Katharina Schumacher

Influence of temperature during cardiopulmonary bypass on leukocyte activation, cytokine balance, and post-operative organ damage

This study examined the hypothesis that core temperature (T(o)) during cardiopulmonary bypass (CPB) influences the perioperative systemic inflammatory response and post-operative organ damage. Twenty-four pigs were assigned to a T(o) regimen during CPB: normothermia (T(o) 37 degrees C; n = 8), moderate hypothermia (T(o) 28 degrees C; n = 8), or deep hypothermia (T(o) 20 degrees C; n = 8). Perioperative leukocyte activation, endotoxin release, and production of tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL10) were examined with regard to post-operative organ damage, which was scored at histological examination of tissue probes of heart, lungs, liver, kidney, and ileum, taken 6 h after CPB. Total blood leukocyte count and TNFalpha plasma levels during CPB were significantly lower and IL10 levels were significantly higher in the moderate hypothermic group than in both other groups. Elastase activity, leukotriene B4-, and endotoxin levels were not affected by T(o) regimen. Moderate hypothermia was associated with the lowest histological organ damage score and normothermia with the highest. In all animals organ damage score for heart, lungs, and kidneys correlated significantly with TNFalpha levels at the end of CPB. Our data demonstrate a clear relationship between TNFalpha production during cardiac operations and post-operative multiple-organ damage. Moderate hypothermia, by stimulating IL10 synthesis and suppressing TNFalpha production during CPB, might provide organ protection.

The Production of Pro- and Anti- Inflammatory Cytokines in Neonates Assessed by Stimulated Whole Cord Blood Culture and by Plasma Levels at Birth

The capability of neonates to achieve cytokine balance was evaluated. Production of the pro-inflammatory cytokines TNFα and IL-8, of the natural anti-inflammatory cytokine IL10 and of the regulator of the acute phase response IL6 was assessed after whole blood stimulation by lipopolysaccharide in cord blood (n = 10), adult volunteers serving as control (n = 17). Additionally, circulating cytokines were determined in cord and in maternal blood immediately after delivery (n = 27, respectively). Significant production of TNFα, IL8, IL10 and IL6 was observed in cord blood after lipopolysaccharide stimulation and was similar to cytokine production in adult blood. The plasma concentrations of TNFα were significantly higher in cord than in maternal blood, while plasma concentrations of IL10 and IL6 were significantly lower. Our results demonstrate fully developed capability of whole cord blood to synthesize pro- and anti-inflammatory cytokines in response to a pro-inflammatory stimulation in vitro. In vivo, however, higher circulating TNFα and lower IL10 and IL6 levels in cord blood suggest that the inflammatory stress associated with normal delivery does not induce detectable anti-inflammatory response in neonates at birth.

Dexamethasone Pretreatment Provides Antiinflammatory and Myocardial Protection in Neonatal Arterial Switch Operation

BACKGROUND This prospective double-blinded randomized study tested the hypothesis that preoperative treatment with dexamethasone would attenuate inflammatory priming of the myocardium, reduce the systemic inflammatory reaction upon cardiac operation, and provide organ protection in neonates. METHODS Twenty neonates (age, 8 to 21 days) with transposition of the great arteries scheduled for arterial switch operation were included. Nine received dexamethasone (1 mg/kg body weight) 4 hours before cardiopulmonary bypass, and 11 received natrium chloride. We studied intramyocardial messenger RNA expression of interleukin (IL)-6, IL-8, IL-1β, and tumor necrosis factor-α (TNF-α), as well as IL-10 and expression of TNF-α on protein level in right atrial tissue taken before institution of CPB. We measured plasma levels of IL-6, IL-10, lipopolysaccharide binding protein, and cardiac troponin T. Cytokine expression was related to postoperative outcome. RESULTS Pretreatment with dexamethasone led to a significant decrease in myocardial expression of IL-6, IL-8, IL-1β, and TNF-α messenger RNA and to a decrease in protein synthesis of TNF-α. Plasma concentrations of IL-6 were significantly lower and those of IL-10 significantly higher in pretreated patients. This was associated with lower cardiac troponin T values and lower dobutamine requirement. Levels of lipopolysaccharide binding protein were significantly higher postoperatively in pretreated neonates. CONCLUSIONS Dexamethasone administration before arterial switch operation leads to a shift in the myocardial and systemic cytokine expression profile in neonates with transposition of the great arteries, with downregulation of proinflammatory and upregulation of antiinflammatory cytokines. Lower myocardial cell damage and lower catecholamine requirement suggest myocardial protection in treated patients.

