dose) within 14 days after NSNB. We classified the patients into two groups according to the presence or absence of OW symptoms and compared them. RESULTS: Of the 50 patients who underwent NSNB, 24 were included in the study. OW was observed in five (20.8%) patients. Pain and opioid use duration were significantly longer in OW patients than in non-OW patients (median pain duration 689 vs. 195 days; P < 0.043 and median opioid use duration 486 vs. 136 days; P < 0.030). The opioid tapering dose was significantly larger in patients with OW than in those without OW (median opioid tapering dose 75 vs. 40 mg; P < 0.046). CONCLUSIONS: OW was observed in 20.8% of the patients in the study. A longer pain and opioid use duration and a larger opioid tapering dose may predispose patients to OW.

Minimally invasive management for multifocal pelvic retroperitoneal malignant paraganglioma: a neuropelveological approach.

BACKGROUND: Pheochromocytoma and Paraganglioma (PGL) are rare neuroendocrine tumors, with an estimated incidence of about 0.6 cases per 100.000 person/year. Overall, 3-8% of them are malignant. These tumors are characterized by a classic triad of symptoms (headaches, palpitations, profuse sweating) due to hypersecretion of catecholamines. Despite several advantages of minimally invasive surgery (MIS) for PGL debulking, the surgical approach is not standardized yet. In this scenario, we aimed to report a case of a multiple recurrent PGL with metastatic retroperitoneal localization involving the pelvic sidewall, excised with MIS. CASE PRESENTATION: We performed complete laparoscopic-assisted neuronavigation (LANN technique) with isolation of the sacral routes and the sciatic nerve to obtain complete exposure of the main anatomic landmarks. Robotic surgery was used to perform neurolysis of sacral plexus, and partial resection of left splanchnic nerves was needed. After the resection of the first mass, extensive neurolysis of all sacral routes, obturator nerve, pudendal nerve till the entrance of the pudendal (Alcock) canal, and sciatic nerve was performed. Finally, the mass was identified after trans gluteal incision and dissection of the maximum gluteal muscle, and a partial resection of the superior gluteal nerve and slicing of the sciatic nerve were needed to obtain a radical excision of the mass. Then neurorrhaphy of the sectioned nerve fibers of the superior gluteal nerve was performed, and nerve protection was obtained using a collagen nerve wrap. After 18 months of follow-up, the patient is free of disease at the MRI imaging and 123I-metaiodobenzylguanidine scintigraphy. CONCLUSIONS: Minimally invasive gynecological surgery with neuropelveological approach could be considered as a feasible option in case of multifocal pelvic retroperitoneal malignant paraganglioma of the pelvic side wall.

Navigation Guidance for Percutaneous Splanchnic Nerve Radiofrequency Neurolysis: Preliminary Results.

Background and Objectives: To describe preliminary results upon the application of the "Cube Navigation System" (CNS) for computed tomography (CT)-guided splanchnic nerve radiofrequency neurolysis. Materials and Methods: CT-guided splanchnic nerve neurolysis was performed in five patients; in all cases, neurolysis was performed under CT guidance using the CNS. The mean patient age was 71.6 years (range 54-81 years; male/female: 5/0). Technical success, parameters of the neurolysis session and complications were evaluated. Technical success was defined as a needle position on the defined target. Session parameters included procedure time and number of scans. The CIRSE reporting system was used for complications' classification and grading. Results: Technical success was obtained in all cases; in 1/5 patients, a slight correction in needle orientation was necessary. Mean procedure time was 12.4 min (range 8-19 min); an average of four CT scans was recorded in the five neurolysis sessions. There were no complications or material failures reported in the present study. Conclusions: Preliminary results of the present study show that computed tomography (CT)-guided splanchnic nerve radiofrequency neurolysis using the CNS is an accurate and time-efficient percutaneous procedure. More prospective and comparative studies with larger patient samples are necessary for verification of this system as well as for drawing broader conclusions.

Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg-1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.

Local ionotropic glutamate receptors are required to trigger and sustain ramping of sympathetic nerve activity by hypothalamic paraventricular nucleus TNFα.

