Small bowel transplant - novel indications and recent progress.

INTRODUCTION: Advances in the management of intestinal failure have led to a reduction in the number of intestinal transplants. The number of bowel transplants has been mainly stable even though a slight increase has been observed in the last 5 years. AREAS COVERED: Standard indication includes patients with a reasonable life expectancy. Recent progress can be deduced by the increased number of intestine transplants in adults: this is due to the continuous improvement of 1-year graft survival worldwide (without differences in 3- and 5-year) associated with better abdominal wall closure techniques. This review aims to provide an update on new indications and changes in trends of pediatric and adult intestine transplantation. This analysis, which stretches through the past 5 years, is based on a collection of related manuscripts from PubMed. EXPERT COMMENTARY: Intestinal transplants should be solely intended for a group of individuals for whom indications for transplantation are clear and both medical and surgical rehabilitations have failed. Nevertheless, many protocols developed over the years have not yet solved the key question represented by the over-immunosuppression. Novel indications and recent progress in the bowel transplant field, minimal yet consistent, represent a pathway to be followed.

An overview of the current management of short-bowel syndrome in pediatric patients.

Short-bowel syndrome (SBS) is defined as a state of malabsorption after resection or loss of a major portion of the bowel due to congenital or acquired factors. This article presents an overview on the recent management of pediatric SBS. The pediatric SBS population is very heterogeneous. The incidence of SBS is estimated to be 24.5 per 100,000 live births. The nutritional, medical, and surgical therapies available require a comprehensive evaluation. Thus, multidisciplinary intestinal rehabilitation programs (IRPs) are necessary for the management of these complex patients. The key points of focus in IRP management are hepato-protective strategies to minimize intestinal failure-associated liver disease; the aggressive prevention of catheter-related bloodstream infections; strategic nutritional supply to optimize the absorption of enteral calories; and the management and prevention of small bowel bacterial overgrowth, nephrocalcinosis, and metabolic bone disease. As the survival rate of children with SBS currently exceeds 90%, the application of small bowel transplantation has been evolving. The introduction of innovative treatments, such as combined therapy of intestinotrophic hormones, including glucagon-like peptide-2, may lead to further improvements in patients' quality of life.

A novel technique for large lateral enterocutaneous fistula management after intestinal transplantation.

BACKGROUND: Enterocutaneous fistula (ECF) is a serious and complex problem when affecting children, being responsible for a high morbidity burden, with an estimated mortality rate of 10 to 20%. There are many therapeutic options, including surgery and a wide variety of nonoperative strategies. Prognosis of ECF closure depends on the output and also on the patency of distal bowel. Spontaneous closure without operative intervention occurs in approximately 50% of patients with lateral ECF and distal bowel transit, but this drastically decreases in high output fistulas. High-volume fistula output and consequent skin damage are a great challenge for the health-care team. METHODS: We describe a postoperative complication that required a new nonoperative technique for the transient management of a lateral high-output ECF, involving the insertion of an occlusive device in order to redirect intestinal content to the distal bowel, reducing the fistula output. RESULTS AND CONCLUSIONS: The main benefit of this nonoperative technique is the ability to occlude a high-output fistula, allowing the distal flow to be restored and reducing abdominal wall damage, as a bridge to definitive surgical closure.

Biliary and duodenal complications after « en bloc¼ liver-small bowel transplantation in children. A single center cohort study.

