Nazima Pathan

Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock

BACKGROUND Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock. METHODS We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection. FINDINGS We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock. INTERPRETATION Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.

A myocardial cytotoxic process is involved in the cardiac dysfunction of meningococcal septic shock.

ObjectiveMyocardial dysfunction is a characteristic component of meningococcal septic shock and contributes to the persisting high mortality from the disease. Specific treatment of the myocardial failure has been hampered by the lack of understanding of its pathophysiology. We were interested to determine whether myocardial cell death was occurring in the presence of meningococcal septicemia and whether it correlated with the degree of left ventricular dysfunction and disease severity. We therefore investigated the release of cardiac troponin I (cTnI), a sensitive and specific marker of myocardial cell death, and related this to the severity of disease and cardiac dysfunction. DesignProspective study SettingPediatric intensive care unit SubjectsPatients admitted to the pediatric intensive care unit with a diagnosis of meningococcal septicemia. InterventionsSerum concentrations of cTnI were determined at admission to intensive care in 101 children with meningococcal septicemia and serially in 37 children. Changes in cTnI were related to disease severity as measured by the Pediatric Risk of Mortality score and two markers of cardiac dysfunction. Measurements and Main ResultsSerum concentrations of cTnI were elevated above the range for healthy children in 24% of children with meningococcal septicemia at admission and in 62% of patients within 48 hrs. The peak concentrations occurred between 12 and 36 hrs after admission. There were significant correlations between cTnI levels and disease severity and between cTnI levels and the degree of myocardial depression measured by quantitative transthoracic echocardiography and peak inotrope requirements. ConclusionsThe elevated serum concentrations of cTnI indicate that myocardial cell death is occurring in meningococcal septicemia. The relationship between cTnI and markers of myocardial function suggest that the cell death may have a role in the pathogenesis of myocardial dysfunction in meningococcal septicemia. Elucidation of the mechanism responsible for myocardial injury may lead to the development of therapeutic interventions to prevent or limit this cardiac damage.

Challenge of predicting resting energy expenditure in children undergoing surgery for congenital heart disease.

Objectives: To determine pre- and postoperative predictors of energy expenditure in children with congenital heart disease requiring open heart surgery; and to compare measured resting energy expenditure with current predictive equations. Design: Prospective resting energy expenditure data were collected, using indirect calorimetry, for ventilated children admitted consecutively to the pediatric intensive care unit after surgery for congenital heart disease. A 30-min steady-state measurement was performed in suitable patients. Resting energy expenditure was compared to pre- and postoperative clinical variables, and to predicted energy expenditure, using currently used predictive equations. Setting: Pediatric intensive care unit at the Royal Brompton Hospital, London. Patients: Children ventilated in the pediatric intensive care unit post surgery for congenital heart disease. Interventions: Measurement of energy expenditure by indirect calorimetry. Measurements and Main Results: Twenty-one mechanically ventilated children (n = 17 boys, 4 girls) were enrolled in the study. Mean ± sd measured resting energy expenditure was 67.8 ± 15.4 kcal/kg/day. Most children had inadequate delivery of nutrients compared with actual requirements. Cardiopulmonary bypass had a significant influence on energy expenditure after surgery; in patients who underwent cardiopulmonary bypass during surgery, mean resting energy expenditure was 73.6 ± 14.45 kcal/kg/day vs. 58.3 ± 10.29 kcal/kg/day in patients undergoing nonbypass surgery. Children who were malnourished preoperatively had greater resting energy expenditure postoperatively. There was also a significant difference between measured energy expenditure and the Schofield (p = .006), World Health Organization (p = .002), and pediatric intensive care unit-specific formula (p < .0001). However, energy expenditure or a relative energy deficit in the early postoperative period was not associated with severity or duration of organ dysfunction. Conclusions: Poor nutritional status preoperatively and cardiopulmonary bypass were associated with a greater energy expenditure post cardiac surgery. None of the current predictive equations predicted energy requirements within acceptable clinical accuracy.

