Vasopressin in newborns with refractory acute pulmonary hypertension.

BACKGROUND: Acute pulmonary hypertension (aPH) in newborns can be life threatening and challenging to manage. In newborns with refractory aPH, there is currently limited therapeutic agents. METHODS: Retrospective single-center cohort study in newborns less than one month old who were treated with vasopressin for a minimum of one hour in the context of refractory aPH in the neonatal and pediatric intensive care units of a tertiary university center between 2016 and 2022. The objective was to evaluate the efficacy and safety of vasopressin in newborns as an adjuvant treatment for refractory aPH. RESULTS: Twenty-five patients met inclusion criteria. In patients who received vasopressin, oxygenation index improved from 28.4 to 14.4 (p = 0.004) after twelve hours of continuous infusion. Oxygen requirements (FiO2) decreased from 0.91 to 0.50 (p = 0.004) and mean arterial pressure increased from 41 to 51 mmHg (p = 0.001). In our cohort, 68% of patients presented an episode of hyponatremia (serum sodium <130 mmol/L). CONCLUSIONS: The use of vasopressin may be associated with improvement in oxygenation and hemodynamic status of neonatal patients with aPH refractory to initial therapy. Further prospective studies are needed to establish the safety profile of vasopressin in newborns, particularly in preterm infants. IMPACT: Vasopressin may be an effective cardiotropic agent to improve oxygenation and hemodynamic status in newborns with acute pulmonary hypertension. Careful monitoring of serum sodium levels are warranted in newborns who are receiving vasopressin infusion. This provides additional evidence for the consideration of vasopressin in newborns with acute pulmonary hypertension refractory to inhaled nitric oxide.

Diagnosis and management of congenital diaphragmatic hernia: a 2023 update from the Canadian Congenital Diaphragmatic Hernia Collaborative.

OBJECTIVE: The Canadian Congenital Diaphragmatic Hernia (CDH) Collaborative sought to make its existing clinical practice guideline, published in 2018, into a 'living document'. DESIGN AND MAIN OUTCOME MEASURES: Critical appraisal of CDH literature adhering to Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Evidence accumulated between 1 January 2017 and 30 August 2022 was analysed to inform changes to existing or the development of new CDH care recommendations. Strength of consensus was also determined using a modified Delphi process among national experts in the field. RESULTS: Of the 3868 articles retrieved in our search that covered the 15 areas of CDH care, 459 underwent full-text review. Ultimately, 103 articles were used to inform 20 changes to existing recommendations, which included aspects related to prenatal diagnosis, echocardiographic evaluation, pulmonary hypertension management, surgical readiness criteria, the type of surgical repair and long-term health surveillance. Fifteen new CDH care recommendations were also created using this evidence, with most related to the management of pain and the provision of analgesia and neuromuscular blockade for patients with CDH. CONCLUSIONS: The 2023 Canadian CDH Collaborative's clinical practice guideline update provides a management framework for infants and children with CDH based on the best available evidence and expert consensus.

Targeted neonatal echocardiography for patent ductus arteriosus in neonates reduces the surgical ligation rate without affecting healthcare outcomes.

Background: Surgical ligation of patent ductus arteriosus (PDA) can be associated with long-term morbidity and adverse outcomes in neonates. Targeted neonatal echocardiography (TNE) has been increasingly used to improve the hemodynamic management. We aimed to evaluate the preoperative assessment impacts of the hemodynamic significance of PDA using TNE on PDA ligation rates and neonatal outcomes. Methods: This observational study included preterm infants who underwent PDA ligation during two epochs (Epoch I: January 2013 to December 2014; Epoch II: January 2015 to June 2016). During Epoch II, a comprehensive TNE assessment was performed preoperatively to evaluate the hemodynamic significance of PDA. Primary outcome was the incidence of PDA ligation. Secondary outcomes included the incidence of postoperative cardiorespiratory instabilities, individual morbidities, and the composite outcome of death. Results: A total of 69 neonates underwent PDA ligation. No difference in baseline demographics was found between the epochs. The incidence of PDA ligation in very low birth weight (VLBW) infants was lower during Epoch II than Epoch I [7.5% vs. 14.6%, rate ratio =0.51 (95% confidence interval =0.30-0.88)]. No differences were observed between epochs in the proportion of VLBW infants who developed post-operative hypotension or oxygenation failure. The composite outcome of death or major morbidity did not significantly differ between Epoch I and Epoch II (91.1% vs. 94.1%, P=1.000). Conclusions: Incorporating TNE into a standardized hemodynamic assessment program, we demonstrated a 49% reduction in PDA ligation rate without any increase in postoperative cardiopulmonary instability or short-term neonatal morbidities in a cohort of VLBW infants.