Tumor necrosis factor-α (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA) in cardiovascular disease models, but mechanisms are incompletely understood. As previously reported, bilateral PVN TNFα (0.6 pmol, 50 nL) induced acute ramping of splanchnic SNA (SSNA) that averaged +64 ± 7% after 60 min and +109 ± 17% after 120 min (P < 0.0001, n = 10). Given that TNFα can rapidly strengthen glutamatergic transmission, we hypothesized that progressive activation of ionotropic glutamate receptors is critically involved. When compared with that of vehicle (n = 5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/α-chloralose) adult male Sprague-Dawley rats dose-dependently (ED50: 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), 2.48 nmol; D-(-)-2-amino-5-phosphonopentanoic acid (APV), 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%), attenuated TNFα-induced SSNA ramping (n = 5/dose). By contrast, combined receptor blockade prevented ramping (1.3 ± 2.1%, P < 0.0001, n = 5). Whereas separate blockade of PVN AMPA or NMDA receptors (n = 5/group) had little effect on continued SSNA ramping when performed 60 min after TNFα injection, combined blockade (n = 5) or PVN inhibition with the GABA-A receptor agonist muscimol (n = 5) effectively stalled, without reversing, the SSNA ramp. Notably, PVN TNFα increased local TNFα immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFα, and that their collective availability and ongoing activity are required to initiate and sustain the ramping response. We conclude that acute sympathetic activation by PVN TNFα involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping.NEW & NOTEWORTHY The proinflammatory cytokine TNFα contributes to heightened SNA in cardiovascular disease models, but mechanisms remain obscure. Here, we demonstrate that TNFα injection into the hypothalamic PVN triggers SNA ramping by mechanisms dependent on local ionotropic glutamate receptor availability, but largely independent of TNFα autoinduction. Continued SNA ramping depends on ionotropic glutamate receptor and neuronal activity in PVN, indicating that strengthening and/or increased efficacy of glutamatergic transmission is necessary for acute sympathoexcitation by PVN TNFα.

The endogenous inflammatory reflex inhibits the inflammatory response to different immune challenges in mice.

The splanchnic anti-inflammatory pathway, the efferent arm of the endogenous inflammatory reflex, has been shown to suppress the acute inflammatory response of rats to systemic lipopolysaccharide (LPS). Here we show for the first time that this applies also to mice, and that the reflex may be engaged by a range of inflammatory stimuli. Experiments were performed on mice under deep anaesthesia. Half the animals were subjected to bilateral section of the splanchnic sympathetic nerves, to disconnect the splanchnic anti-inflammatory pathway, while the remainder underwent a sham operation. Mice were then challenged intravenously with one of three inflammatory stimuli: the toll-like receptor (TLR)-4 agonist, LPS (60 µg/kg), the TLR-3 agonist Polyinosinic:polycytidylic acid (Poly I:C, 1 mg/kg) or the TLR-2 and -6 agonist dipalmitoyl-S-glyceryl cysteine (Pam2cys, 34 µg/kg). Ninety minutes later, blood was sampled by cardiac puncture for serum cytokine analysis. The splanchnic anti-inflammatory reflex action was assessed by comparing cytokine levels between animals with cut versus those with intact splanchnic nerves. A consistent pattern emerged: Tumor necrosis factor (TNF) levels in response to all three challenges were raised by prior splanchnic nerve section, while levels of the anti-inflammatory cytokine interleukin 10 (IL-10) were reduced. The raised TNF:IL-10 ratio after splanchnic nerve section indicates an enhanced inflammatory state when the reflex is disabled. These findings show for the first time that the inflammatory reflex drives a coordinated anti-inflammatory action also in mice, and demonstrate that its anti-inflammatory action is engaged, in similar fashion, by inflammatory stimuli mimicking a range of bacterial and viral infections.

Neurolytic Splanchnic Nerve Block and Pain Relief, Survival, and Quality of Life in Unresectable Pancreatic Cancer: A Randomized Controlled Trial.

