Feeding intolerance after pediatric cardiac surgery is associated with dysbiosis, barrier dysfunction, and reduced short-chain fatty acids.

Congenital heart disease (CHD) is the most common birth defect, occurring in roughly 40,000 U.S. births annually. Malnutrition and feeding intolerance (FI) in CHD range from 30% to 42% and are associated with longer hospitalization and increased mortality. Cardiopulmonary bypass (CPB) required for surgical repair of CHD induces a systemic inflammatory response worsening intestinal dysbiosis and leading to intestinal epithelial barrier dysfunction (EBD), possibly contributing to postoperative FI. The objective of this study was to determine the relationship of postoperative FI with intestinal microbiome, short-chain fatty acids (SCFAs), and EBD in pediatric CHD after cardiac surgery. This was a prospective study of patients aged 0-15 years undergoing cardiac surgery with CPB. Samples were collected preoperatively and postoperatively to evaluate the gut microbiome, plasma EBD markers, short-chain fatty acids (SCFAs), and plasma cytokines. Clinical data were collected to calculate a FI score and evaluate patient status postoperatively. We enrolled 26 CPB patients and identified FI (n = 13). Patients with FI had unique microbial shifts with the reduced SCFA-producing organisms Rothia, Clostridium innocuum, and Intestinimonas. Patients who developed FI had associated elevations in the plasma EBD markers claudin-2 (P < 0.05), claudin-3 (P < 0.01), and fatty acid binding protein (P < 0.01). Patients with FI had reduced plasma and stool SCFAs. Mediation analysis showed the microbiome functional shift was associated with reductions in stool butyric and propionic acid in patients with FI. In conclusion, we provide novel evidence that intestinal dysbiosis, markers of EBD, and SCFA depletion are associated with FI. These data will help identify mechanisms and therapeutics to improve clinical outcomes following pediatric cardiac surgery.NEW & NOTEWORTHY Feeding intolerance contributes to postoperative morbidity following pediatric cardiac surgery. The intestinal microbiome and milieu play a vital role in gut function. Short-chain fatty acids are gut and cardioprotective metabolites produced by commensal bacteria and help maintain appropriate barrier function. Depletion of these metabolites and barrier dysfunction contribute to postoperative feeding intolerance following cardiac surgery. Identifying mechanistic targets to improve the intestinal milieu with the goal of improved nutrition and clinical outcomes is critical.

S100A9 is a functional effector of infarct wall thinning after myocardial infarction.

Neutrophils infiltrate into the left ventricle (LV) early after myocardial infarction (MI) and launch a proinflammatory response. Along with neutrophil infiltration, LV wall thinning due to cardiomyocyte necrosis also peaks at day 1 in the mouse model of MI. To understand the correlation, we examined a previously published data set that included day 0 (n = 10) and MI day (D) 1 (n = 10) neutrophil proteome and echocardiography assessments. Out of 123 proteins, 4 proteins positively correlated with the infarct wall thinning index (1/wall thickness): histone 1.2 (r = 0.62, P = 0.004), S100A9 (r = 0.60, P = 0.005), histone 3.1 (r = 0.55, P = 0.01), and fibrinogen (r = 0.47, P = 0.04). As S100A9 was the highest ranked secreted protein, we hypothesized that S100A9 is a functional effector of infarct wall thinning. We exogenously administered S100A8/A9 at the time of MI to mice [C57BL/6J, male, 3-6 mo of age, n = 7 M (D1), and n = 5 M (D3)] and compared with saline vehicle control-treated mice [n = 6 M (D1) and n = 6 M (D3)] at MI days 1 and 3. At MI day 3, the S100A8/A9 group showed a 22% increase in the wall thinning index compared with saline (P = 0.02), along with higher dilation and lower ejection fraction. The decline in cardiac physiology occurred subsequent to increased neutrophil and macrophage infiltration at MI day 1 and increased macrophage infiltration at D3. Our results reveal that S100A9 is a functional effector of infarct wall thinning.NEW & NOTEWORTHY S100A9 is a functional marker of infarct wall thinning.

Faster skin wound healing predicts survival after myocardial infarction.