BACKGROUND: The technique of « en bloc¼ liver and small bowel transplantation (L-BT) spares a biliary anastomosis, but does not protect against biliary complications. We analyze biliary and duodenal complications (BDC) in our pediatric series. METHODS: Between 1994 and 2020, 54 L-BT were performed in 53 children. The procurement technique included in situ vascular dissection and pancreatic reduction to the head until 2009 (group A). Thereafter, the whole pancreas was recovered (group B). RESULTS: Nine BDCs occurred in 8/53 (15%) patients (7 in group A and 1 in group B): leak of the donor's duodenal stump (2), stenosis of the extra-pancreatic bile duct (5), and intra-pancreatic bile duct stenosis (2). Median delay for diagnosis of stricture was 8 months (4-168). Interventional radiology was successful in one child only, the others required reoperations. Two patients died, of biliary cirrhosis or cholangitis, 15-month and 12-year post-L-BT. One was listed and liver re-transplanted 13 years post-L-BT. At last follow-up, two patients only had normal liver tests and ultrasound. CONCLUSION: BDC after L-BT can cause severe morbidities. Pancreatic reduction might increase this risk. Early surgical complications or chronic pancreatic rejection might be co-factors. Early diagnosis and treatment are key to the long-term prognosis.

Paraneoplastic pemphigus associated with post-transplant lymphoproliferative disorder after small bowel transplantation.

BACKGROUND: PNP is a malignancy-associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP-causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children. METHODS: Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein-losing enteropathy. RESULTS: The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years. CONCLUSION: It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T-cell suppressive treatments for her small bowel transplantation.

Perioperative alterations in the intestinal microbiota and functional changes mediate innate immune activation after small bowel transplantation.

AIM: Small bowel transplantation (SBT) is the only therapy for end-stage short bowel syndrome. However, complicated pathological changes and an increased risk of postoperative infections in the perioperative period are major obstacles to patient survival, but the associated mechanisms remain unclear. METHODS: To explore perioperative alterations in the intestinal microbiota and their functional changes after SBT, 16S rRNA sequencing of ileostomy effluents and plasma analysis were performed pre-SBT and periodically post-SBT. RESULTS: The results suggested that the presence of Proteobacteria accelerated bacterial motility and chemotaxis during the first week in post-SBT recipients. Altered gut microbiota impaired intestinal barrier integrity and upregulated 16S rDNA, pathogen-associated molecular pattern (PAMP) and pattern-recognition molecule (PRM) levels in peripheral circulation. Importantly, the levels of neutrophils, monocytes, cytotoxic T lymphocytes, and natural killer cells and the expression of proinflammatory cytokines were increased in the peripheral blood and had potential roles in activating innate immune-mediated inflammatory injury after SBT. CONCLUSION: Together, our results suggest that altered microbiota and functional changes are probably related to innate immune-mediated inflammatory injury and graft survival after SBT, suggesting that the monitoring and regulation of intestinal microbiota are necessary for SBT patients.

Ex vivo normothermic perfusion of isolated segmental porcine bowel: a novel functional model of the small intestine.

BACKGROUND: There is an unmet need for suitable ex vivo large animal models in experimental gastroenterology and intestinal transplantation. This study details a reliable and effective technique for ex vivo normothermic perfusion (EVNP) of segmental porcine small intestine. METHODS: Segments of small intestine, 1.5-3.0 m in length, were retrieved from terminally anaesthetized pigs. After a period of cold ischaemia, EVNP was performed for 2 h at 37°C with a mean pressure of 80 mmHg using oxygenated autologous blood diluted with Ringer's solution. The duration of EVNP was extended to 4 h for a second set of experiments in which two segments of proximal to mid-ileum (1.5-3.0 m) were retrieved from each animal and reperfused with whole blood (control) or leucocyte-depleted blood to examine the impact of leucocyte depletion on reperfusion injury. RESULTS: After a mean cold ischaemia time of 5 h and 20 min, EVNP was performed in an initial group of four pigs. In the second set of experiments, five pigs were used in each group. In all experiments bowel segments were well perfused and exhibited peristalsis during EVNP. Venous glucose levels significantly increased following luminal glucose stimulation (mean(s.e.m.) basal level 1.8(0.6) mmol/l versus peak 15.5(5.8) mmol/l; P < 0.001) and glucagon-like peptide 1 (GLP-1) levels increased in all experiments, demonstrating intact absorptive and secretory intestinal functions. There were no significant differences between control and leucocyte-depleted animals regarding blood flow, venous glucose, GLP-1 levels or histopathology at the end of 4 h of EVNP. CONCLUSIONS: This novel model is suitable for the investigation of gastrointestinal physiology, pathology and ischaemia reperfusion injury, along with evaluation of potential therapeutic interventions.