BACKGROUND: Neurolytic splanchnic nerve block is used to manage pancreatic cancer pain. However, its impact on survival and quality of life remains controversial. The authors' primary hypothesis was that pain relief would be better with a nerve block. Secondarily, they hypothesized that analgesic use, survival, and quality of life might be affected. METHODS: This randomized, double-blind, parallel-armed trial was conducted in five Chinese centers. Eligible patients suffering from moderate to severe pain conditions were randomly assigned to receive splanchnic nerve block with either absolute alcohol (neurolysis) or normal saline (control). The primary outcome was pain relief measured on a visual analogue scale. Opioid consumption, survival, quality of life, and adverse effects were also documented. Analgesics were managed using a protocol common to all centers. Patients were followed up for 8 months or until death. RESULTS: Ninety-six patients (48 for each group) were included in the analysis. Pain relief with neurolysis was greater for the first 3 months (largest at the first month; mean difference, 0.7 [95% CI, 0.3 to 1.0]; adjusted P < 0.001) compared with placebo injection. Opioid consumption with neurolysis was lower for the first 5 months (largest at the first month; mean difference, 95.8 [95% CI, 67.4 to 124.1]; adjusted P < 0.001) compared with placebo injection. There was a significant difference in survival (hazard ratio, 1.56 [95% CI, 1.03 to 2.35]; P = 0.036) between groups. A significant reduction in survival in neurolysis was found for stage IV patients (hazard ratio, 1.94 [95% CI, 1.29 to 2.93]; P = 0.001), but not for stage III patients (hazard ratio, 1.08 [95% CI, 0.59 to 1.97]; P = 0.809). No differences in quality of life were observed. CONCLUSIONS: Neurolytic splanchnic nerve block appears to be an effective option for controlling pain and reducing opioid requirements in patients with unresectable pancreatic cancer.

Treatment and Management of Loin Pain Hematuria Syndrome.

PURPOSE OF REVIEW: Loin pain hematuria syndrome (LPHS) is rare and seldom diagnosed, yet it has a particularly significant impact on those affected. This is a review of the latest and seminal evidence of the pathophysiology and diagnosis of LPHS and presents the typical clinical presentation and treatment options available. RECENT FINDINGS: LPHS is typically found in young women with characteristic symptoms, including severe recurrent flank pain and gross or microscopic hematuria. The majority of patients will experience crippling pain for many years without effective therapy, often requiring frequent use of narcotic medication. However, the lack of conclusive pathophysiology, in conjunction with the rarity of LPHS, has prohibited the development and trial of definitive treatment options. Nevertheless, in order to combat this rare but severe disease, management strategies have continued to evolve, ranging from conservative measures to invasive procedures. This review presents an overview of the current hypotheses on the pathophysiology of LPHS in addition to summarizing the management strategies that have been utilized. Only 30% of LPHS patients will experience spontaneous resolution, whereas the majority will continue to face chronic, crippling pain. Several methods of treatment, including invasive and non-invasive, may provide an improved outcome to these patients. Treatment should be individually tailored and multi-disciplinary in nature. Further research is required to further elucidate the pathophysiology and develop new, specific, treatment options.

Systematic Nerve Sparing during Surgery for Deep-infiltrating Posterior Endometriosis Improves Immediate Postoperative Urinary Outcomes.