Intestinal Injury and Endotoxemia in Children Undergoing Surgery for Congenital Heart Disease

RATIONALE Children with congenital heart disease are at risk of gut barrier dysfunction and translocation of gut bacterial antigens into the bloodstream. This may contribute to inflammatory activation and organ dysfunction postoperatively. OBJECTIVES To investigate the role of intestinal injury and endotoxemia in the pathogenesis of organ dysfunction after surgery for congenital heart disease. METHODS We analyzed blood levels of intestinal fatty acid binding protein and endotoxin (endotoxin activity assay) alongside global transcriptomic profiling and assays of monocyte endotoxin receptor expression in children undergoing surgery for congenital heart disease. MEASUREMENTS AND MAIN RESULTS Levels of intestinal fatty acid binding protein and endotoxin were greater in children with duct-dependent cardiac lesions. Endotoxemia was associated with severity of vital organ dysfunction and intensive care stay. We identified activation of pathogen-sensing, antigen-processing, and immune-suppressing pathways at the genomic level postoperatively and down-regulation of pathogen-sensing receptors on circulating immune cells. CONCLUSIONS Children undergoing surgery for congenital heart disease are at increased risk of intestinal mucosal injury and endotoxemia. Endotoxin activity correlates with a number of outcome variables in this population, and may be used to guide the use of gut-protective strategies.

Anti-inflammatory modalities: Their current use in pediatric cardiac surgery in the United Kingdom and Ireland*

Objective: To determine the use of anti-inflammatory therapies in infants and children undergoing cardiac surgery in the United Kingdom and Ireland. Design: Questionnaire survey. Subjects: All centers that undertake pediatric cardiac surgery in the United Kingdom and Ireland. Results: All centers use at least one anti-inflammatory therapy, with 46% of centers using more than one. Both modified ultrafiltration (80%) and steroids (80%) are widely used as anti-inflammatory strategies. Among centers that use steroids, dose, preparation, and timing of steroid administered was highly variable. Heparin-bonded circuits and aprotinin are infrequently used as anti-inflammatory techniques. Conclusion: Although anti-inflammatory interventions are believed to contribute to improved patient outcome following cardiopulmonary bypass, this survey has shown that there are still widespread variations in practice. Rather than reflecting poor clinical practice, we believe this reflects a lack of good evidence supporting clinical benefit.

Timing of Death In Children Referred For Intensive Care With Severe Sepsis: Implications For Interventional Studies

Objective: Early deaths in pediatric sepsis may limit the impact of therapies that can only be provided on PICUs. By introducing selection and survivorship biases, these very early deaths may also undermine the results of trials that employ standard consent procedures. We hypothesized that: 1) the majority of deaths in children with severe sepsis occur very early, within 24 hours of referral to PICU; and 2) a significant proportion of deaths occur before PICU admission. Design, Setting, and Patients: We studied consecutive referrals of newborns through to 16 years of age, between 2005 and 2011 to the Children’s Acute Transport Service, the North Thames regional pediatric intensive care transport service, with a working diagnosis of “sepsis,” “severe sepsis,” “meningococcal sepsis,” or “septic shock.” Interventions: The primary outcome measure was the proportion of deaths within 24 hours of referral. Survival distributions of previously healthy children were compared with those with significant comorbidities. Measurements and Main Results: Thirteen thousand four hundred and nine referrals were made to Children’s Acute Transport Service, of whom 703 (5%) met inclusion criteria. Data on survival to 1 year were available in 627 of 703 patients (89%). One hundred thirty children (130/627; 21%; 95% CI, 18–24%) died in the first year. A higher proportion of children with comorbidity cases (46/85, 54%, 44–64) died compared with previously healthy cases (84/542; 16%; 13–19; p < 0.0005, Fisher exact test). Seventy-one deaths occurred within 24 hours of PICU referral (71/130, 55%, 46–63). The timing of death differed with comorbidity. Similar proportions of children survived to 24 hours (previously healthy children 90% vs children with comorbidity 83%, p = 0.06). However, deaths after 24 hours were infrequent among previously healthy cases (28/84 deaths, 33%, 24–44%) compared with children with comorbidity cases (31/46 deaths, 66%, 53–79%) (p < 0.001, Fisher exact test). Conclusions: This majority of deaths among children referred for pediatric intensive care with for severe sepsis occur within 24 hours. This has important implications for future clinical trials and quality improvement initiatives aimed at improving sepsis outcomes.