Both skin wound healing and the cardiac response to myocardial infarction (MI) progress through similar pathways involving inflammation, resolution, tissue repair, and scar formation. Due to the similarities, we hypothesized that the healing response to skin wounding would predict future response to MI. Mice were given a 3-mm skin wound using a disposable biopsy punch and the skin wound was imaged daily until closure. The same set of animals was given MI by permanent coronary artery ligation 28 days later and followed for 7 days. Cardiac physiology was measured by echocardiography at baseline and MI days 3 and 7. Animals that survived until day 7 were grouped as survivors, and animals that died from MI were grouped as nonsurvivors. Survivors had faster skin wound healing than nonsurvivors. Faster skin wound healing predicted MI survival better than commonly used cardiac functional variables (e.g., infarct size, fractional shortening, and end diastolic dimension). N-glycoproteome profiling of MI day 3 plasma revealed α2-macroglobulin and ELL-associated factor 1 as strong predictors of future MI death and progression to heart failure. A second cohort of MI mice validated these findings. To investigate the clinical relevance of α2-macroglobulin, we mapped the plasma glycoproteome in patients with MI 48 h after admission and in healthy controls. In patients, α2-macroglobulin was increased 48 h after MI. Apolipoprotein D, another plasma glycoprotein, detrimentally regulated both skin and cardiac wound healing in male but not female mice by promoting inflammation. Our results reveal that the skin is a mirror to the heart and common pathways link wound healing across organs.NEW & NOTEWORTHY Faster skin wound healers had more efficient cardiac healing after myocardial infarction (MI). Two plasma proteins at D3 MI, EAF1 and A2M, predicted MI death in 66% of cases. ApoD regulated both skin and cardiac wound healing in male mice by promoting inflammation. The skin was a mirror to the heart and common pathways linked wound healing across organs.

Three-dimensional Analysis of How Radiation Affects Deep Inferior Epigastric Perforator (DIEP) Flap Volume, Projection, and Position in Breast Cancer Reconstruction.

BACKGROUND: The deep inferior epigastric perforator (DIEP) flap has gained popularity for autologous free flap breast reconstruction. Historically, patients receiving post mastectomy radiation therapy (PMRT) were not candidates for immediate autologous reconstruction due to concerns for flap volume depletion, fat necrosis, and flap failure. However, this literature is anecdotal and lacks case controls. We objectively analyzed the effects radiation imparts on immediate DIEP flap reconstruction using 3-dimensional software and inherent controls. METHODS: We performed a cohort study on breast cancer patients who underwent immediate bilateral DIEP flap reconstructions followed by PMRT between 2005 and 2014. Exclusion criteria included patients less than 6 months from PMRT completion and bilateral PMRT. Three-dimensional photographs were analyzed using Geomagic (Rock Hill, SC) software to compare flap position, projection, and volume between the irradiated and nonirradiated reconstructed breasts. Breast Q survey evaluated patients' satisfaction. RESULTS: Eleven patients met inclusion criteria. Average time from PMRT completion to photo acquisition was 1.93 years. There was no statistical difference in average volume or projection in the irradiated versus nonirradiated side (P = 0.087 and P = 0.176, respectively). However, position of the irradiated flaps was significantly higher on the chest wall compared to controls (mean difference, 1.325 cm; P < 0.004). CONCLUSIONS: Three-dimensional analysis exhibited no statistical differences in projection or volume between irradiated DIEP flaps and nonirradiated controls. However, irradiated DIEP flaps were positioned higher on the chest wall, similar to observations in irradiated tissue expanders/implants. Patients were satisfied as measured by Breast Q. Immediate bilateral DIEP flap reconstructions can safely be performed with PMRT with satisfactory results.

Simulated surgery and cutting guides enhance spatial positioning in free fibular mandibular reconstruction.