Post-stapedotomy reparative granuloma following use of acellular porcine small intestinal submucosa.

PURPOSE: There have been multiple proposed etiologies of reparative granuloma following stapes surgery. In this report, we present the first case of post-stapedectomy reparative granuloma following the use of Biodesign (Cook Medical, Bloomington, IN) otologic graft material, an acellular matrix derived from porcine small intestinal submucosa, and review the literature of post-stapes surgery reparative granuloma. PATIENT: 50-year-old woman who developed a reparative granuloma following stapedotomy with acellular porcine intestinal submucosa presenting with profound hearing loss and vertigo. INTERVENTION: Middle ear exploration with excision of granuloma and revision stapedotomy. MAIN OUTCOME MEASURES: Audiologic outcomes as measured by pure-tone air and bone conduction thresholds and word recognition scores. Improvement in vertigo. MAIN FINDINGS: Surgical excision of the reparative granuloma with revision stapedotomy resolved vertigo. Hearing has improved progressively postoperatively. CONCLUSIONS: We report the first case of post-stapedotomy reparative granuloma following the use of acellular porcine intestinal submucosa. Although exact etiology cannot be determined from a single case report, this illustrates the need for careful use of novel foreign graft material. This case additionally confirms that removal of granuloma and inciting materials can salvage serviceable hearing.

De novo hepatocellular carcinoma 18 years after liver and small bowel transplantation in a one-year-old pediatric patient.

De novo HCC following transplantation in a child is a rare occurrence. Even within the adult liver transplantation population, there are a limited number of published cases. In this report, we present a case of de novo HCC found in a child, post-multivisceral transplantation. A 19-year-old boy, at the age of one, received liver and small bowel transplantation due to short gut syndrome secondary to midgut volvulus and total parenteral nutrition-associated liver disease. Eighteen years later, he was found to have a large mass involving the right hepatic dome consistent with HCC. To the best of our knowledge, this is the second reported case after gut transplantation and the third case post-liver transplantation in the pediatric population.

Ultrasound-guided double central venous access for azygos vein via the ninth and tenth intercostal veins.

Some patients with intestinal failure, who are dependent on total parenteral nutrition for long periods, suffer from a lack of suitable conventional venous access points, including axillary, external jugular, internal jugular, subclavian, saphenous, and the brachio-cephalic and femoral veins, due to their occlusion. Furthermore, extensive central venous stenosis and/or thrombosis of the superior and inferior vena cava may preclude further catheterization, so uncommon routes must be used, which can be challenging. In such patients, the azygos vein via the intercostal vein is a viable candidate. Thoracotomy-assisted, thoracoscopy-assisted, and cut-down procedures are currently suggested such access. We found that ultrasound-guided percutaneous puncture method was a safe and minimally invasive approach and successfully placed two central venous lines in preparation for small bowel transplantation via two different intercostal veins (ninth and tenth). Although the lung was actually located just below the target veins, an ultrasound provided augmented and clear vision, which contributed to the safe performance of the procedure without the need for invasive surgical intervention, such as thoracotomy, thoracoscopy, or rib resection using the cut-down technique. Furthermore, constant positive-pressure ventilation during vein puncture under general anesthesia also helps avoid venous collapse. Despite carrying a slight risk of light injury to the lung, artery, and nerve along with the vein compared to other procedures, we believe that ultrasound-guided puncture under general anesthesia is feasible as a minimally invasive method.

Multiple rare-earth magnet bead ingestion in a pediatric liver-small bowel-pancreas transplant recipient: A case report and lessons learned.

