Use of a Postoperative Care Management Pathway Reduces the Incidence of Chylothorax Post-Fontan Palliation.

Pleural effusions and chylothorax are challenging morbidities post-Fontan palliation. We sought to evaluate the efficacy of our Fontan Care Pathway (FCP) in reducing the incidence of post-operative chylothorax and Time to Chest Tube Removal (TTCTR), and to determine risk factors associated with longer TTCTR. Between 2016 and 2022 our institutional approach to post-Fontan care fell into three categories: Group 1 (n = 36): no standardized approach; Group 2 (n = 30): a prophylactic chylothorax diet (fat content < 5%); Group 3 (n = 57): the FCP (a chylothorax diet, fluid restriction, supplemental O2 and aggressive diuresis). The incidence of chylothorax and TTCTR was compared between groups. Predictors of TTCTR were analyzed using linear regression modelling, adjusting for covariates. Chylothorax rate decreased in Group 3 compared to Groups 1 and 2 (9% vs. 28% and 33% respectively, p = 0.011), without alteration in TTCTR. Univariate factors associated with median TTCTR included chylothorax (+ 13.7 days, p = 0.001), additional procedures at time of Fontan (+ 2.4 days per procedure p = 0.017), Fontan revision or takedown (+ 11.7 days, p = 0.018) and minor/major complications (+ 5.1, p = 0.01 and + 15.8, p < 0.001, respectively). On multivariable analysis, chylothorax (+ 6.5 days, p = 0.005) and major complications (+ 15.8 days, p = 0.001) were associated with increased TTCTR. When chylothorax was excluded from multivariable analysis, the FCP showed a significant decrease in TTCTR (- 3.3 days, p = 0.034). A bundled therapy approach was associated with reduced laboratory confirmed chylothorax post-Fontan, whereas diet change alone was not. Additional studies in this area, with larger sample sizes are warranted.

Acute kidney injury and renal recovery following Fontan surgery.

Objectives: Acute kidney injury has been described after Fontan surgery, but the duration and outcomes are unknown. We sought to describe the incidence of and risk factors for acute kidney injury and the phenotype of renal recovery, and evaluate the impact of renal recovery phenotype on outcomes. Methods: All children who underwent a Fontan operation at a single center between 2009 and 2022 were included. Data collected included Fontan characteristics, vasopressor use, all measures of creatinine, and postoperative outcomes. Logistic regression models were used to assess predictors of acute kidney injury and the association between acute kidney injury and outcomes. Results: We enrolled 141 children (45% female). Acute kidney injury occurred in 100 patients (71%). Acute kidney injury duration was transient (<48 hours) in 77 patients (55%), persistent (2-7 days) in 15 patients (11%), more than 7 days in 4 patients (3%), and unknown in 4 patients (3%). Risk factors for acute kidney injury included higher preoperative indexed pulmonary vascular resistance (odds ratio, 3.90; P = .004) and higher postoperative inotrope score on day 0 (odds ratio, 1.13, P = .047). Risk factors for acute kidney injury duration more than 48 hours included absence of a fenestration (odds ratio, 3.43, P = .03) and longer duration of cardiopulmonary bypass (odds ratio, 1.22 per 15-minute interval, P = .01). Acute kidney injury duration more than 48 hours was associated with longer length of stay compared with transient acute kidney injury (median 18 days [interquartile range, 9-62] vs 10 days [interquartile range, 8-16], P = .006) and more sternal wound infections (17% vs 4%, P = .049). Conclusions: Acute kidney injury after the Fontan operation is common. The occurrence and duration of acute kidney injury have significant implications for postoperative outcomes.

Evaluating a Telemedicine Video Game-Linked High-Intensity Interval Training Exercise Programme in Paediatric Heart Transplant Recipients.