INTRODUCTION: The free fibular flap is the workhorse for mandibular reconstruction. Three-dimensional (3D) planning, with use of cutting guides and prebent plates, has been introduced. The purpose of this study is to evaluate the interfragmentary gap size and symmetry between conventional freehand preparation versus those using 3D planning. METHODS: A retrospective review was performed. Conventional free form and 3D planned fibular reconstructions performed by the senior authors at a single institution were included. Reconstructions were further subdivided into "body only" and "complex." Demographic and intraoperative data were collected. Postoperative CT scans were analyzed using Materialize software. Interfragmentary gap distances (mm) and symmetry (degrees) were assessed. RESULTS: Nineteen fibular reconstructions met inclusion criteria, ten conventional free form, and nine 3D planned reconstructions. Interfibular gaps measured 0.36 ± 0.50 mm in the 3D group versus 1.88 ± 1.09 mm in the non-3D group (P = 0.004). Overall symmetry (a ratio between right and left angles) measured versus 1.027 ± 0.08 in the 3D-planned versus 1.024 ± 0.09 in the non-3D group in (P = 0.944). Within only mandibular body reconstructions, symmetry was similar between the two techniques: 1.05 ± 0.12 in the 3D group versus 0.97 ± 0.05 in the non-3D group (P = 0.295). CONCLUSIONS: 3D planning lessens interfibular gap dimensions and may enhance axial symmetry. Space between native mandible and fibula is not appreciably altered using planning. Future efforts will focus on the accuracy and reproducibility of the 3D planned to actual results as well as clinical significance and efficiency benefits.

Acute respiratory distress syndrome: A review of ARDS across the life course.

Acute respiratory distress syndrome (ARDS) is a multifactorial, inflammatory lung disease with significant morbidity and mortality that predominantly requires supportive care in its management. Although initially described in adult patients, the diagnostic definitions for ARDS have evolved over time to accurately describe this disease process in pediatric and, more recently, neonatal patients. The management of ARDS in each age demographic has converged in the application of lung-protective ventilatory strategies to mitigate the primary disease process and prevent its exacerbation by limiting ventilator-induced lung injury. However, differences arise in the preferred ventilatory strategies or adjunctive pulmonary therapies used to mitigate each type of ARDS. In this review, we compare and contrast the epidemiology, common etiologies, pathophysiology, diagnostic criteria, and outcomes of ARDS across the lifespan. Additionally, we discuss in detail the different management strategies used for each subtype of ARDS and spotlight how these strategies were applied to mitigate poor outcomes during the COVID-19 pandemic. This review is geared toward both clinicians and clinician-scientists as it not only summarizes the latest information on disease pathogenesis and patient management in ARDS across the lifespan but also highlights knowledge gaps for further investigative efforts. We conclude by projecting how future studies can fill these gaps in research and what improvements may be envisioned in the management of NARDS and PARDS based on the current breadth of literature on adult ARDS treatment strategies.

Immediate nipple reconstruction utilizing the DIEP flap in areola-sparing mastectomy.

The surgical treatment of breast cancer has dramatically evolved over the past decade toward an approach combining oncologic safety with aesthetic outcomes. The skin-sparing mastectomy initiated this paradigm shift amongst breast surgeons and can be oncologically safe, in some cases sparing both the areola and the nipple. In accordance with the emphasis on aesthetics, some general surgeons have adopted new methods of resecting only the nipple, sparing the areola in select patients. The superior aesthetic results, durability, and decreased donor site morbidity of perforator flaps have brought autologous reconstruction back to the forefront of breast reconstruction with the deep inferior epigastric artery perforator (DIEP) flap as the gold standard. We describe a technique utilizing the DIEP flap skin paddle for immediate nipple reconstruction at the time of mastectomy and reconstruction, eliminating the need for delayed reconstruction and limiting donor site morbidity by concealing the donor site below the mastectomy skin flaps. In the six cases described performed between 2010 and 2012 (mean with 53 years; range 46-59 years), there have been no complications to the flap or the nipple postoperatively, nor has there been a need for further nipple revisions for 6 months. The nipple position relative to the flap breast mound has remained unchanged for up to 6 months. The immediate nipple reconstruction does not significantly lengthen operative time, requiring approximately 30 additional operative minutes per nipple. Immediate nipple reconstruction utilizing the DIEP flap can be a cost-effective and feasible technique for recreating a natural-appearing and aesthetic nipple in select patients.

Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis.