Ingestion of rare-earth magnet beads in children has been a public health concern. The potential risk of swallowing multiple magnets is related to magnet attraction to each other, resulting in serious gastrointestinal complications, such as entero-enteric fistula formation, peritonitis, bowel ischemia or necrosis, bowel perforation, and potentially death. We describe the clinical outcome of a 10-year-old child with a liver-small bowel-pancreas transplant who swallowed 26 rare-earth magnetic beads. The patient presented with fever and abdominal pain. Due to difficulty locating the magnets and post-surgical anatomy changes, only 25 magnets were removed endoscopically. After the procedure, she continued to have abdominal distention and fever, leading to further investigation and subsequently an exploratory laparotomy, which confirmed a walled-off perforation. She was treated conservatively with bowel rest and antibiotics, without the need for small bowel graft resection. She recovered well and was eventually discharged on her home enteral feeding regimen. This case emphasizes the importance of taking a good history and having a high index of suspicion to diagnose this dangerous clinical condition, especially in children with an associated predisposing condition for foreign body ingestion, such as developmental delay. Early diagnosis of multiple magnet bead ingestion and prompt detection of its complications in pediatric intestinal transplant recipients could help initiate appropriate intervention and prevent intestinal graft loss.

Post-transplant hepatic fibrosis in pediatric liver-small bowel transplant recipients: A single-center, retrospective, observational study.

BACKGROUND: Little is known about the prevalence of hepatic graft fibrosis in combined LSBT children. We aimed to determine the prevalence of and identify potential predictors for hepatic graft fibrosis in LSBT children and to compare them with those in LT children. METHODS: We retrospectively included children younger than 19 years who had received a primary LT/LSBT between 2000 and 2018 and had a liver biopsy performed at least 6 months post-transplant. A Cox proportional hazards regression model was used to determine predictors associated with significant hepatic graft fibrosis (≥F2) in LSBT vs LT children. RESULTS: Ninety-six children (47 LSBT, 54 females) were included. The median post-transplant follow-up (years) was 12.8 in LT vs 10.5 in LSBT patients (P = .06). Hepatic graft fibrosis was found in 81.6% of LT vs 70.2% of LSBT children (P = .19), after a median time of 2.5 years and 2.6 years, respectively. On multivariate analyses, having post-transplant biliary complications was found to be associated with significant graft fibrosis in LT children, whereas AST/ALT ratio was found to predict significant hepatic graft fibrosis in LSBT children. The use of parenteral nutrition after transplant was not associated with significant hepatic graft fibrosis. CONCLUSIONS: The prevalence of hepatic graft fibrosis in LSBT children did not significantly differ from that in LT children, but the predictors may differ. Future studies should investigate the role of post-transplant autoimmune antibodies and donor-specific antibodies in the development and progression of hepatic graft fibrosis in LSBT children.

Surveillance of Rejection After Intestinal Transplantation Using an Image Enhanced Endoscopy "VENCH" Scoring System.

BACKGROUND: Graft rejection after intestinal transplantation remains challenging. We aimed to use endoscopy for rejection prediction. MATERIALS AND METHODS: Patients ≥7 years old who underwent intestinal transplantation between November 2016 and September 2019 were prospectively enrolled. Magnifying endoscopy under narrow-band imaging was performed through ileostomy. Endoscopic findings were reported as five components (each graded from 0-2): "V" (villi appearance), "E" (erythema), "N" (capillary network), "C" (crypt widening), and "H" (heterogeneity). The correlation between histological severity and endoscopic score was analyzed. RESULTS: Ninety-nine endoscopic biopsies from three female and one male patient were analyzed. The mean ± SD age was of 41.25±13.77 (range 29-58) years. Three short bowel syndrome patients after multiple intestinal resections and one with chronic intestinal pseudo-obstruction were indicated for intestinal transplantation. Sensitivity, specificity, and accuracy of V, E, N, C, and H scores for predicting rejection were 97.4%, 45.9%, 65.7%; 94.7%, 70.5%, 79.8%; 97.4%, 52.5%, 69.7%; 94.7%, 54.1%, 69.7%; and 97.4%, 62.3%, 75.8%, respectively. Pearson's correlation coefficients between total and individual V, E, N, C, H scores and histological rejection were 0.79, 0.64, 0.70, 0.71, 0.73, and 0.66, respectively (P < .001). To predict mild and moderate/severe rejection, total scores more than 4 and 6 had the sensitivity/specificity of 87.50%/57.38% and 96.67%/85.25%, respectively (area under the ROC 0.791 and 0.987). CONCLUSION: Endoscopic VENCH scoring is promising for predicting rejection after IT. More studies are warranted to validate such results. (ClinicalTrials.gov number, NCT03616548.).