Paediatric heart transplant recipients (HTRs) have reduced exercise capacity, physical activity (PA), health-related quality of life (HRQoL), and self-efficacy towards PA. Exercise interventions have demonstrated improvements in exercise capacity and functional status in adult HTRs, with a specific emerging interest in the role of high-intensity interval training (HIIT). Studies of exercise interventions in paediatric HTRs have been limited and nonrandomized to date. HIIT has not yet been evaluated in paediatric HTRs. We thus seek to evaluate the safety and feasibility of a randomized crossover trial of a 12-week, home-based, video game-linked HIIT intervention using a cycle ergometer with telemedicine and remote physiological monitoring capabilities (MedBIKE) in paediatric HTRs. The secondary objective is to evaluate the impact of the intervention on (1) exercise capacity, (2) PA, (3) HRQoL and self-efficacy towards PA, and (4) sustained changes in secondary outcomes at 6 and 12 months after intervention. After a baseline assessment of the secondary outcomes, participants will be randomized to receive the MedBIKE intervention (12 weeks, 36 sessions) or usual care. After the intervention and a repeated assessment, all participants will cross over. Follow-up assessments will be administered at 6 and 12 months after the MedBIKE intervention. We anticipate that the MedBIKE intervention will be feasible and safely yield sustained improvements in exercise capacity, PA, HRQoL, and self-efficacy towards PA in paediatric HTRs. This study will serve as the foundation for a larger, multicentre randomized crossover trial and will help inform exercise rehabilitation programmes for paediatric HTRs.

La tolérance à l'effort, le niveau d'activité physique (AP), le score de la qualité de vie liée à la santé (QVLS) ainsi que l'auto-efficacité à la pratique d'une AP se trouvent diminués chez les patients pédiatriques ayant reçu une transplantation cardiaque. Il a été montré que les exercices physiques permettent d'améliorer la tolérance à l'effort ainsi que le statut fonctionnel chez les patients adultes ayant reçu une transplantation cardiaque. D'ailleurs, le rôle de l'entraînement par intervalles de haute intensité (EIHI) suscite depuis peu un nouvel intérêt à cet égard. Les études réalisées à ce jour sur les programmes d'activité physique chez les patients pédiatriques ayant reçu une transplantation cardiaque sont toutefois peu nombreuses et ne reposent pas sur une répartition aléatoire. De plus, l'EIHI n'a pas encore été évalué chez ce groupe de patients. La présente étude a donc pour objectif d'évaluer la faisabilité et l'innocuité d'un essai clinique croisé à répartition aléatoire d'une durée de 12 semaines chez des patients pédiatriques ayant reçu une transplantation cardiaque. Le programme d'activité physique prendra la forme d'un EIHI à la maison au moyen d'un jeu vidéo et d'une bicyclette ergométrique permettant une assistance et une surveillance des données physiologiques à distance (MedBIKE). Les objectifs secondaires de l'étude consistent à évaluer les effets du programme sur : 1) la tolérance à l'effort; 2) le niveau d'AP; 3) la QVLS ainsi que l'auto-efficacité à la pratique d'une AP; et 4) le maintien des améliorations relatives aux critères d'évaluation se-condaires à 6 et 12 mois. Après une évaluation initiale des critères d'évaluation secondaires, les participants seront répartis aléatoirement dans le groupe suivant le programme à l'aide du vélo MedBIKE (36 séances réparties sur 12 semaines) ou dans le groupe recevant le traitement usuel. Tous les participants changeront ensuite de groupe, et une nouvelle évaluation des critères d'évaluation se-condaires sera effectuée. Les évaluations de suivi auront lieu 6 et 12 mois après la fin du programme. On s'attend à ce que ce dernier soit sûr, facile à suivre et accompagné d'améliorations soutenues de la tolérance à l'effort, du niveau d'AP, de la QVLS et de l'auto-efficacité à la pratique d'une AP chez les patients pédiatriques ayant reçu une transplantation cardiaque. Cette étude servira de modèle à un essai clinique croisé, multicentrique, à répartition aléatoire de plus grande envergure. Elle permettra aussi de générer des renseignements utiles pour les programmes de réadaptation destinés aux patients pédiatriques ayant reçu une transplantation cardiaque.

Exploring the Promise of Telemedicine Exercise Interventions in Children and Adolescents With Congenital Heart Disease.

