Gut permeability and myocardial damage in paediatric cardiac surgery

Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) in patients following cardiac surgery that can lead to major organ injury and postoperative morbidity. Initiation of CPB sets in motion an extremely complex and multifaceted response involving complement activation along with activation of platelets, neutrophils, monocytes, and macrophages. This in turn initiates the coagulation, fibrinolytic, and kallikrein cascades, increasing blood concentrations of various endotoxins and cytokines and increasing endothelial cell permeability. The basic physiological insults caused by CPB have been associated with major postoperative morbidity, including neurological, pulmonary adrenal dysfunction, and/or haematological abnormalities. Additional clinical manifestations associated with the SIRS include increased metabolism (fever), fluid retention, myocardial oedema, and detrimental haemodynamic alterations. The use of steroids to minimize or prevent the consequences of SIRS in the postoperative period has been extensively investigated in adults. Clinical investigations in the paediatric population are scarce. Our aim was to investigate how dexamethasone could influence the associated side effects of CPB in two organs, the small intestine and the heart. To that effect we chose two surrogate markers, gut permeability and cardiac troponin T production. Intestinal mucosal ischaemia, although transient, can occur in infants and children during and after CPB. Gut permeability had not been previously investigated in children undergoing cardiac surgery. In chapter two we describe, in an observational study, the natural course of gut permeability in patients undergoing cardiac surgery with and without CPB. Gut permeability has been investigated in healthy children and neonates not undergoing surgical or medical interventions during the study period. Patients with congenital cardiac diseases have preoperative gut permeability values up to seven times what we could expect in healthy children of similar age. In patients operated without CPB gut permeability was reduced in the postoperative period returning to near normal values 24 hours after surgery. On the other hand, in patients undergoing surgery with CPB gut permeability deteriorated even further in the postoperative period. 98 In chapter three we report the results of a study designed to test the hypothesis that dexamethasone has beneficial effects on intestinal permeability during the postoperative period. Dexamethasone given before CPB starts reduced intestinal permeability within 24 h after surgery. The differences are highly significant when compared to control patients not given dexamethasone. In the investigation reported in chapter four we studied the changes in intestinal permeability in patients undergoing stage I of the Norwood procedure. Neonates with hypoplastic left heart syndrome (HLHS) undergo surgical repair in three stages. These patients suffer from an imbalanced circulation potentially exposing the intestine to chronic ischaemia. The surgical repair requires a period of circulatory arrest. It comes as no surprise, therefore, that HLHS patients are at high risk of developing necrotizing enterocolitis in the postoperative period, with devastating consequences. We found that HLHS patients have abnormal intestinal permeability before and after surgery. Rhamnose is one of the four sugars used to test intestinal permeability. For the last thirty years it has been assumed that rhamnose is an inert sugar not metabolized by the human body. We have found this not to be the case, and the results are presented in chapter five. The type of anaesthetic agent used during adult coronary bypass surgery may influence considerably the postoperative production of cardiac troponin T (cTnT), a protein that reflects the extent of myocardial damage after a period of hypoxia. In particular halogenated ethers may exert its effect through a process called anaesthetic preconditioning, a phenomenon similar to ischaemic preconditioning. Anaesthetic preconditioning has not been investigated in paediatric cardiac surgery to the same extent as in adult cardiac surgery. In chapter six we present a study of the effects of three different anaesthetic agents, propofol, midazolam and sevoflurane, on the postoperative production of cTnT in paediatric cardiac surgical patients. Contrary to what happens in adult patients we could not find significant differences in the postoperative production of cTnT when midazolam, propofol or sevoflurane were used as anaesthetic agents. In chapter seven, we report on a study designed to test the hypothesis that dexamethasone given before CPB starts may have myocardial protective effects as assessed by the postoperative production of cTnT. Subgroup analysis in cyanotic and neonatal patients was also evaluated for the same hypothesis. 99 We found that dexamethasone did reduce postoperative cTnT concentrations. However, the reduction was short lived and was not accompanied by improvements in any of the other clinical parameters measured.Dutch Heart FundationUBL - phd migration 201

A Novel Patient-Specific Model for Predicting Severe Oliguria; Development and Comparison With Kidney Disease: Improving Global Outcomes Acute Kidney Injury Classification