Luminal preloading with hydrogen-rich saline ameliorates ischemia-reperfusion injury following intestinal transplantation in rats.

Prolonged intestinal cold storage causes considerable mucosal breakdown, which could bolster bacterial translocation and cause life-threatening infection for the transplant recipient. The intestine has an intraluminal compartment, which could be a target for intervention, but has not yet been fully investigated. Hydrogen gas exerts organ protection and has used been recently in several clinical and basic research studies on topics including intestinal transplantation. In this study, we aimed to investigate the cytoprotective efficacy of intraluminally administered hydrogen-rich saline on cold IR injury in intestinal transplantation. Isogeneic intestinal transplantation with 6 hours of cold ischemia was performed on Lewis rats. Hydrogen-rich saline (H2 concentration at 5 ppm) or normal saline was intraluminally introduced immediately before preservation. Graft intestine was excised 3 hours after reperfusion and analyzed. Histopathological analysis of control grafts revealed blunting of the villi and erosion. These mucosal changes were notably attenuated by intraluminal hydrogen. Intestinal mucosa damage caused by IR injury led to considerable deterioration of gut barrier function 3 h post-reperfusion. However, this decline in permeability was critically prevented by hydrogen treatment. IR-induced upregulation of proinflammatory cytokine mRNAs such as IL-6 was mitigated by hydrogen treatment. Western blot revealed that hydrogen treatment regulated loss of the transmembrane protein ZO-1. Hydrogen-rich saline intraluminally administered in the graft intestine modulated IR injury to transplanted intestine in rats. Successful abrogation of intestinal IR injury with a novel strategy using intraluminal hydrogen may be easily clinically applicable and will compellingly improve patient care after transplantation.

Human Small Intestine Transplantation: Segmental Susceptibility to Ischemia Using Different Preservation Solutions and Conditions.

BACKGROUND AND AIMS: Among all transplanted abdominal organs, the small intestine is one of the most ischemia sensitive. Appropriate graft selection, procurement, and preservation are crucial for optimum graft and patient survival. We evaluated ischemic damage in human small intestine grafts under different hypothermic preservation conditions (cold static and continuous perfusion) and solutions: histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW). METHODS: Fourteen small intestinal grafts were procured from deceased donors. HTK and UW were used for the vascular perfusion at the cross clamp, and UW, HTK, or Ringer Lactate were used for the luminal flush at the back table. Therefore, part of the same harvested intestine was stored in cold static storage and in continuous perfusion preservation (with intestinal perfusion unit) simultaneously. Histological samples were collected from the jejunum and ileum at different time points and different preservation conditions. The samples were collected before the initiation of cold storage (T0), after 8 hours of cold static (ST8), or after 8 hours of continuous perfusion preservation (PT8) (n = 161 samples). Blinded histological evaluation was conducted and ischemic damage was determined using the Park/Chiu scale. RESULTS: The ileum had less ischemic damage than the jejunum, regardless of using static or continuous perfusion preservation. There was no significantly ischemic damage difference between intestinal grafts flushed and perfused with UW or HTK. CONCLUSION: The jejunum is more susceptible to ischemic injury than the ileum. UW and HTK are equivalent to preserve intestinal graft. This suggests that selective transplantation of ileum could reduce ischemia-related postoperative complications.

30-Day Outcomes Following Esophageal Replacement in Children: A National Surgical Quality Improvement Project Pediatric Analysis.