Very Early Diagnosis and Management of Congenital Erythropoietic Porphyria.

Congenital erythropoietic porphyria (CEP), a rare form of porphyria, is caused by a defect in the heme biosynthesis pathway of the enzyme uroporphyrinogen III synthase (UROS). Uroporphyrinogen III synthase deficiency leads to an accumulation of nonphysiological porphyrins in bone marrow, red blood cells, skin, bones, teeth, and spleen. Consequently, the exposure to sunlight causes severe photosensitivity, long-term intravascular hemolysis, and eventually, irreversible mutilating deformities. Several supportive therapies such as strict sun avoidance, physical sunblocks, red blood cells transfusions, hydroxyurea, and splenectomy are commonly used in the management of CEP. Currently, the only available curative treatment of CEP is hematopoietic stem cell transplantation (HSCT). In this article, we present a young girl in which precocious genetic testing enabled early diagnosis and allowed curative treatment with HSCT for CEP at the age of 3 months of age, that is, the youngest reported case thus far.

Potential Heart, Liver, and Kidney Donation after Circulatory Determination of Death in a Neonatal Intensive Care Unit.

BACKGROUND: Pediatric organ donation after circulatory determination of death (DCD) has increased in recent years; however, there are few data reporting the number of neonatal potential DCD organ donors and no Canadian-specific reports. OBJECTIVE: The main objective of this study was to estimate the number of patients who may have become actual DCD organ donors from a single, tertiary neonatal intensive care unit (NICU) over 5 years. METHODS: We reviewed all medical charts of newborns ≥2.5 kg, who died in our center's NICU from January 2013 to December 2017. We determined how many could have become actual organ donors after brain death (DBD) or DCD based on 3 sets of organ-specific eligibility criteria defined as conservative, standard, and liberal. RESULTS: Of the 39 deceased patients, none met the criteria for DBD. Twenty-nine (75%) died after the withdrawal of life-sustaining therapies. According to the conservative criteria, 1 patient would have been eligible for kidneys and liver donation. Three patients met standard criteria for kidneys and 1 for liver. Eight patients would have been eligible donors for kidneys, 7 for liver, and 2 for heart according to liberal criteria. Only 2 patients were evaluated for DCD, and no organ donation was performed. CONCLUSIONS: While uncommon, we identified potential DCD organ donors in the NICU population for kidney, heart, and liver transplants. The substantial variability in the number of potential donors depending on the selected eligibility criteria emphasizes the need for a standardized definition adapted to local capacities.

Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth.

We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD+/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.

Inhaled Epoprostenol for Pulmonary Hypertension Treatment in Neonates: A 12-Year Experience.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) occurs in 10% of neonatal respiratory insufficiency. To selectively reduce pulmonary vascular resistance, several treatments have been tried. Inhaled epoprostenol (iPGI2) has been used for 12 years in our institution for the management of refractory PPHN despite the gaps in the literature to support this use. OBJECTIVES: The primary objective was to evaluate the efficacy of iPGI2 for PPHN. The secondary objectives were to describe its use in neonates and assess side effects. STUDY DESIGN: This retrospective cohort study included infants < 28 days with PPHN treated with iPGI2 in the neonatal or pediatric intensive care units of our institution between 2004 and 2016. RESULTS: We reviewed 43 patient' care episodes (mean gestational age of 36 weeks). This was an extremely ill population with 54% mortality rate. Oxygenation index improved significantly after 12-hour treatment (p = 0.047), with a rebound effect when discontinuing nebulization. By the end of the therapy, the fraction of inspired oxygen had significantly dropped (p = 0.0018). Echocardiographic markers tended to normalize during treatment. No potential side effects were reported. CONCLUSION: In these sick newborns, we observed an improvement in PPHN under iPGI2 without significant adverse effects. To our knowledge, this is the largest neonatal cohort reported to have received iPGI2 for PPHN.

Neuroprotective effect of rLosac on supplement-deprived mouse cultured cortical neurons involves maintenance of monocarboxylate transporter MCT2 protein levels.

