Association Between Lactates, Blood Glucose, and Systemic Oxygen Delivery in Children After Cardiopulmonary Bypass.

Objective: Lactate is often used as a surrogate marker of inappropriate oxygen delivery. It has been shown that hyperlactatemia is associated with worse clinical outcome in children after cardiac surgery. The purpose of this study is to evaluate the association of hyperlactatemia, low systemic oxygen delivery, and hyperglycemia, in children admitted to the pediatric critical care unit after cardiopulmonary bypass. Design: Secondary analysis of an observational cohort study. Setting: Tertiary pediatric critical care unit (PICU). Patients: Ninety-three patients, aged 6 months to 16 years, undergoing cardiac surgery with cardiopulmonary bypass. Interventions: None. Measurements and Main Results: Metabolic tests (blood glucose, lactate, lactate/pyruvate ratio, and ketones) and oxygen extraction (SaO2-SvO2) were performed before anesthesia, at the end of cardiopulmonary bypass, at PICU admission, and at 4 and 12 h after PICU admission. Four hours after PICU admission, 62% of the patients had hyperlactatemia (>2 mmol/L), of whom 55% had normal oxygen extraction (SaO2-SvO2 < 30%). There was no correlation between lactate and oxygen extraction (R = -0.09, p = 0.41) but there was a moderate correlation between lactate and blood glucose (R = 0.55, p < 0.001). Using a logistic regression model, hyperlactatemia at 4 h after PICU admission was independently associated with hyperglycemia (p = 0.007) and lactate/pyruvate ratio (p = 0.007) at the same timepoint, as well as with lactate at PICU admission (p = 0.002), but not with weight (p = 0.45), severity of the cardiac lesion (p = 0.85), duration of bypass (p = 0.16), or oxygen extraction, as evaluated by SaO2-SvO2 (p = 0.54). At 12 h after PICU admission, there was a very week correlation between lactate and blood glucose (R = 0.27, p = 0.007), but none between lactate and oxygen extraction (R = 0.13, p = 0.20). Conclusion: In children after cardiopulmonary bypass, lactates are not correlated with higher oxygen extraction, but are correlated with hyperglycemia, at both 4 and 12 h after PICU admission. Future research is warranted to better define this relationship.

Combined Pancreatic Islet-Lung-Liver Transplantation in a Pediatric Patient with Cystic Fibrosis-Related Diabetes.

BACKGROUND: Cystic fibrosis-related diabetes (CFRD) is the most frequent extrapulmonary complication of cystic fibrosis (CF). METHODS: We report the first combined pancreatic islet-lung-liver transplantation in a 14-year-old adolescent. CFTR was analyzed by Sanger sequencing. Further genes were analyzed by high-throughput sequencing. RESULTS: The patient was diagnosed with CF at the age of 14 months. Nine years later, after diagnosis of CFRD, the patient's BMI and lung function began to decline. Bilateral lung transplantation with simultaneous liver transplantation was performed at the age of 14.5 years. The first islet transplantation (IT) was carried out 10 days later. Six months later, C-peptide secretion after arginine stimulation showed peak values of 371 pmol/L (vs. 569 pmol/L before IT) and insulin doses had slightly increased (1.40 vs. 1.11 units/kg/day before IT). A second IT was performed at the age of 15 years, a third at 16 years. Two years after the first IT, arginine-stimulated C-peptide secretion increased to 2,956 pmol/L and insulin doses could be reduced to 0.82 units/kg/day. HbA1c decreased from 7.3% (57.4 mmol/mol) to 5.9% (41.0 mmol/mol). CONCLUSION: IT following lung and liver transplantation, with injection of islets into a transplanted organ, is feasible. It improves C-peptide secretion, decreases insulin needs, and lowers HbA1c.

Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets.