Dysregulation of both the gut barrier and microbiota (dysbiosis) promotes susceptibility to and severity of Inflammatory Bowel Diseases (IBD). Leaky gut and dysbiosis often coexist; however, potential interdependence and molecular regulation are not well understood. Robust expression of claudin-3 (CLDN3) characterizes the gut epithelium, and studies have demonstrated a positive association between CLDN3 expression and gut barrier maturity and integrity, including in response to probiotics. However, the exact status and causal role of CLDN3 in IBD and regulation of gut dysbiosis remain unknown. Analysis of mouse and human IBD cohorts helped examine CLDN3 expression in IBD. The causal role was determined by modeling CLDN3 loss of expression during experimental colitis. 16S sequencing and in silico analysis helped examine gut microbiota diversity between Cldn3KO and WT mice and potential host metabolic responses. Fecal microbiota transplant (FMT) studies were performed to assess the role of gut dysbiosis in the increased susceptibility of Cldn3KO mice to colitis. A significant decrease in CLDN3 expression characterized IBD and CLDN3 loss of expression promoted colitis. 16S sequencing analysis suggested gut microbiota changes in Cldn3KO mice that were capable of modulating fatty acid metabolism and oxidative stress response. FMT from naïve Cldn3KO mice promoted colitis susceptibility in recipient germ-free mice (GFM) compared with GFM-receiving microbiota from WT mice. Our data demonstrate a critical role of CLDN3 in maintaining normal gut microbiota and inflammatory responses, which can be harnessed to develop novel therapeutic opportunities for patients with IBD.

The diet-microbiota axis: a key regulator of intestinal permeability in human health and disease.

The intestinal barrier orchestrates selective permeability to nutrients and metabolites while excluding noxious stimuli. Recent scientific advances establishing a causal role for the gut microbiota in human health outcomes have generated a resurgent interest toward intestinal permeability. Considering the well-established role of the gut barrier in protection against foreign antigens, there is mounting evidence for a causal link between gut permeability and the microbiome in regulating human health. However, an understanding of the dynamic host-microbiota interactions that govern intestinal barrier functions remains poorly defined. Furthermore, the system-level mechanisms by which microbiome-targeted therapies, such as probiotics and prebiotics, simultaneously promote intestinal barrier function and host health remain an area of active investigation. This review summarizes the recent advances in understanding the dynamics of intestinal permeability in human health and its integration with gut microbiota. We further summarize mechanisms by which probiotics/prebiotics influence the gut microbiota and intestinal barrier functions.

Piglet cardiopulmonary bypass induces intestinal dysbiosis and barrier dysfunction associated with systemic inflammation.

The intestinal microbiome is essential to human health and homeostasis, and is implicated in the pathophysiology of disease, including congenital heart disease and cardiac surgery. Improving the microbiome and reducing inflammatory metabolites may reduce systemic inflammation following cardiac surgery with cardiopulmonary bypass (CPB) to expedite recovery post-operatively. Limited research exists in this area and identifying animal models that can replicate changes in the human intestinal microbiome after CPB is necessary. We used a piglet model of CPB with two groups, CPB (n=5) and a control group with mechanical ventilation (n=7), to evaluate changes to the microbiome, intestinal barrier dysfunction and intestinal metabolites with inflammation after CPB. We identified significant changes to the microbiome, barrier dysfunction, intestinal short-chain fatty acids and eicosanoids, and elevated cytokines in the CPB/deep hypothermic circulatory arrest group compared to the control group at just 4 h after intervention. This piglet model of CPB replicates known human changes to intestinal flora and metabolite profiles, and can be used to evaluate gut interventions aimed at reducing downstream inflammation after cardiac surgery with CPB.

Single-Pass Albumin Dialysis as Rescue Therapy for Pediatric Calcium Channel Blocker Overdose.

Calcium channel blocker ingestions remain one of the leading causes of death related to cardiovascular medication ingestion in both adults and pediatric patients. We report a case of a 17-year-old, 103 kg female presenting after an intentional polypharmacy ingestion, including 500 to 550 mg of amlodipine. She presented with profound vasoplegia and cardiovascular collapse requiring high-dose inotropes and eventual life support with extracorporeal membrane oxygenation (ECMO). Current available treatments, designed for adults, including lipid emulsion and methylene blue, provided no sustained clinical improvement. This resulted in the initiation of single-pass albumin dialysis (SPAD). We aim to describe the clinical implications, amlodipine toxic dose effects, and clinical challenges associated with large pediatric patients and high-dose medications. We also discuss several challenges encountered related to dosing and concentration of medications, which led to fluid overload. Given the ongoing obesity epidemic, we routinely see pediatric patients of adult size. This will continue to challenge pediatric use of adult dosing and concentrations to avoid excessive fluid administration for high-dose medications, such as insulin and vasoactive agents. To our knowledge, this is the first successful case of using SPAD in conjunction with ECMO for salvage therapy after refractory life-threatening calcium channel blocker toxicity.