INTRODUCTION: The optimal method of esophageal replacement remains controversial. The aim of this study was to evaluate 30-d outcomes of children in the National Surgical Quality Improvement Project Pediatric (NSQIP-P) database who underwent esophageal replacement from 2012 to 2018. METHODS: Demographics, comorbidities, and procedural technique was identified in NSQIP-P and reviewed. Thirty-day outcomes were assessed and stratified by gastric pull-up or tube interposition versus small bowel or colonic interposition. Categorical and continuous variables were assessed by Pearson's chi-square, Fisher's exact, and Wilcoxon rank-sum tests, respectively. Multivariate logistic regression was performed to estimate the effects of procedure technique and clinical risk factors on patient outcomes. RESULTS: Of the 99 cases of esophageal replacement included, 52 (52.5%) utilized a gastric conduit, whereas 47 (47.5%) involved small bowel/colonic esophageal interposition. Overall risk of complications was 52.5%, the most common of which were perioperative transfusion (30.3%), surgical site infection (11.1%), and sepsis (9.1%). Risk of unplanned reoperation was 17.2%, and risk of mortality was 3.0%. Risk for complications, reoperation, and readmission did not differ significantly between those who underwent gastric esophageal replacement and those who underwent small bowel or colonic interposition. Median operative time was shorter in the gastric esophageal replacement group (5.2 versus 8.1 h, P = 0.009). CONCLUSIONS: Among children in NSQIP-P who underwent esophageal replacement from 2012 to 2018, the risk of 30-d complications, unplanned reoperation, and mortality was relatively frequent and was similar across operative techniques. Opportunities exist to improve preoperative optimization, utilization of blood transfusion services, and infectious complications in the perioperative period irrespective of operative technique. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Guideline for Management of Mesenteric Ischemia: Shiraz Intestinal Failure Unit Protocol.

We have recently established an intestinal rehabilitation unit (IRU) in Abu Ali Sina transplantation center affiliated to Shiraz University of Medical Sciences, Iran. Our intestinal failure rehabilitation and transplant program aims to provide state-of-the-art care for adult patients with different degrees of intestinal insufficiency and failure. In the IRU, we aimed to design an algorithmic approach to patients with small bowel ischemia and short bowel syndrome (SBS) based on our institutional experience in our country and based on other pioneering studies from other regions of the world.

Mitral Valve Posterior Leaflet Reconstruction Using Extracellular Matrix: In Vitro Evaluation.

PURPOSE: To investigate the anatomical and functional effects of complete surgical reconstruction of the posterior mitral leaflet and associated chordae tendineae with a patch made of 2-ply small intestinal submucosal extracellular matrix in vitro. METHODS: Seven explanted mitral valves with intact subvalvular apparatus from 80-kg pigs were evaluated in a left heart simulator and served as their own controls. After testing the native valve, the mitral posterior leaflet and associated chordae tendineae were excised and reconstructed by using the 2-ply small intestinal submucosa extracellular matrix patch. The characterization of the reconstruction was based on geometric data from digital images, papillary muscle force, annular tethering force and leaflet pressure force. RESULTS: The reconstructed valves were fully functional without regurgitation, tearing or rupture during incrementally increased pressure from 0 to 120 mmHg. The leaflet areas were preserved after reconstruction, with a normal configuration of the coaptation line. However, the coaptation midpoint moved posteriorly after reconstruction (A2: 15.8 ± 1.4 vs. 18.9 ± 1.5 mm, p = 0.002, diff = 3.1 mm, 95% CI 1.3 to 4.8 mm). The anterior papillary muscle force increased significantly (3.9 vs. 4.6 N, p = 0.029, diff = 0.7 N, 95% CI 0.1 to 1.4 N at 120mmHg) after reconstruction. The posterior papillary muscle force, leaflet pressure force and annular pressure force did not change significantly. CONCLUSIONS: In this in vitro model, mitral valve anatomy and function were comparable between the native mitral valve and our new surgical technique for complete reconstruction of the posterior mitral leaflet and associated chordae tendineae. These promising results warrant further in vivo evaluation.