Type 1 diabetes (T1DM) results from destruction of most insulin-secreting pancreatic ß-cells. The persistence of ß-cells decades after the onset of the disease indicates that the resistance of individual cells to the autoimmune insult is heterogeneous and might depend on the metabolic status of a cell at a given moment. The aim of this study is to investigate whether activation of nicotinic acetylcholine receptors (nACh-Rs) could increase ß-cell resistance against the adverse environment prevailing at the onset of T1DM. Here, we show that nACh-R activation by nicotine and choline, 2 agonists of the receptor, decreases murine and human ß-cell apoptosis induced by proinflammatory cytokines known to be present in the islet environment at the onset of T1DM. The protective mechanism activated by nicotine and choline involves attenuation of mitochondrial outer membrane permeabilization via modulation of endoplasmic reticulum stress, of the activity of B-cell lymphoma 2 family proteins and cytoplasmic calcium levels. Local inflammation and endoplasmic reticulum stress being key determinants of ß-cell death in T1DM, we conclude that pharmacological activation of nACh-R could represent a valuable therapeutic option in the modulation of ß-cell death in T1DM.

Ketosis After Cardiopulmonary Bypass in Children Is Associated With an Inadequate Balance Between Oxygen Transport and Consumption.

OBJECTIVES: Hyperglycemia after cardiac surgery and cardiopulmonary bypass in children has been associated with worse outcome; however, causality has never been proven. Furthermore, the benefit of tight glycemic control is inconsistent. The purpose of this study was to describe the metabolic constellation of children before, during, and after cardiopulmonary bypass, in order to identify a subset of patients that might benefit from insulin treatment. DESIGN: Prospective observational study, in which insulin treatment was initiated when postoperative blood glucose levels were more than 12 mmol/L (216 mg/dL). SETTING: Tertiary PICU. PATIENTS: Ninety-six patients 6 months to 16 years old undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Metabolic tests were performed before anesthesia, at the end of cardiopulmonary bypass, at PICU admission, and 4 and 12 hours after PICU admission, as well as 4 hours after initiation of insulin treatment. Ketosis was present in 17.9% patients at the end of cardiopulmonary bypass and in 31.2% at PICU admission. Young age was an independent risk factor for this condition. Ketosis at PICU admission was an independent risk factor for an increased difference between arterial and venous oxygen saturation. Four hours after admission (p = 0.05). Insulin corrected ketosis within 4 hours. CONCLUSIONS: In this study, we found a high prevalence of ketosis at PICU admission, especially in young children. This was independently associated with an imbalance between oxygen transport and consumption and was corrected by insulin. These results set the basis for future randomized controlled trials, to test whether this subgroup of patients might benefit from increased glucose intake and insulin during surgery to avoid ketosis, as improving oxygen transport and consumption might improve patient outcome.

Connexin-dependent signaling in neuro-hormonal systems.

The advent of multicellular organisms was accompanied by the development of short- and long-range chemical signalling systems, including those provided by the nervous and endocrine systems. In turn, the cells of these two systems have developed mechanisms for interacting with both adjacent and distant cells. With evolution, such mechanisms have diversified to become integrated in a complex regulatory network, whereby individual endocrine and neuro-endocrine cells sense the state of activity of their neighbors and, accordingly, regulate their own level of functioning. A consistent feature of this network is the expression of connexin-made channels between the (neuro)hormone-producing cells of all endocrine glands and secretory regions of the central nervous system so far investigated in vertebrates. This review summarizes the distribution of connexins in the mammalian (neuro)endocrine systems, and what we know about the participation of these proteins on hormone secretion, the life of the producing cells, and the action of (neuro)hormones on specific targets. The data gathered since the last reviews on the topic are summarized, with particular emphasis on the roles of Cx36 in the function of the insulin-producing beta cells of the endocrine pancreas, and of Cx40 in that of the renin-producing juxta-glomerular epithelioid cells of the kidney cortex. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Connexins protect mouse pancreatic ß cells against apoptosis.

Type 1 diabetes develops when most insulin-producing ß cells of the pancreas are killed by an autoimmune attack. The in vivo conditions modulating the sensitivity and resistance of ß cells to this attack remain largely obscure. Here, we show that connexin 36 (Cx36), a trans-membrane protein that forms gap junctions between ß cells in the pancreatic islets, protects mouse ß cells against both cytotoxic drugs and cytokines that prevail in the islet environment at the onset of type 1 diabetes. We documented that this protection was at least partially dependent on intercellular communication, which Cx36 and other types of connexin channels establish within pancreatic islets. We further found that proinflammatory cytokines decreased expression of Cx36 and that experimental reduction or augmentation of Cx36 levels increased or decreased ß cell apoptosis, respectively. Thus, we conclude that Cx36 is central to ß cell protection from toxic insults.