Youth with congenital heart disease (CHD) have reduced exercise capacity via various physical and psychosocial mechanisms. In addition to limited physiologic exercise capacity, these patients experience lower levels of physical activity, physical activity self-efficacy, health-related quality of life, and endothelial function. The study of exercise interventions and cardiac rehabilitation programs in pediatric CHD populations remains limited, particularly home-based interventions that incorporate real-time physiologic monitoring. Home-based interventions provide improved access and convenience to patients. This is principally important for patients from geographically disperse regions who receive their care at centralized subspecialty centres, as is the case for Canadian pediatric cardiac care. These programs, however, have traditionally not permitted the supervision of safety, technique, and adherence that are afforded by hospital/facility-based programs. As such, telemedicine is an important evolving area that combines the benefits of traditional home and facility-based cardiac rehabilitation. An additional key area lacking study surrounds the types of exercise interventions in youth with CHD. To date, interventions have often centred around moderate-intensity continuous exercise. High-intensity interval training might offer superior cardiorespiratory advantages but remains understudied in the CHD population. In this review, we highlight the existing evidence basis for exercise interventions in youth with CHD, explore the promise of incorporating telemedicine home-based solutions, and highlight key knowledge gaps. To address identified knowledge gaps, we are undertaking a 12-week randomized crossover trial of a home-based telemedicine high-intensity interval training intervention in youth with repaired moderate-severe CHD using a video game-linked cycle ergometer (known as the MedBIKE; https://spaces.facsci.ualberta.ca/ahci/projects/medical-projects/remote-rehab-bike-projects).

Incidence and impact of malnutrition in patients with Fontan physiology.

BACKGROUND: Single-ventricle patients require a series of surgeries, with the final stage being the Fontan. This form of circulation results in several long-term complications, but the impact and consequences of nutrition status remain unclear. We sought to evaluate the incidence of malnutrition in Fontan patients and the impact on outcomes. METHODS: This study was a retrospective cohort study of children who underwent Fontan surgery between 1997 and 2018. Clinical, demographic, and nutrition data were collected, including weight, height, body mass index (BMI), and their respective z scores (z score for weight-for-age [WAZ], z score for height-for-age [HAZ], and z score for BMI-for-age [BMIZ]) pre-Fontan, at discharge, 6 months, and 1, 5, and 10 years post-Fontan. Malnutrition status was categorized using the American Society for Parenteral and Enteral Nutrition guidelines and the Michigan MTool. Fontan failure was defined as listing for heart transplant or death. RESULTS: Of the 69 patients, moderate-severe malnutrition occurred at any time point in 11% (n = 8) by WAZ, 16% (n = 11) by HAZ, and 6% (n = 4) by BMIZ. Moderate-severe malnutrition persisted in 6.5%-12.9% at 10 years post-Fontan. Compared with the pre-Fontan period, there was no change in these parameters over time. There was no statistically significant difference in Fontan failure between degrees of pre-Fontan malnutrition. CONCLUSION: There is a 6%-16% incidence of moderate-severe malnutrition in Fontan patients. Malnutrition is a condition that remains present in follow-up. There was no association with anthropometric parameters and transplant-free survival. A prospective multi-institutional study is needed to understand the impact of malnutrition on long-term outcomes.

Within-Stool and Within-Day Sample Variability of Fecal Calprotectin in Patients With Inflammatory Bowel Disease: A Prospective Observational Study.

BACKGROUND AND GOALS: The use of fecal calprotectin (FC) as a stool biomarker for differentiating inflammatory bowel disease (IBD) from IBS has been well validated, and there is a strong correlation between FC and the presence of endoscopic inflammatory lesions. However, recent studies have demonstrated intraindividual sample variability in patients with IBD, possibly limiting the reliability of using a single sample for monitoring disease activity. Our aim was to assess the within-stool and within-day sample variability of FC concentrations in patients with IBD. STUDY: We examined a cross-sectional cohort of 50 adult IBD patients. Eligible patients were instructed to collect 3 samples from different parts of the stool from their first bowel movement of the day and 3 samples from each of up to 2 additional bowel movements within 24 hours. FC concentrations were measured by a rapid, quantitative point-of-care test using lateral flow technology (Quantum Blue). Descriptive statistics were used to assess FC variability within a single bowel movement and between different movements at different FC positivity cutoffs. RESULTS: Within a single bowel movement, there was clinically significant sample variability ranging from 8% to 23% depending on the time of the day or on the FC positivity cutoff value. Between bowel movements, there was clinically significant sample variability ranging from 13% to 26% depending on the FC positivity cutoff. CONCLUSIONS: Considering a single FC sample, the first sample of the day with an FC positivity cutoff of 250 µg/g provided the most reliable indication of disease activity.