The hypoxia-inducible factor HIF-1 promotes intramyocardial expression of VEGF in infants with congenital cardiac defects.

AbstractObjectivesThe response to hypoxia is primarily mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) which leads to the induction of a variety of adaptive gene products including vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). This study was designed to test the hypothesis that HIF-1 and its target genes would be upregulated in the ventricular myocardium of infants with cyanotic congenital cardiac defects.Methods14 infants with cyanotic (n = 7) or acyanotic cardiac defects (n = 7) were investigated. Samples from the right ventricular myocardium taken immediately after aortic clamping were studied for protein expression and DNA-binding activity.ResultsProtein levels of HIF-1α were significantly elevated in patients with cyanotic compared to acyanotic congenital heart disease and inversely correlated with the degree of hypoxemia. This response was accompanied by significantly enhanced HIF-1 DNA binding activity. Furthermore, protein levels of VEGF and eNOS were significantly higher in the myocardium of cyanotic than of acyanotic infants. To test the potential involvement of upstream regulatory pathways, activation of MAP kinases was determined. Intramyocardial levels of phosphorylated p38 MAP kinase, but not of ERK1/2 were significantly higher in infants with cyanotic compared to those with acyanotic congenital heart disease and inversely correlated to hypoxemia.ConclusionsThese findings show that chronic hypoxemia is associated with the induction and stabilization of the transcription factor HIF-1 as well as its target genes VEGF and eNOS in the myocardium of infants with cyanotic cardiac defects. Thus, stabilization of HIF-1 and induction of the adaptive hypoxia response could particularly participate in myocardial remodeling in children with congenital cardiac defects and chronic hypoxemia.

Children undergoing cardiac surgery for complex cardiac defects show imbalance between pro- and anti-thrombotic activity

IntroductionCardiac surgery with cardiopulmonary bypass (CPB) is associated with the activation of inflammatory mediators that possess prothrombotic activity and could cause postoperative haemostatic disorders. This study was conducted to investigate the effect of cardiac surgery on prothrombotic activity in children undergoing cardiac surgery for complex cardiac defects.MethodsEighteen children (ages 3 to 163 months) undergoing univentricular palliation with total cavopulmonary connection (TCPC) (n = 10) or a biventricular repair (n = 8) for complex cardiac defects were studied. Prothrombotic activity was evaluated by measuring plasma levels of prothrombin fragment 1+2 (F1+2), thromboxane B2 (TxB2), and monocyte chemoattractant protein-1 (MCP-1). Anti-thrombotic activity was evaluated by measuring levels of tissue factor pathway inhibitor (TFPI) before, during, and after cardiac surgery.ResultsIn all patients, cardiac surgery was associated with a significant but transient increase of F1+2, TxB2, TFPI, and MCP-1. Maximal values of F1+2, TxB2, and MCP-1 were found at the end of CPB. In contrast, maximal levels of TFPI were observed at the beginning of CPB. Concentrations of F1+2 at the end of CPB correlated negatively with the minimal oesophageal temperature during CPB. Markers of prothrombotic activity returned to preoperative values from the first postoperative day on. Early postoperative TFPI levels were significantly lower and TxB2 levels significantly higher in patients with TCPC than in those with biventricular repair. Thromboembolic events were not observed.ConclusionOur data suggest that children with complex cardiac defects undergoing cardiac surgery show profound but transient imbalance between pro- and anti-thrombotic activity, which could lead to thromboembolic complications. These alterations are more important after TCPC than after biventricular repair but seem to be determined mainly by low antithrombin III.

Myocardial cardiotrophin-1 is differentially induced in congenital cardiac defects depending on hypoxemia.