STUDY OBJECTIVE: Evaluate the feasibility and risk-benefit ratio of systematic nerve sparing by complete dissection of the inferior hypogastric nerves and afferent pelvic splanchnic nerves during surgery for deep-infiltrating endometriosis (DIE) on the basis of complication rates and postoperative bladder morbidity. DESIGN: Observational before (2012-2014)-and-after (2015-2017) study based on a prospectively completed database of all patients treated medically or surgically for endometriosis. SETTING: Unicentric study at the Centre Hospitalier Intercommunal de Poissy-St-Germain-en-Laye. PATIENTS: This study included patients undergoing laparoscopic surgery for DIE (pouch of Douglas resection with or without colpectomy or bilateral uterosacral ligament resection), with complete excision of all identifiable endometriotic lesions, with or without an associated digestive procedure, between 2012 and 2017. The exclusion criteria included prior history of surgery for DIE or colorectal DIE excision, unilateral uterosacral ligament resection, and bladder endometriotic lesions. INTERVENTIONS: For the patients in group 1 (2012-2014, n = 56), partial dissection of the pelvic nerves was carried out only if they were macroscopically caught in endometriotic lesions, without dissection of the pelvic splanchnic nerves. The patients in group 2 (2015-2017, n = 65) systematically underwent nerve sparing during DIE surgery, with dissection of the inferior hypogastric nerves and pelvic splanchnic nerves. MEASUREMENTS AND MAIN RESULTS: Both groups were comparable in terms of patient age, parity, body mass index, and previous abdominal surgery. The operating times were similar in both groups (228 ± 105 minutes in group 2 vs 219 ± 71 minutes in group 1), as were intra- and postoperative complication rates. Time to voiding was significantly longer in the patients in group 1 (p <.01), with 7 (12.9%) patients requiring self-catheterization in this group compared with no patients (0%) in group 2. The duration of self-catheterization for the 7 patients in group 1 was 28, 21, 3, 60, 21, 1 (stopped by the patient), and 28 days, respectively. Uroflowmetry on postoperative day 10 was abnormal in 5/25 patients in group 1 compared with 1/33 in group 2 (p = .031). CONCLUSION: Systematic and complete nerve sparing, including pelvic splanchnic nerve dissection, during surgery for posterior DIE improves immediate postoperative urinary outcomes, reducing the need for self-catheterization without increasing operating time or complication rates.

A Novel Direct Approach to the Deep Uterine Vein in Laparoscopic Radical Hysterectomy.

STUDY OBJECTIVE: To describe a direct approach to the deep uterine vein in laparoscopic radical hysterectomy. DESIGN: Demonstration of the laparoscopic technique with narrated video footage. SETTING: Securing sufficient radicality is extremely important when performing a radical hysterectomy for cervical cancer, either by laparotomy or by minimally invasive surgery. The nerve-sparing Okabayashi radical hysterectomy (NS-RH) was originally aimed at achieving both radical resection and function preservation [1-3]. A key procedure when performing NS-RH is intraoperative identification of the relationship between the deep uterine vein and pelvic splanchnic nerve fibers [4]. With this in mind, a safe and easy method for identifying the crossing point of the deep uterine vein and pelvic splanchnic nerve in the initial phase of the surgery may greatly improve the safety and efficacy of functional preservation in NS-RH. Herein, we describe a minimally invasive "direct approach" to the deep uterine vein. INTERVENTIONS: Before undergoing the pelvic lymphadenectomy, all steps of laparoscopic radical hysterectomy were performed. First, we identified the ureter on the posterior peritoneum, and the peritoneum was dissected just above the ureter. By continuously exploring the pelvic cavity along the ureter, especially through the opening of the space below the ureter in a cranial to caudal direction, we could easily identify the deep uterine vein. This procedure also exposed the fibers of the hypogastric nerve, clarifying the relationship of these structures. CONCLUSION: Because the relationship between the deep uterine vein and nerve fibers is the most important guidepost of this surgery, their identification in the early phase of the surgery enables us to perform the subsequent procedure precisely and securely. This direct approach to the deep uterine vein can be easily and safely performed.

Pelvic Neuroanatomy: An Overview of Commonly Encountered Pelvic Nerves in Gynecologic Surgery.