Urine metabolomics as a predictor of patient tolerance and response to adjuvant chemotherapy in colorectal cancer.

Colorectal cancer is the third leading cause of cancer-associated mortality in the western world. The ability to predict a patient's response to chemotherapy may be of great value for clinicians and patients when planning cancer treatment. The aim of the current study was to develop a urine metabolomics-based biomarker panel to predict adverse events and response to chemotherapy in patients with colorectal cancer. A retrospective chart review of patients diagnosed with stage III or IV colorectal cancer between 2008 and 2012 was performed. The exclusion criteria included chemotherapy for palliation and patients living outside of Alberta. Data was collected concerning the chemotherapy regimen, adverse events associated with chemotherapy, disease progression and recurrence and 5-year survival. Adverse events were subdivided as follows: Delays in treatment, dose reductions, hospitalizations and chemotherapy regime changes. Patients provided urine samples for analysis prior to any intervention. Nuclear magnetic resonance (NMR) spectra of urine samples were acquired. The 1H NMR spectrum of each urine sample was analyzed using Chenomx NMRSuite v7.0. Using machine learning, predictors were generated and evaluated using 10-fold cross-validation. Urine spectra were obtained for 62 patients. The best predictors resulted in area under the receiver operating characteristic curve values of: 0.542 for chemotherapy dose reduction, 0.612 for 5-year survival, 0.650 for cancer recurrence and 0.750 for treatment delay. Therefore, predictors were developed for response to and adverse events from chemotherapy for patients with colorectal cancer patients. The predictor for treatment delay has the most promise, and further studies will aid its refinement and improvement of its accuracy.

Development and Validation of a High-Throughput Mass Spectrometry Based Urine Metabolomic Test for the Detection of Colonic Adenomatous Polyps.

Background: Colorectal cancer is one of the leading causes of cancer deaths worldwide. The detection and removal of the precursors to colorectal cancer, adenomatous polyps, is the key for screening. The aim of this study was to develop a clinically scalable (high throughput, low cost, and high sensitivity) mass spectrometry (MS)-based urine metabolomic test for the detection of adenomatous polyps. Methods: Prospective urine and stool samples were collected from 685 participants enrolled in a colorectal cancer screening program to undergo colonoscopy examination. Statistical analysis was performed on 69 urine metabolites measured by one-dimensional nuclear magnetic resonance spectroscopy to identify key metabolites. A targeted MS assay was then developed to quantify the key metabolites in urine. A MS-based urine metabolomic diagnostic test for adenomatous polyps was established using 67% samples (un-blinded training set) and validated using the remaining 33% samples (blinded testing set). Results: The MS-based urine metabolomic test identifies patients with colonic adenomatous polyps with an AUC of 0.692, outperforming the NMR based predictor with an AUC of 0.670. Conclusion: Here we describe a clinically scalable MS-based urine metabolomic test that identifies patients with adenomatous polyps at a higher level of sensitivity (86%) over current fecal-based tests (<18%).

Noninvasive Fecal Immunochemical Testing and Fecal Calprotectin Predict Mucosal Healing in Inflammatory Bowel Disease: A Prospective Cohort Study.

BACKGROUND: The noninvasive biomarkers fecal immunochemical testing (FIT) and fecal calprotectin (FCP) are sensitive for prediction of mucosal inflammation in inflammatory bowel disease. However, neither test has yet been shown to independently and accurately predict mucosal healing (MH). We aimed to assess the specificity of noninvasive FIT and FCP for MH prediction. METHODS: In this prospective cohort study of adult inflammatory bowel disease outpatients presenting for colonoscopy, stool samples for FIT and FCP were collected 48 hours before endoscopy. Using MH defined by Simple Endoscopic Score for Crohn's disease (SES-CD = 0), Rutgeert's score (i0), and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS = 3), receiver operator characteristic curves were plotted, and sensitivity, specificity, positive and negative predictive values, and areas under the curve were calculated. Multivariate logistic regression analysis was used to develop a clinical model for noninvasively predicting MH. RESULTS: Eighty patients (40 Crohn's disease and 40 ulcerative colitis) were enrolled. The specificities of FIT <100 ng/mL and FCP <250 µg/g for MH were 0.57 (95% confidence interval, 0.38-0.74) and 0.77 (0.57-0.89), respectively. Positive predictive values for MH for FIT <100 ng/mL and FCP <250 µg/g were 0.78 (0.64-0.87) and 0.77 (0.58-0.90), respectively. In multivariate modeling, combining FIT, FCP, and clinical symptomatic remission improved specificity for MH to 0.90 (0.72-0.97) with positive predictive values of 0.84 (0.60-0.96). Areas under the curve for FIT was higher for patients with ulcerative colitis (0.88) than for patients with Crohn's disease (0.69, P = 0.05). CONCLUSIONS: FIT and FCP have similar performance characteristics for identifying MH. Combined, low FIT, low FCP, and clinical remission are specific for MH.

