Sampling Thoracic Duct Lymph After Esophagectomy: A Pilot Study Investigating the "Gut-Lymph" Concept.

Background: Gut-lymph in animal models of acute disease is altered by intestinal ischemia and contributes to the development of systemic inflammation and organ dysfunction. Investigating gut-lymph in humans is hampered difficulty in accessing the thoracic duct (TD) for lymph sampling. The aims of this study were to develop and pilot a technique of intraoperative TD cannulation with delayed embolization to serially measure TD lymph pressure, flow, and composition (including markers of intestinal injury) during the early postoperative period and in response to enteral feeding and vasopressor treatment. Methods: A Seldinger technique was used for percutaneous TD cannulation during an Ivor Lewis esophagogastrectomy. Lymph flow rate and pressure were measured. TD lymph and plasma were sampled at 12 hourly intervals for up to 120 hours after surgery and before TD embolization. Biochemistry, lipids, cytokines, and markers of intestinal injury were measured before and after enteral feeding commenced at 36 hours. Results: Intraoperative TD cannulation was technically feasible in three of four patients. Delayed TD embolization was only successful in one of three patients, with two patients requiring a re-thoracotomy to treat chylothorax. Profound changes in TD composition, but not flow rate, occurred over time and in response to enteral feeding and vasopressors. TD lymph compared with plasma had significantly higher lipase (1.4-17 × ), interleukin-6 (8-108 × ), tumor necrosis factor-α (2.7-17 × ), d-lactate (0.3-23 × ), endotoxin (0.1-41 × ), and intestinal fatty acid binding protein (1.1-853 × ). Conclusions: Although TD cannulation and lymph sampling were successful, TD embolization failed in two of three patients. The composition of sampled TD lymph changed dramatically in response to enteral feeding, indicating intestinal ischemia that could be exacerbated by nonselective vasopressors. The higher concentration of proinflammatory cytokines and gut injury markers in TD lymph, compared with plasma, lends support to the gut-lymph concept.

The Challenges and Effects of Ascorbic Acid Treatment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies.

Background: Oxidative stress has been implicated in the pathogenesis of acute pancreatitis (AP), and ascorbic acid (AA), as an important endogenous antioxidant substance, has been shown to reduce AP severity in preclinical studies. However, the effects of AA supplementation in clinical settings remain controversial. Methods: PubMed, EMBASE, MEDLINE, and SCOPUS databases were searched, and both preclinical and clinical studies were included. For clinical trials, the primary outcome was incidence of organ failure, and for preclinical studies, the primary outcome was histopathological scores of pancreatic injuries. Results: Meta-analysis of clinical trials showed that compared with controls, AA administration did not reduce the incidence of organ failure or mortality during hospitalization but was associated with significantly reduced length of hospital stay. Meta-analysis of preclinical studies showed that AA supplementation reduced pancreatic injury, demonstrated as decreased histological scores and serum amylase, lipase levels. Conclusion: AA administration has no effect on survival or organ failure in patients with AP but may reduce the length of hospital stay. However, the evidence to date remains sparse, scattered, and of suboptimal quality, making it difficult to draw any firm conclusion on the clinical benefits of AA in AP.

An Updated Systematic Review With Meta-analysis: Efficacy of Prebiotic, Probiotic, and Synbiotic Treatment of Patients With Severe Acute Pancreatitis.

OBJECTIVES: The aim of this study was to systematically review the clinical outcomes of all randomized controlled trials of patients with severe acute pancreatitis (SAP) and treated with pre/pro/synbiotics. METHODS: A systematic literature search of the MEDLINE, Embase, clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials was conducted. Eligible studies were randomized controlled trials that evaluated the clinical outcomes of patients with SAP treated with pre/pro/synbiotics. RESULTS: Eleven trials comprising 930 patients were included. Patients treated with pre/pro/synbiotics had a significantly shorter hospital stay [weighted mean difference, -4.33 days; 95% confidence interval (CI), -7.71 to -0.95; P = 0.010; I2 = 66.9%] compared with control. In a subgroup analysis where only patients classified as SAP were included, those treated with pre/pro/synbiotics had lower risk of single- or multiple-organ failure (relative risk, 0.62; 95% CI, 0.44-0.88; P = 0.995; I2 = 0.0%) and decreased hospital stay (weighted mean difference, -0.65 days; 95% CI, -0.90 to -0.41; P = 0.121; I2 = 45.3%) compared with control. CONCLUSIONS: Patients with SAP treated with pre/pro/synbiotics did not have a worse clinical outcome and had lower risk of organ failure and duration of hospital stay. Further studies should examine the optimal timing, type, and dosages of these promising treatments.

Anatomy of the lymphovenous valve of the thoracic duct in humans.