Neutrophil signaling during myocardial infarction wound repair.

Neutrophils are key effector cells of the innate immune system, serving as a first line of defense in the response to injury and playing essential roles in the wound healing process. Following myocardial infarction (MI), neutrophils infiltrate into the infarct region to propagate inflammation and begin the initial phase of cardiac wound repair. Pro-inflammatory neutrophils release proteases to degrade extracellular matrix (ECM), a necessary step for the removal of necrotic myocytes as a prelude for scar formation. Neutrophils transition their phenotype over time to regulate MI inflammation resolution and stabilize scar formation. Neutrophils contribute to the evolution from inflammation to resolution and scar formation by serving anti-inflammatory and repair functions. As anti-inflammatory cells, neutrophils contribute ECM proteins during scar formation, in particular fibronectin, galectin-3, and vimentin. The diverse and polarizing functions that contribute to MI wound repair make this innate immune cell a viable target to improve MI outcomes. Thus, understanding the signaling involved in neutrophil physiology in the context of MI may help to identify novel therapeutic targets.

Infarct in the Heart: What's MMP-9 Got to Do with It?

Over the past three decades, numerous studies have shown a strong connection between matrix metalloproteinase 9 (MMP-9) levels and myocardial infarction (MI) mortality and left ventricle remodeling and dysfunction. Despite this fact, clinical trials using MMP-9 inhibitors have been disappointing. This review focuses on the roles of MMP-9 in MI wound healing. Infiltrating leukocytes, cardiomyocytes, fibroblasts, and endothelial cells secrete MMP-9 during all phases of cardiac repair. MMP-9 both exacerbates the inflammatory response and aids in inflammation resolution by stimulating the pro-inflammatory to reparative cell transition. In addition, MMP-9 has a dual effect on neovascularization and prevents an overly stiff scar. Here, we review the complex role of MMP-9 in cardiac wound healing, and highlight the importance of targeting MMP-9 only for its detrimental actions. Therefore, delineating signaling pathways downstream of MMP-9 is critical.

Dysbiosis and Intestinal Barrier Dysfunction in Pediatric Congenital Heart Disease Is Exacerbated Following Cardiopulmonary Bypass.

There are no data evaluating the microbiome in congenital heart disease following cardiopulmonary bypass. The authors evaluated patients with congenital heart disease undergoing cardiopulmonary bypass and noncardiac patients undergoing surgery without bypass. Patients with congenital heart disease had differences in baseline microbiome compared with control subjects, and this was exacerbated following surgery with bypass. Markers of barrier dysfunction were similar for both groups at baseline, and surgery with bypass induced significant intestinal barrier dysfunction compared with control subjects. This study offers novel evidence of alterations of the microbiome in congenital heart disease and exacerbation along with intestinal barrier dysfunction following cardiopulmonary bypass.

An unusual log-splitter injury leading to radial artery thrombosis, ulnar artery laceration, and scapholunate dissociation.

A log splitter is a gasoline- or diesel-powered machine that uses a hydraulic-powered cutting wedge to do the work of an axe. Log-splitter injuries that do not result in amputation of digits or limbs are uncommon and not well described in the literature. We present a unique case of a patient who sustained a log-splitter injury that resulted in thrombosis of the radial artery and avulsion laceration of the ulnar artery leading to acute hand ischemia, in addition to scapholunate ligament disruption leading to a DISI deformity. In this case, thrombolytic therapy was contraindicated and surgical revascularization was the best possible treatment option. Our case illustrates the pitfalls of using this modality in a crush injury, since the use of thrombolytics in this instance would have resulted in severe hemorrhage. An important clinical caveat is the potentially misleading arteriographic diagnosis of thrombosis and/or spasm.