Objectives: The Kidney Disease: Improving Global Outcomes urine output criteria for acute kidney injury lack specificity for identifying patients at risk of adverse renal outcomes. The objective was to develop a model that analyses hourly urine output values in real time to identify those at risk of developing severe oliguria. Design: This was a retrospective cohort study utilizing prospectively collected data. Setting: A cardiac ICU in the United Kingdom. Patients: Patients undergoing cardiac surgery between January 2013 and November 2017. Interventions: None. Measurement and Main Results: Patients were randomly assigned to development (n = 981) and validation (n = 2,389) datasets. A patient-specific, dynamic Bayesian model was developed to predict future urine output on an hourly basis. Model discrimination and calibration for predicting severe oliguria ( 0.8) were identified and their outcomes were compared with those for low-risk patients and for patients who met the Kidney Disease: Improving Global Outcomes urine output criterion for acute kidney injury. Model discrimination was excellent at all time points (area under the curve > 0.9 for all). Calibration of the model’s predictions was also excellent. After adjustment using multivariable logistic regression, patients in the high-risk group were more likely to require renal replacement therapy (odds ratio, 10.4; 95% CI, 5.9–18.1), suffer prolonged hospital stay (odds ratio, 4.4; 95% CI, 3.0–6.4), and die in hospital (odds ratio, 6.4; 95% CI, 2.8–14.0) (p < 0.001 for all). Outcomes for those identified as high risk by the model were significantly worse than for patients who met the Kidney Disease: Improving Global Outcomes urine output criterion. Conclusions: This novel, patient-specific model identifies patients at increased risk of severe oliguria. Classification according to model predictions outperformed the Kidney Disease: Improving Global Outcomes urine output criterion. As the new model identifies patients at risk before severe oliguria develops it could potentially facilitate intervention to improve patient outcomes

Pediatric anesthesia in Europe:Variations within uniformity

Organization of healthcare strongly differs between European countries and results in country-specific requirements in postgraduate medical training. Within the European Union (EU), the European Board of Anaesthesiology has set recommendations of training for the Specialty of Anaesthesiology including standards for Postgraduate Medical Specialist training including a description for providing service in pediatric anesthesia. However, these standards are advisory and not mandatory. Here we aimed to review the current state and associated challenges of pediatric anesthesia training in Europe. We report an important country-specific variability both in training and regulations of practice of pediatric anesthesia in the EU and in the United Kingdom. The requirements for training in pediatric anesthesia varies between nothing specified (Belgium) or providing anesthesia with direct supervision to a minimum of 50 cases below 5 years of age (Germany) to 3–6 month clinical practice in a specialized pediatric hospital (France). Likewise, the regulations for providing anesthesia to children varies from no regulations at all (Belgium) to age specific requirements and centralization of all children below 4 years of age to specified centers (United Kingdom). Officially recognized pediatric anesthesia fellowship programs are not available in most countries of Europe. It remains unclear if and how country-specific differences in pediatric anesthesia training are associated with clinical outcomes in pediatric perioperative care. There is converging interest and support for the establishment of a European pediatric anesthesia curriculum.</p

Candidate Massive Galaxies at z~4 in the Dark Energy Survey

Using stellar population models, we predicted that the Dark Energy Survey (DES) - due to its special combination of area (5000 deg. sq.) and depth ($i = 24.3$) - would be in the position to detect massive ($\gtrsim 10^{11}$ M$_{\odot}$) galaxies at $z \sim 4$. We confront those theoretical calculations with the first $\sim 150$ deg. sq. of DES data reaching nominal depth. From a catalogue containing $\sim 5$ million sources, $\sim26000$ were found to have observed-frame $g-r$ vs $r-i$ colours within the locus predicted for $z \sim 4$ massive galaxies. We further removed contamination by stars and artefacts, obtaining 606 galaxies lining up by the model selection box. We obtained their photometric redshifts and physical properties by fitting model templates spanning a wide range of star formation histories, reddening and redshift. Key to constrain the models is the addition, to the optical DES bands $g$, $r$, $i$, $z$, and $Y$, of near-IR $J$, $H$, $K_{s}$ data from the Vista Hemisphere Survey. We further applied several quality cuts to the fitting results, including goodness of fit and a unimodal redshift probability distribution. We finally select 233 candidates whose photometric redshift probability distribution function peaks around $z\sim4$, have high stellar masses ($\log($M$^{*}$/M$_{\odot})\sim 11.7$ for a Salpeter IMF) and ages around 0.1 Gyr, i.e. formation redshift around 5. These properties match those of the progenitors of the most massive galaxies in the local universe. This is an ideal sample for spectroscopic follow-up to select the fraction of galaxies which is truly at high redshift. These initial results and those at the survey completion, which we shall push to higher redshifts, will set unprecedented constraints on galaxy formation, evolution, and the re-ionisation epoch