The majority of lymph generated in the body is returned to the blood circulation via the lymphovenous junction (LVJ) of the thoracic duct (TD). A lymphovenous valve (LVV) is thought to guard this junction by regulating the flow of lymph to the veins and preventing blood from entering the lymphatic system. Despite these important functions, the morphology and mechanism of this valve remains unclear. The aim of this study was to investigate the anatomy of the LVV of the TD. To do this, the TD and the great veins of the left side of the neck were harvested from 16 human cadavers. The LVJs from 12 cadavers were successfully identified and examined macroscopically, microscopically, and using microcomputed tomography. In many specimens, the TD branched before entering the veins. Thus, from 12 cadavers, 21 LVJs were examined. Valves were present at 71% of LVJs (15/21) and were absent in the remainder. The LVV, when present, was typically a bicuspid semilunar valve, although the relative size and position of its cusps were variable. Microscopically, the valve cusps comprised luminal extensions of endothelium with a thin core of collagenous extracellular matrix. This study clearly demonstrated the morphology of the human LVV. This valve may prevent blood from entering the lymphatic system, but its variability and frequent absence calls into question its utility. Further structural and functional studies are required to better define the role of the LVV in health and disease.

Spinal Cord Stimulation for Management of Pain in Chronic Pancreatitis: A Systematic Review of Efficacy and Complications.

OBJECTIVES: Spinal cord stimulation (SCS) has been used to manage pain in patients with chronic pancreatitis (CP). The aim of this systematic review was to summarize the effectiveness and complications of SCS in the management of pain associated with CP. MATERIALS AND METHODS: An exploratory systematic review was performed through a literature search of the PubMed, Medline, EMBASE, SCOPUS, and Cochrane databases. RESULTS: Seven studies including 31 patients met the inclusion criteria. There was one observational cohort study, two case series, and four case reports. The estimated median age of the study group was 44 years (range 21-87 years) in primarily nonalcoholic CP (74%, 23/31). The SCS leads were typically placed at the level of T6-T8 in the epidural space. All patients reported an improvement in pain. The estimated median reduction of visual analogue pain scores was 61% (range 50%-100%) with an estimated median reduction of morphine equivalent opioid use of 69% (range 25%-100%) at the end of follow-up (less than one to greater than two years). Infection at the site of the lead occurred in 2 of the 31 (6%) and lead migration in 2 of the 31 (6%) patients. CONCLUSIONS: This systematic review suggests that SCS has a potentially efficacious role in reducing pain and opioid use in patients with CP.

Patient characteristics and clinical outcomes following initial surgical intervention for MEN1 associated pancreatic neuroendocrine tumours: A systematic review and exploratory meta-analysis of the literature.

BACKGROUND: This systematic review aimed to define the outcomes of different pancreatic resection procedures for multiple endocrine neoplasia type 1 (MEN1) associated pancreatic neuroendocrine neoplasms (pNENs). METHODS: A search of PubMed, MEDLINE and SCOPUS databases were performed in accordance with PRISMA guidelines. RESULTS: Twenty-seven studies including 533 patients undergoing initial pancreatic resection for MEN1 associated pNENs were included in this systematic review. Three hundred and sixty-six (68.7%) distal pancreatectomies (DP), 120 (22.5%) sole enucleations (SE) and 47 (8.8%) pancreaticoduodenectomies (PD) were identified. SE was associated with a higher rate of recurrence than DP (25/67, 37% vs 40/190, 21% respectively, P = 0.008) but a lower rate of endocrine insufficiency than PD (1/20, 5% vs 8/21, 38% respectively, P = 0.010). A meta-analysis of major pancreatic resections (PD or DP) vs SE in 15 studies showed that SE is associated with an increased rate of recurrence (Major resection 42/184, 23% vs SE 20/53, 38% RR 0.65 CI 0.43-0.96 P = 0.032) but reduced rate of postoperative endocrine insufficiency (Resection 37/93, 40% vs SE 0/24, 0% RR 7.37 CI 1.57-34.64 P = 0.008). Similarly, insulinomas and functional pNENs overall had lower rates of recurrence and reoperation with major resection. There was no difference in the reoperation rates or survival outcomes after SE compared with major pancreatic resections at follow-up (pooled overall mean duration: 85 months). CONCLUSION: Major pancreatic resections for MEN1 associated pNENs have a lower risk of recurrence and a higher risk of postoperative endocrine insufficiency when compared to sole enucleation, but a similar rate of reoperation and survival.

Renal Lymphatics: Anatomy, Physiology, and Clinical Implications.

Renal lymphatics are abundant in the cortex of the normal kidney but have been largely neglected in discussions around renal diseases. They originate in the substance of the renal lobule as blind-ended initial capillaries, and can either follow the main arteries and veins toward the hilum, or penetrate the capsule to join capsular lymphatics. There are no valves present in interlobular lymphatics, which allows lymph formed in the cortex to exit the kidney in either direction. There are very few lymphatics present in the medulla. Lymph is formed from interstitial fluid in the cortex, and is largely composed of capillary filtrate, but also contains fluid reabsorbed from the tubules. The two main factors that contribute to renal lymph formation are interstitial fluid volume and intra-renal venous pressure. Renal lymphatic dysfunction, defined as a failure of renal lymphatics to adequately drain interstitial fluid, can occur by several mechanisms. Renal lymphatic inflow may be overwhelmed in the setting of raised venous pressure (e.g., cardiac failure) or increased capillary permeability (e.g., systemic inflammatory response syndrome). Similarly, renal lymphatic outflow, at the level of the terminal thoracic duct, may be impaired by raised central venous pressures. Renal lymphatic dysfunction, from any cause, results in renal interstitial edema. Beyond a certain point of edema, intra-renal collecting lymphatics may collapse, further impairing lymphatic drainage. Additionally, in an edematous, tense kidney, lymphatic vessels exiting the kidney via the capsule may become blocked at the exit point. The reciprocal negative influences between renal lymphatic dysfunction and renal interstitial edema are expected to decrease renal function due to pressure changes within the encapsulated kidney, and this mechanism may be important in several common renal conditions.