The recombinant Lonomia obliqua Stuart-factor activator (rLosac) is a recombinant hemolin which belongs to the immunoglobulin superfamily of cell adhesion molecules. It is capable of inducing pro-survival activity in serum-deprived human umbilical vein endothelial cells (HUVECs) and fibroblasts by increasing mitochondrial metabolism. We hypothesize that it could promote neuronal survival by acting on neuroenergetics. Our study reveals that treatment of primary mouse cortical neurons cultured in neurobasal medium lacking B27 supplement with rLosac led to an enhancement of cell viability in a time- and concentration-dependent manner. In parallel, preserved or enhanced phosphorylation of Akt, p44, and p42 MAPK, as well as mTOR was observed following treatment with rLosac. During deprivation, as assessed by western blot and qRT-PCR, protein and mRNA expression of MCT2 (the predominant neuronal monocarboxylate transporter allowing lactate use as an alternative energy substrate) decreased significantly in B27 supplement-deprived cortical neurons and was hardly detected after 24 h of deprivation. Interestingly, rLosac maintained MCT2 protein expression after 24 h of deprivation including at the cell surface without preventing mRNA loss. MCT2 knockdown reduced rLosac-enhanced cell viability, confirming its involvement in rLosac effect. Enhanced uptake of lactate was detected following rLosac treatment and might contribute to rLosac-enhanced viability during deprivation. In the presence of both lactate and rLosac, cell viability was higher than in the presence of lactate alone. Our observations suggest that rLosac promotes cell viability in stressed (B27 supplement-deprived) neurons by facilitating the use of lactate as energy substrate via the preservation of MCT2 protein expression. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Neuroprotective effect of rLosac on supplement-deprived mouse cultured cortical neurons involves maintenance of monocarboxylate transporter MCT2 protein levels

The recombinant Lonomia obliqua Stuart-factor activator (rLosac) is a recombinant hemolin which belongs to the immunoglobulin superfamily of cell adhesion molecules. It is capable of inducing pro-survival activity in serum-deprived human umbilical vein endothelial cells (HUVECs) and fibroblasts by increasing mitochondrial metabolism. We hypothesize that it could promote neuronal survival by acting on neuroenergetics. Our study reveals that treatment of primary mouse cortical neurons cultured in neurobasal medium lacking B27 supplement with rLosac led to an enhancement of cell viability in a time- and concentration-dependent manner. In parallel, preserved or enhanced phosphorylation of Akt, p44, and p42 MAPK, as well as mTOR was observed following treatment with rLosac. During deprivation, as assessed by western blot and qRT-PCR, protein and mRNA expression of MCT2 (the predominant neuronal monocarboxylate transporter allowing lactate use as an alternative energy substrate) decreased significantly in B27 supplement-deprived cortical neurons and was hardly detected after 24h of deprivation. Interestingly, rLosac maintained MCT2 protein expression after 24h of deprivation including at the cell surface without preventing mRNA loss. MCT2 knockdown reduced rLosac-enhanced cell viability, confirming its involvement in rLosac effect. Enhanced uptake of lactate was detected following rLosac treatment and might contribute to rLosac-enhanced viability during deprivation. In the presence of both lactate and rLosac, cell viability was higher than in the presence of lactate alone. Our observations suggest that rLosac promotes cell viability in stressed (B27 supplement-deprived) neurons by facilitating the use of lactate as energy substrate via the preservation of MCT2 protein expression.

Neuroprotective effect of rLosac on supplement-deprived mouse cultured cortical neurons involves maintenance of monocarboxylate transporter MCT2 protein levels

The recombinant Lonomia obliqua Stuart-factor activator (rLosac) is a recombinant hemolin which belongs to the immunoglobulin superfamily of cell adhesion molecules. It is capable of inducing pro-survival activity in serum-deprived human umbilical vein endothelial cells (HUVECs) and fibroblasts by increasing mitochondrial metabolism. We hypothesize that it could promote neuronal survival by acting on neuroenergetics. Our study reveals that treatment of primary mouse cortical neurons cultured in neurobasal medium lacking B27 supplement with rLosac led to an enhancement of cell viability in a time- and concentration-dependent manner. In parallel, preserved or enhanced phosphorylation of Akt, p44, and p42 MAPK, as well as mTOR was observed following treatment with rLosac. During deprivation, as assessed by western blot and qRT-PCR, protein and mRNA expression of MCT2 (the predominant neuronal monocarboxylate transporter allowing lactate use as an alternative energy substrate) decreased significantly in B27 supplement-deprived cortical neurons and was hardly detected after 24h of deprivation. Interestingly, rLosac maintained MCT2 protein expression after 24h of deprivation including at the cell surface without preventing mRNA loss. MCT2 knockdown reduced rLosac-enhanced cell viability, confirming its involvement in rLosac effect. Enhanced uptake of lactate was detected following rLosac treatment and might contribute to rLosac-enhanced viability during deprivation. In the presence of both lactate and rLosac, cell viability was higher than in the presence of lactate alone. Our observations suggest that rLosac promotes cell viability in stressed (B27 supplement-deprived) neurons by facilitating the use of lactate as energy substrate via the preservation of MCT2 protein expression.