Clinical validation of a novel urine-based metabolomic test for the detection of colonic polyps on Chinese population.

PURPOSE: Colorectal cancer is the fifth leading cause of cancer-related deaths in China. When detected early, with the removal of adenomatous polyps, precursors of colorectal cancer, it is preventable. The aim of this study was to evaluate a novel urine-based metabolomic diagnostic test for the detection of adenomatous polyps, PolypDx™, that was originally developed and validated using 1000 samples from Canadian Cohort, on Chinese population. METHODS: Prospective urine samples were collected from 1000 participants undergoing colonoscopy examination, from March 2013 to July 2014 at Minhang District, Shanghai Centre for Disease Control and Prevention. One-dimensional nuclear magnetic resonance spectra of urine metabolites were analyzed to determine the concentrations of three key metabolites used in PolypDx™. The predicted results were then compared to the gold standard for colorectal cancer diagnostic, colonoscopy. Area under curve (AUC) was calculated specifically for the Chinese population and compared with the Canadian dataset. Sensitivity and specificity of this urine-based metabolomic diagnostic test were also compared with three commercially available fecal-based tests. RESULTS: An AUC of 0.717 for PolypDx™ was calculated on Chinese dataset which is slightly lower than the AUC on the Canadian dataset. A sensitivity of 82.6% and a specificity of 42.4% were achieved on Chinese dataset. CONCLUSIONS: Here, we validated a novel urine-based metabolomic diagnostic test for the detection of adenomatous polyps, PolypDx™, on Chinese population through a sample size of 1000 participants with a greater level of sensitivity than fecal-based tests.

Metabolomic profiles are gender, disease and time specific in the interleukin-10 gene-deficient mouse model of inflammatory bowel disease.

Metabolomic profiling can be used to study disease-induced changes in inflammatory bowel diseases (IBD). The aim of this study was to investigate the difference in the metabolomic profile of males and females as they developed IBD. Using the IL-10 gene-deficient mouse model of IBD and wild-type mice, urine at age 4, 6, 8, 12, 16, and 20 weeks was collected and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Multivariate data analysis was employed to assess differences in metabolomic profiles that occurred as a consequence of IBD development and severity (at week 20). These changes were contrasted to those that occurred as a consequence of gender. Our results demonstrate that both IL-10 gene-deficient and wild-type mice exhibit gender-related changes in urinary metabolomic profile over time. Some male-female separating metabolites are common to both IL-10 gene-deficient and control wild-type mice and, therefore, appear to be related predominantly to gender maturation. In addition, we were able to identify gender-separating metabolites that are unique for IL-10 gene-deficient and wild-type mice and, therefore, may be indicative of a gender-specific involvement in the development and severity of the intestinal inflammation. The comparison of the gender-separating metabolomic profile from IL-10 gene-deficient mice and wild-type mice during the development of IBD allowed us to identify changes in profile patterns that appear to be imperative in the development of intestinal inflammation, but yet central to gender-related differences in IBD development. The knowledge of metabolomic profile differences by gender and by disease severity has potential clinical implications in the design of both biomarkers of disease as well as the development of optimal therapies.

Intravenous injection of endogenous microbial components abrogates DSS-induced colitis.