AIM Cardiotrophin-1 (CT-1) is upregulated by hypoxemia and hemodynamic overload and is characterized by potent hypertrophic and protective properties on cardiac cells. This study aimed to investigate whether CT-1 is differentially induced in the myocardium of infants with congenital cardiac defects depending on hypoxemia. METHODS & RESULTS Infants with Tetralogy of Fallot (n = 8) or with large nonrestrictive ventricular septal defect (n = 8) undergoing corrective surgery were investigated. Expression of CT-1 was assessed at mRNA and protein levels in the right atrial and ventricular myocardium. The activation of the STAT-3 and VEGF were measured. Degradation of cardiac troponin-I served as a marker of myocardial damage. CT-1 was detected in all patients with levels negatively correlating to the arterial oxygen saturation. Higher CT-1 expression in Tetralogy of Fallot patients was associated with activation of the JAK/STAT pathway and higher cardiac troponin-I degradation. CONCLUSION CT-1 may mediate myocardial hypertrophy and dysfunction in infants with congenital cardiac defects, particularly in those with hypoxemia.

Dispatcher-Assisted Telephone Cardiopulmonary Resuscitation Using a French-Language Compression-Ventilation Pediatric Protocol

Objective Out-of-hospital cardiac arrest (OHCA) in pediatrics is a devastating event associated with poor survival rates. Although telephone dispatcher-assisted cardiopulmonary resuscitation (CPR; T-CPR) instructions improve the frequency and quality of bystander CPR for OHCA in adults, this support remains undeveloped in children. Our objective was to assess the effectiveness of a pediatric T-CPR protocol in untrained and trained bystanders. Secondarily, we sought to determine the feasibility and the effectiveness of ventilation in such a protocol. Methods Eligible adults with no CPR experience were recruited in a movie theater in Liege, as well as bachelor nursing students in Liege. All volunteers were randomly assigned either to T-CPR or to no–T-CPR using randomization. The volunteers were exposed to a pediatric manikin model cardiac arrest. On the basis of Cardiff evaluation test, data were collected to evaluate CPR performance. Results A total of 115 volunteers were assigned to 4 groups: untrained nonguided group (n = 27), untrained guided group (n = 32), trained nonguided group (n = 26), and trained guided group (n = 30). We found an improvement in CPR performance in the guided groups. Most volunteers (81.2%) in untrained guided group and 83.3% in the trained guided group were able to give 2 ventilations after each compressions cycle. Conclusions In a pediatric manikin model of OHCA, T-CPR instructions including mouth-to-mouth ventilations and chest compressions produced a significant increase in resuscitation performance not only among previously untrained but also among trained volunteers.

Implementation of a 2-day Simulation-based Course to Prepare Medical Graduates on Their First Year of Residency

Objectives Residents beginning their specialization in pediatrics and emergency medicine (EM) are rapidly involved in oncall duties. Early acquisition of crisis resource management by novice residents is essential for patient safety, but traditional training may be insufficient. Our aim was to investigate the impact of a 2-day simulation-based course on residents to manage pediatric and neonatal patients. Methods First year residents participated in the course. They completed two questionnaires concerning perceived stress and self-efficacy in technical skills (TSs) and non-TSs (NTSs) at 3 times: before (T0), after (T1), and 6 weeks after the course (T2). Results Eleven pediatric and 5 EM residents participated. At T0, stress about “communicating with parents” (P = 0.022) and “coordinating the team” (P = .037) was significantly higher among pediatric compared with EM residents; self-efficacy was not different between the specialities. After training, perceived stress about “managing a critical ill child” and perceived stress total significantly decreased among EM residents, whereas it remained the same among pediatricians (respectively, P = 0.001 and P = 0.016). Regarding self-efficacy, it had significantly increased in both groups (P < 0.001). Specifically, the increase in TSs self-efficacy was significant after the training (p = .008) and after 6 weeks (p < .001), and the increase in NTs self-efficacy was only significant after 6 weeks (P = 0.014). Conclusions Our course improved perceived stress, TSs, and NTSs self-efficacy of residents. This encourages us to formalize this as a prerequisite for admission to the pediatric and EM residency.