A Time-Based Analysis of Inflammation in Infants at Risk of Bronchopulmonary Dysplasia.

OBJECTIVE: To precisely delineate the timing and contribution of inflammation to bronchopulmonary dysplasia (BPD) in preterm infants during the neonatal period. STUDY DESIGN: Longitudinal study of blood inflammatory biomarkers (interleukin [IL]-6, IL-8, and granulocyte colony-stimulating factor) measured between birth and 42 days of age, at high temporal (daily) resolution, in infants born at or below 30 weeks of gestation. Cytokine predictors of BPD at 36 weeks postmenstrual age were adjusted for infant-specific and time-dependent factors, using hierarchical mixed effects regressions models. RESULTS: A total of 1518 data points were obtained in 62 infants (mean gestational age of 27 weeks). Infants who developed BPD later on presented increased inflammation after birth compared with infants without BPD. Inflammation was sustained, with gradual attenuation over 2 weeks (IL-8: OR: 6.5 [95% CI: 1.8-24]; granulocyte colony-stimulating factor: 3.3 [1.5-7.6]) and was higher in boys and in infants of lower birth weight. This inflammation preceded the clinical increased requirement in supplemental oxygen characteristic of BPD, and preceded the peak occurrence of neonatal sepsis or necrotizing enterocolitis. CONCLUSIONS: Systemic inflammation occurs early in the neonatal period and precedes clinical symptoms in infants with BPD. These data provide a discrete vulnerability window period, supporting a role for targeted intensive care interventions during the early phase of BPD.

Effect of measuring vital signs on recognition and treatment of septic children.

BACKGROUND AND OBJECTIVES: A majority of children presenting with sepsis do not receive adequate fluid resuscitation and have a delay in antibiotic administration despite recommendations from the Surviving Sepsis Campaign. The objective of this study was to evaluate the association of measuring a complete set of five vital signs in the emergency department (ED) with recognition and treatment of septic children presenting to the ED. METHODS: Records of 218 patients aged 1 month to 17 years treated between February 2011 and December 2011 in a single academic centre with clinical criteria of sepsis, severe sepsis or septic shock were retrospectively evaluated. The presence or absence of complete vital signs was analyzed in relation to timing of fluid resuscitation, and if antibiotics were given in the first hour of medical evaluation. RESULTS: Seventy-six per cent of children who had all five vital signs measured in the ED received fluid resuscitation in the first hour after medical evaluation as opposed to 61% of those who had an incomplete set of vital signs (P<0.04). Twenty per cent of children who had all five vital signs measured received antibiotics in the first hour as opposed to 9% in children who had fewer vital signs measured (P<0.02). CONCLUSION: In our study population, the measurement of all vital signs in the ED, including blood pressure, was associated with faster administration of antibiotics and improved compliance with existing fluid bolus recommendations, which may have been the result of better recognition of sepsis in children through vital signs measurement.

L'effet de la mesure des signes vitaux pour dépister et traiter les enfants atteints de sepsis. HISTORIQUE ET OBJECTIFS: La majorité des enfants ayant un sepsis ne reçoivent pas de solutés de réanimation et doivent attendre avant de se faire administrer des antibiotiques, malgré les recommandations de la Surviving Sepsis Campaign. La présente étude visait à évaluer l'association entre la mesure de l'ensemble des cinq signes vitaux à la salle d'urgence (SU) et le dépistage et le traitement des enfants atteints de sepsis qui s'y présentaient. MÉTHODOLOGIE: Les dossiers de 218 patients de 11 mois à 17 ans traités entre février et décembre 2011 dans un seul centre universitaire en raison de critères cliniques de sepsis, de grave sepsis ou de choc septique ont fait l'objet d'une évaluation rétrospective. Les chercheurs ont analysé le lien entre la présence ou l'absence de tous les signes vitaux et le moment d'administrer des solutés de réanimation et ont vérifié si des antibiotiques avaient été administrés dans l'heure suivant l'évaluation médicale. RÉSULTATS: Au total, 76 % des enfants dont les cinq signes vitaux avaient été mesurés à la SU avaient reçu des solutés de réanimation dans l'heure suivant leur évaluation médicale, par rapport à 61 % de ceux dont les signes vitaux n'avaient pas tous été mesurés (P<0,04). De plus, 20 % des enfants dont les cinq signes vitaux avaient été mesurés à la SU avaient reçu des antibiotiques dans l'heure suivant leur évaluation médicale, par rapport à 9 % de ceux dont les signes vitaux n'avaient pas tous été mesurés (P<0,02). CONCLUSION: Au sein de la population à l'étude, la mesure de tous les signes vitaux en SU, y compris la tension artérielle, s'associait à une administration plus rapide d'antibiotiques et à une meilleure compliance aux recommandations sur le bolus de liquide, ce qui peut être attribuable à un meilleur dépistage du sepsis chez les enfants grâce à la mesure des signes vitaux.