Validation of Modified Determinant-Based Classification of severity for acute pancreatitis in a tertiary teaching hospital.

BACKGROUND: The relative merits of two recent classifications of acute pancreatitis severity, the Determinant-Based Classification (DBC) and the Revised Atlanta Classification (RAC), have been debated. A Modified DBC (MDBC) was recently proposed in intensive care unit (ICU) patients. By dividing the DBC 'severe' category into two groups, the MDBC classified non-mild acute pancreatitis into 4 groups rather than 2 in RAC and 3 in DBC. In this study we aim to validate MDBC in both ICU and non-ICU patients and evaluate infected necrosis as a determinant of severity. METHODS: Prospective data collected on consecutive patients admitted to a tertiary teaching hospital were retrospectively analyzed. Patients were assigned to the categories of severity defined by the DBC, RAC and MDBC. Clinical interventions and outcomes were compared between categories. RESULTS: A total of 1102 patients were enrolled and the overall mortality was 5.7%. When MDBC was applied, the four Groups were significantly different in regard to ICU admission rates (30%, 40%, 69% and 87%) and mortality (2%, 15%, 40% and 57%). Groups 2 and 3 were different in intervention rates and morbidity, providing evidence that IN is an important determinant of severity. CONCLUSIONS: This study validates the MDBC proposal to subdivide the DBC 'severe' category into two groups for ICU and non-ICU patients in a tertiary hospital.

The anatomy and physiology of the terminal thoracic duct and ostial valve in health and disease: potential implications for intervention.

The thoracic duct (TD) transports lymph drained from the body to the venous system in the neck via the lymphovenous junction. There has been increased interest in the TD lymph (including gut lymph) because of its putative role in the promotion of systemic inflammation and organ dysfunction during acute and critical illness. Minimally invasive TD cannulation has recently been described as a potential method to access TD lymph for investigation. However, marked anatomical variability exists in the terminal segment and the physiology regarding the ostial valve and terminal TD is poorly understood. A systematic review was conducted using three databases from 1909 until May 2017. Human and animal studies were included and data from surgical, radiological and cadaveric studies were retrieved. Sixty-three articles from the last 108 years were included in the analysis. The terminal TD exists as a single duct in its terminal course in 72% of cases and 13% have multiple terminations: double (8.5%), triple (1.8%) and quadruple (2.2%). The ostial valve functions to regulate flow in relation to the respiratory cycle. The patency of this valve found at the lymphovenous junction opening, is determined by venous wall tension. During inspiration, central venous pressure (CVP) falls and the valve cusps collapse to allow antegrade flow of lymph into the vein. During early expiration when CVP and venous wall tension rises, the ostial valve leaflets cover the opening of the lymphovenous junction preventing antegrade lymph flow. During chronic disease states associated with an elevated mean CVP (e.g. in heart failure or cirrhosis), there is a limitation of flow across the lymphovenous junction. Although lymph production is increased in both heart failure and cirrhosis, TD lymph outflow across the lymphovenous junction is unable to compensate for this increase. In conclusion the terminal TD shows marked anatomical variability and TD lymph flow is controlled at the ostial valve, which responds to changes in CVP. This information is relevant to techniques for cannulating the TD, with the aid of minimally invasive methods and high resolution ultrasonography, to enable longitudinal physiology and lymph composition studies in awake patients with both acute and chronic disease.

Indications, techniques, and clinical outcomes of thoracic duct interventions in patients: a forgotten literature?

BACKGROUND: The evolution of the "gut-lymph concept" has promoted thoracic duct (TD) lymph drainage as a possible treatment to reduce systemic inflammation and end-organ dysfunction in acute illness. The aim was to review the published experience of thoracic duct interventions (TDIs) aimed at improving clinical outcomes. METHODS: A search of three databases (MEDLINE, EMBASE, and EMBASE CLASSIC) over the last 60 y. The indications for intervention, the technique, and clinical outcomes were reviewed. RESULTS: There were a wide range of indications for TDI. These included reducing rejection after transplantation, treating inflammatory diseases, and reducing chronic failure of the liver, kidney, and heart. The techniques included TD cannulation and lymphovenuous fistula. The outcomes were variable and often equivocal, and this appears to reflect poor design quality. There is clinical equipoise regarding a therapeutic role of (TD lymph drainage in acute pancreatitis, and probably other acute diseases. CONCLUSIONS: Until well-designed clinical trials are undertaken, the clinical benefits of TDIs will remain promising, but uncertain.