BACKGROUND: The etiology of inflammatory bowel diseases (IBD) is largely unknown, but appears to be perpetuated by uncontrolled responses to antigenic components of the endogenous flora. Tolerance to antigenic stimulation can be achieved by exposure to a given antigen in high amounts (high dose tolerance). Colitis induced by feeding of Dextran Sodium Sulfate (DSS) is an often-used animal model mimicking clinical and histological features of human IBD. AIMS: We investigated whether treatment with high doses of endogenous bacterial components can affect the response to these antigenic components and thus impact the course of the inflammatory response induced by DSS. METHODS: 129/SvEv mice were injected intravenously in the tail vein with lysates prepared from fecal material of conventionally-raised mice. Control mice received a solution of bacterial antigen-free lysates prepared from fecal material of germ-free mice. Seven days later, colitis was induced in these mice by introducing DSS (3.5%) in the drinking water for 5 days. Onset and course of the inflammatory response was monitored by assessment of weight loss. Mice were sacrificed at day 7 post colitis induction and tested for histopathologic injury, intestinal cytokine release, and systemic response to bacterial antigens. RESULTS: Intravenous injection with fecal lysates reduced intestinal and antigen-stimulated systemic pro-inflammatory cytokine release and prevented DSS-induced weight loss and intestinal injury. CONCLUSION: Pretreatment with high amount of endogenous bacterial components has a profound tolerogenic effect on the systemic and mucosal immune responses resulting in reduced intestinal inflammation and abrogates colitis-induced weight loss.

Naturally occurring glycoalkaloids in potatoes aggravate intestinal inflammation in two mouse models of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) may be initiated following disruption of the intestinal epithelial barrier. This disruption, in turn, permits luminal antigens unfettered access to the mucosal immune system and leads to an uncontrolled inflammatory response. Glycoalkaloids, which are found in potatoes, disrupt cholesterol-containing membranes such as those of the intestinal epithelium. Glycoalkaloid ingestion through potatoes may play a role in the initiation and/or perpetuation of IBD. AIM: To determine if commercial and high glycoalkaloids containing fried potato skins aggravate intestinal inflammation using two different animal models of IBD. METHODS: Fried potato skins from commercial potatoes containing low/medium glycoalkaloid levels and high glycoalkaloids potatoes were fed for 20 days to interleukin 10 gene-deficient mice and dextran sodium sulfate-induced colitic mice. Intestinal permeability, mucosal cytokine and myeloperoxidase levels and body weight were determined to assess intestinal injury. RESULTS: Deep frying potato skins markedly increased glycoalkaloid content. Interleukin 10 gene-deficient mice fed fried commercial potato skins with medium glycoalkaloid content exhibited significantly elevated levels of ileal IFN-γ relative to controls. Mice in the dextran sodium sulfate colitis model that were fed the same strain of potatoes demonstrated significantly elevated levels of pro-inflammatory cytokines IFN-γ, TNF-α, and IL-17 in the colon in addition to an enhanced colonic permeability. Inflammatory response was intensified when the mice were fed potatoes with higher glycoalkaloid contents. CONCLUSIONS: Our results demonstrate that consumption of potato skins containing glycoalkaloids can significantly aggravate intestinal inflammation in predisposed individuals.

Oral administration of curcumin emulsified in carboxymethyl cellulose has a potent anti-inflammatory effect in the IL-10 gene-deficient mouse model of IBD.

Curcumin is a tumeric-derived, water-insoluble polyphenol with potential beneficial health effects for humans. It has been shown to have preventive as well as therapeutic effects in chemically induced murine models of colitis. To investigate whether curcumin exerts a similar effect on the spontaneous colitis in interleukin (IL)-10 gene-deficient mice, we gavaged these mice daily for 2 weeks with 200 mg/kg per day curcumin emulsified in carboxymethyl cellulose, a food additive generally used as a viscosity modifier. Mice fed the curcumin/carboxymethyl cellulose mixture and those receiving carboxymethyl cellulose alone demonstrated similar reductions in histological injury score and colon weight/length ratio compared to water-fed controls. However, significant reductions in pro-inflammatory cytokine release in intestinal explant cultures were only seen in mice treated with the curcumin mixture. Our data demonstrate that in IL-10 gene-deficient mice, both oral curcumin and carboxymethyl cellulose, appear to have modifying effects on colitis. However, curcumin has additional anti-inflammatory effects mediated through a reduced production of potent pro-inflammatory mucosal cytokines.