Hypothalamic sensing of ketone bodies after prolonged cerebral exposure leads to metabolic control dysregulation.

Ketone bodies have been shown to transiently stimulate food intake and modify energy homeostasis regulatory systems following cerebral infusion for a moderate period of time (<6 hours). As ketone bodies are usually enhanced during episodes of fasting, this effect might correspond to a physiological regulation. In contrast, ketone bodies levels remain elevated for prolonged periods during obesity, and thus could play an important role in the development of this pathology. In order to understand this transition, ketone bodies were infused through a catheter inserted in the carotid to directly stimulate the brain for a period of 24 hours. Food ingested and blood circulating parameters involved in metabolic control as well as glucose homeostasis were determined. Results show that ketone bodies infusion for 24 hours increased food intake associated with a stimulation of hypothalamic orexigenic neuropeptides. Moreover, insulinemia was increased and caused a decrease in glucose production despite an increased resistance to insulin. The present study confirms that ketone bodies reaching the brain stimulates food intake. Moreover, we provide evidence that a prolonged hyperketonemia leads to a dysregulation of energy homeostasis control mechanisms. Finally, this study shows that brain exposure to ketone bodies alters insulin signaling and consequently glucose homeostasis.

ß-Hydroxybutyrate supports synaptic vesicle cycling but reduces endocytosis and exocytosis in rat brain synaptosomes.

The ketogenic diet is used as a prophylactic treatment for different types of brain diseases, such as epilepsy or Alzheimer's disease. In such a diet, carbohydrates are replaced by fats in everyday food, resulting in an elevation of blood-borne ketone bodies levels. Despite clinical applications of this treatment, the molecular mechanisms by which the ketogenic diet exerts its beneficial effects are still uncertain. In this study, we investigated the effect of replacing glucose by the ketone body ß-hydroxybutyrate as the main energy substrate on synaptic vesicle recycling in rat brain synaptosomes. First, we observed that exposing presynaptic terminals to nonglycolytic energy substrates instead of glucose did not alter the plasma membrane potential. Next, we found that synaptosomes were able to maintain the synaptic vesicle cycle monitored with the fluorescent dye acridine orange when glucose was replaced by ß-hydroxybutyrate. However, in presence of ß-hydroxybutyrate, synaptic vesicle recycling was modified with reduced endocytosis. Replacing glucose by pyruvate also led to a reduced endocytosis. Addition of ß-hydroxybutyrate to glucose-containing incubation medium was without effect. Reduced endocytosis in presence of ß-hydroxybutyrate as sole energy substrate was confirmed using the fluorescent dye FM2-10. Also we found that replacement of glucose by ketone bodies leads to inhibition of exocytosis, monitored by FM2-10. However this reduction was smaller than the effect on endocytosis under the same conditions. Using both acridine orange in synaptosomes and the genetically encoded sensor synaptopHluorin in cortical neurons, we observed that replacing glucose by ß-hydroxybutyrate did not modify the pH gradient of synaptic vesicles. In conclusion, the nonglycolytic energy substrates ß-hydroxybutyrate and pyruvate are able to support synaptic vesicle recycling. However, they both reduce endocytosis. Reduction of both endocytosis and exocytosis together with misbalance between endocytosis and exocytosis could be involved in the anticonvulsant activity of the ketogenic diet.

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice.

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

Benzimidazolium-based synthetic chloride and calcium transporters in bacterial membranes.

Herein, we present the first example of a benzimidazolium-based artificial transmembrane chloride transporter and a synthetic calcium ionophore that can regulate intracellular calcium concentrations in bacteria.