OBJECTIVE: This video tutorial identifies key anatomic landmarks useful in identifying the path of the most commonly encountered pelvic nerves in benign gynecologic surgery. DESIGN: This is a narrated overview of commonly encountered pelvic nerves during benign gynecology, their origin, sensory, and motor function, as well as sequelae related to injury. SETTING: The unintended injury of pelvic neural connections can be a complication of any pelvic surgery, however, surgery for malignancy or endometriosis may increase the likelihood of encountering these nerves. The majority of focus surrounding surgical nerve injury, however, relates to patient positioning [1]. Injury to the pelvic nerves can lead to lifelong sexual, bladder, and defecatory dysfunction [2]. INTERVENTIONS: We review the Genitofemoral, Lateral Femoral Cutaneous, Ilioinguinal, Obturator, Superior and Inferior Hypogastric nerves, Pelvic Splanchnic nerves, and the Sacral nerves. Surgical illustrations are used (Fig. 1) alongside real-time narrated video to help viewers recognize the normal course of commonly encountered pelvic nerves at the time of gynecologic surgery (Figs2-3). CONCLUSION: The surgical management of complex pelvic disease can unfortunately carry significant patient morbidity [3]. The neural pathways traveling through the pelvis via the hypogastric nerves are responsible for proprioception, vaginal lubrication, and proper functioning or the urethral and anal sphincters [4]. Sparing these nerves during pelvic surgery, and especially when anatomic planes are distorted by pelvic disease, requires surgical expertise and an immense understanding of pelvic neuroanatomy [4,5]. Preservation of the pelvic neural pathways is necessary to deliver the best patient outcomes while minimizing unwanted surgical complications. This video tutorial also highlights the origin of these nerves, their anatomic location, procedures in which these nerves may be encountered, and what sequelae occur from their unintended injury.

Cholinergic and peptidergic neurotransmission in the adrenal medulla: A dynamic control of stimulus-secretion coupling.

Synaptic neurotransmission at the splanchnic nerve-chromaffin cell synapse is a chief element of the stimulus-secretion coupling in the adrenal medullary tissue, managing and regulating the secretion of catecholamines. Making the state of play more intricate than initially envisioned, the synaptic vesicles of nerve terminals innervating the medulla contain various compounds, including various neurotransmitters and neuropeptides. Under basal conditions associated with a low splanchnic nerve discharge rate, neurotransmission is ensured by the synaptic release of the primary neurotransmitter acetylcholine (ACh). Under sustained and repetitive stimulations of the splanchnic nerve, as triggered in response to stressors, the synaptic release of neuropeptides, such as the pituitary adenylate cyclase-activating polypeptide PACAP, supplants ACh release. The anatomical and functional changes that occur presynaptically at the preganglionic splanchnic nerve, combined with changes occurring postsynaptically at nicotinic acetylcholine receptors (nAChRs), confer the adrenomedullary synapses a solid and persistent aptitude to functional remodeling, from birth to aging. The present review focuses on the composite cholinergic and noncholinergic nature of neurotransmission occurring at the splanchnic nerve-chromaffin cell synapse and its remodeling in response to physiological or pathological stimuli.

Anatomy of the female pelvic nerves: a macroscopic study of the hypogastric plexus and their relations and variations.

The autonomic nerves of the lesser pelvis are particularly prone to iatrogenic lesions due to their exposed position during manifold surgical interventions. Nevertheless, the cause of rectal and urinary incontinence or sexual dysfunctions, for example after rectal cancer resection or hysterectomy, remains largely understudied, particularly with regard to the female pelvic autonomic plexuses. This study focused on the macroscopic description of the superior hypogastric plexus, hypogastric nerves, inferior hypogastric plexus, the parasympathetic pelvic splanchnic nerves and the sympathetic fibres. Their arrangement is described in relation to commonly used surgical landmarks such as the sacral promontory, ureters, uterosacral ligaments, uterine and rectal blood vessels. Thirty-one embalmed female pelvises from 20 formalin-fixed and 11 Thiel-fixed cadavers were prepared. In all cases explored, the superior hypogastric plexus was situated anterior to the bifurcation of the abdominal aorta. In 60% of specimens, it reached the sacral promontory, whereas in 40% of specimens, it continued across the pelvic brim until S1. In about 25% of the subjects, we detected an accessory hypogastric nerve, which has not been systematically described so far. It originated medially from the inferior margin of the superior hypogastric plexus and continued medially into the presacral space. The existence of an accessory hypogastric nerve was confirmed during laparoscopy and by histological examination. The inferior hypogastric plexuses formed fan-shaped plexiform structures at the end of both hypogastric nerves, exactly at the junction of the ureter and the posterior wall of the uterine artery at the uterosacral ligament. In addition to the pelvic splanchnic nerves from S2-S4, which joined the inferior hypogastric plexus, 18% of the specimens in the present study revealed an additional pelvic splanchnic nerve originating from the S1 sacral root. In general, form, breadth and alignment of the autonomic nerves displayed large individual variations, which could also have a clinical impact on the postoperative function of the pelvic organs. The study serves as a basis for future investigations on the autonomic innervation of the female pelvic organs.