Gut permeability and myocardial damage in paediatric cardiac surgery

Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) in patients following cardiac surgery that can lead to major organ injury and postoperative morbidity. Initiation of CPB sets in motion an extremely complex and multifaceted response involving complement activation along with activation of platelets, neutrophils, monocytes, and macrophages. This in turn initiates the coagulation, fibrinolytic, and kallikrein cascades, increasing blood concentrations of various endotoxins and cytokines and increasing endothelial cell permeability. The basic physiological insults caused by CPB have been associated with major postoperative morbidity, including neurological, pulmonary adrenal dysfunction, and/or haematological abnormalities. Additional clinical manifestations associated with the SIRS include increased metabolism (fever), fluid retention, myocardial oedema, and detrimental haemodynamic alterations. The use of steroids to minimize or prevent the consequences of SIRS in the postoperative period has been extensively investigated in adults. Clinical investigations in the paediatric population are scarce. Our aim was to investigate how dexamethasone could influence the associated side effects of CPB in two organs, the small intestine and the heart. To that effect we chose two surrogate markers, gut permeability and cardiac troponin T production. Intestinal mucosal ischaemia, although transient, can occur in infants and children during and after CPB. Gut permeability had not been previously investigated in children undergoing cardiac surgery. In chapter two we describe, in an observational study, the natural course of gut permeability in patients undergoing cardiac surgery with and without CPB. Gut permeability has been investigated in healthy children and neonates not undergoing surgical or medical interventions during the study period. Patients with congenital cardiac diseases have preoperative gut permeability values up to seven times what we could expect in healthy children of similar age. In patients operated without CPB gut permeability was reduced in the postoperative period returning to near normal values 24 hours after surgery. On the other hand, in patients undergoing surgery with CPB gut permeability deteriorated even further in the postoperative period. 98 In chapter three we report the results of a study designed to test the hypothesis that dexamethasone has beneficial effects on intestinal permeability during the postoperative period. Dexamethasone given before CPB starts reduced intestinal permeability within 24 h after surgery. The differences are highly significant when compared to control patients not given dexamethasone. In the investigation reported in chapter four we studied the changes in intestinal permeability in patients undergoing stage I of the Norwood procedure. Neonates with hypoplastic left heart syndrome (HLHS) undergo surgical repair in three stages. These patients suffer from an imbalanced circulation potentially exposing the intestine to chronic ischaemia. The surgical repair requires a period of circulatory arrest. It comes as no surprise, therefore, that HLHS patients are at high risk of developing necrotizing enterocolitis in the postoperative period, with devastating consequences. We found that HLHS patients have abnormal intestinal permeability before and after surgery. Rhamnose is one of the four sugars used to test intestinal permeability. For the last thirty years it has been assumed that rhamnose is an inert sugar not metabolized by the human body. We have found this not to be the case, and the results are presented in chapter five. The type of anaesthetic agent used during adult coronary bypass surgery may influence considerably the postoperative production of cardiac troponin T (cTnT), a protein that reflects the extent of myocardial damage after a period of hypoxia. In particular halogenated ethers may exert its effect through a process called anaesthetic preconditioning, a phenomenon similar to ischaemic preconditioning. Anaesthetic preconditioning has not been investigated in paediatric cardiac surgery to the same extent as in adult cardiac surgery. In chapter six we present a study of the effects of three different anaesthetic agents, propofol, midazolam and sevoflurane, on the postoperative production of cTnT in paediatric cardiac surgical patients. Contrary to what happens in adult patients we could not find significant differences in the postoperative production of cTnT when midazolam, propofol or sevoflurane were used as anaesthetic agents. In chapter seven, we report on a study designed to test the hypothesis that dexamethasone given before CPB starts may have myocardial protective effects as assessed by the postoperative production of cTnT. Subgroup analysis in cyanotic and neonatal patients was also evaluated for the same hypothesis. 99 We found that dexamethasone did reduce postoperative cTnT concentrations. However, the reduction was short lived and was not accompanied by improvements in any of the other clinical parameters measured

Intra-abdominal hypertension complicating pancreatitis-induced acute respiratory distress syndrome in three patients on extracorporeal membrane oxygenation

Background: Severe acute pancreatitis is associated with sever multiorgan failure from 15 to 50%, depending on theseries. In some of these patients, conventional methods of ventilation and respiratory support will fail, demandingthe use of extracorporeal membrane oxygenation (ECMO). Abdominal compartment syndrome is potentially harmfulin this cohort of patients. We describe the successful treatment of three patients with severe acute pancreatitis whounderwent respiratory ECMO and where intra abdominal pressure was monitored regularly. Methods: Retrospective review of case notes. Results: Three patients with severe acute pancreatitis requiring ECMO suffered from increased intra abdominalpressure during their ICU stay. No surgical interventions were taken to relieve abdominal compartment syndrome.Survival to hospital discharge was 100%. Conclusions: Monitoring intraabdominal pressure is a valuable adjunct to decision making while caring for thesehigh-risk critically ill patients.Background: Severe acute pancreatitis is associated with sever multiorgan failure from 15 to 50%, depending on theseries. In some of these patients, conventional methods of ventilation and respiratory support will fail, demandingthe use of extracorporeal membrane oxygenation (ECMO). Abdominal compartment syndrome is potentially harmfulin this cohort of patients. We describe the successful treatment of three patients with severe acute pancreatitis whounderwent respiratory ECMO and where intra abdominal pressure was monitored regularly. Methods: Retrospective review of case notes. Results: Three patients with severe acute pancreatitis requiring ECMO suffered from increased intra abdominalpressure during their ICU stay. No surgical interventions were taken to relieve abdominal compartment syndrome.Survival to hospital discharge was 100%. Conclusions: Monitoring intraabdominal pressure is a valuable adjunct to decision making while caring for thesehigh-risk critically ill patients