Functional segregation within the pelvic nerve of male rats: a meso- and microscopic analysis.

The pelvic splanchnic nerves are essential for pelvic organ function and have been proposed as targets for neuromodulation. We have focused on the rodent homologue of these nerves, the pelvic nerves. Our goal was to define within the pelvic nerve the projections of organ-specific sensory axons labelled by microinjection of neural tracer (cholera toxin, subunit B) into the bladder, urethra or rectum. We also examined the location of peptidergic sensory axons within the pelvic nerves to determine whether they aggregated separately from sacral preganglionic and paravertebral sympathetic postganglionic axons travelling in the same nerve. To address these aims, microscopy was performed on the major pelvic ganglion (MPG) with attached pelvic nerves, microdissected from young adult male Sprague-Dawley rats (6-8 weeks old) and processed as whole mounts for fluorescence immunohistochemistry. The pelvic nerves were typically composed of five discrete fascicles. Each fascicle contained peptidergic sensory, cholinergic preganglionic and noradrenergic postganglionic axons. Sensory axons innervating the lower urinary tract (LUT) consistently projected in specific fascicles within the pelvic nerves, whereas sensory axons innervating the rectum projected in a complementary group of fascicles. These discrete aggregations of organ-specific sensory projections could be followed along the full length of the pelvic nerves. From the junction of the pelvic nerve with the MPG, sensory axons immunoreactive for calcitonin gene-related peptide (CGRP) showed several distinct patterns of projection: some projected directly to the cavernous nerve, others projected directly across the surface of the MPG to the accessory nerves and a third class entered the MPG, encircling specific cholinergic neurons projecting to the LUT. A subpopulation of preganglionic inputs to noradrenergic MPG neurons also showed CGRP immunoreactivity. Together, these studies reveal new molecular and structural features of the pelvic nerves and suggest functional targets of sensory nerves in the MPG. These anatomical data will facilitate the design of experimental bioengineering strategies to specifically modulate each axon class.

Differential biomechanical properties of mouse distal colon and rectum innervated by the splanchnic and pelvic afferents.

Visceral pain is one of the principal complaints of patients with irritable bowel syndrome, and this pain is reliably evoked by mechanical distension and stretch of distal colon and rectum (colorectum). This study focuses on the biomechanics of the colorectum that could play critical roles in mechanical neural encoding. We harvested the distal 30 mm of the colorectum from mice, divided evenly into three 10-mm-long segments (colonic, intermediate and rectal), and conducted biaxial mechanical stretch tests and opening-angle measurements for each tissue segment. In addition, we determined the collagen fiber orientations and contents across the thickness of the colorectal wall by nonlinear imaging via second harmonic generation (SHG). Our results reveal a progressive increase in tissue compliance and prestress from colonic to rectal segments, which supports prior electrophysiological findings of distinct mechanical neural encodings by afferents in the lumbar splanchnic nerves (LSN) and pelvic nerves (PN) that dominate colonic and rectal innervations, respectively. The colorectum is significantly more viscoelastic in the circumferential direction than in the axial direction. In addition, our SHG results reveal a rich collagen network in the submucosa and orients approximately ±30° to the axial direction, consistent with the biaxial test results presenting almost twice the stiffness in axial direction versus the circumferential direction. Results from current biomechanical study strongly indicate the prominent roles of local tissue biomechanics in determining the differential mechanical neural encoding functions in different regions of the colorectum. NEW & NOTEWORTHY Mechanical distension and stretch-not heat, cutting, or pinching-reliably evoke pain from distal colon and rectum. We report different local mechanics along the longitudinal length of the colorectum, which is consistent with the existing literature on distinct mechanotransduction of afferents innervating proximal and distal regions of the colorectum. This study draws attention to local mechanics as a potential determinant factor for mechanical neural encoding of the colorectum, which is crucial in visceral nociception.