Cardioprotective Effects of Insulin How Intensive Insulin Therapy May Benefit Cardiac Surgery Patients

Interest in the effects of insulin on the heart came with the recognition that hyperglycemia in the context of myocardial infarction is associated with increased risks of mortality, congestive heart failure, or cardiogenic shock.1–3 More recently, instigated by research findings on stress hyperglycemia in critical illness, this interest has been extended to the influence of insulin on clinical outcome after cardiac surgery. Even in nondiabetic individuals, stress hyperglycemia commonly occurs as a key metabolic response to critical illness, eg, after surgical trauma. It is recognized as a major pathophysiological feature of organ dysfunction in the critically ill. The condition stems from insulin resistance brought about by dysregulation of key homeostatic processes, which implicates immune/inflammatory, endocrine, and metabolic pathways.4 It has been associated with adverse clinical outcomes, including increased mortality, increased duration of mechanical ventilation, increased intensive care unit (ICU) and hospital stay, and increased risk of infection.5–8 Hyperglycemia in critical illness is managed with exogenous insulin as standard treatment; however, there is considerable disagreement among experts in the field as to what target blood glucose level is optimal for the critically ill patient. Conventionally, the aim of insulin therapy has been to maintain blood glucose levels below the renal threshold, typically 220 mg/dL (12.2 mmol/L). In recent years, some have advocated tight glycemic control (TGC) with intensive insulin therapy (IIT) to normalize blood glucose levels to within the euglycemic range, typically 80 to 110 mg/dL (4.4–6.1 mmol/L). Current evidence on the applicability of TGC to critical illness in general is inconclusive. Although early studies showed that IIT reduced mortality and morbidity in the ICU,9–11 more recent systematic studies and meta-analyses have largely failed to support some or all of these findings, with some suggesting that IIT may increase the risk …

The challenge of developing a new predictive formula to estimate energy requirements in ventilated critically ill children.

BACKGROUND Traditionally, energy requirements have been calculated using predictive equations. These methods have failed to calculate energy expenditure accurately. Routine indirect calorimetry has been suggested, but this method is technically demanding and costly. This study aimed to develop a new predictive equation to estimate energy requirements for critically ill children. METHODS This prospective, observational study on ventilated children included patients with an endotracheal tube leak of < 10% and fractional inspired oxygen of < 60%. An indirect calorimetry energy expenditure measurement was performed and polynomial regression analysis was used to develop new predictive equations. The new formulas were then compared with existing prediction equations. RESULTS Data from 369 measurements were included in the formula design. Only weight and diagnosis influenced energy expenditure significantly. Three formulas (A, B, C) with an R² > 0.8 were developed. When we compared the new formulas with commonly used equations (Schofield, Food and Agriculture Organization/World Health Organization/United Nations University, and White equation), all formulas performed very similar, but the Schofield equation seemed to have the lowest SD. CONCLUSIONS All 3 new pediatric intensive care unit equations have R² values of > 0.8; however, the Schofield equation still performed better than other predictive methods in predicting energy expenditure in these patients. Still, none of the predictive equations, including the new equations, predicted energy expenditure within a clinically accepted range, and further research is required, particularly for patients outside the technical scope of indirect calorimetry.

Nutritional status and clinical outcome in postterm neonates undergoing surgery for congenital heart disease.

Objective: Poor growth is a common complication in infants with congenital heart disease. There has been much focus on low birth weight as having increased risk of adverse outcomes following neonatal heart surgery. In this study, we examined whether preoperative nutritional status, measured by admission weight-for-age z score, was associated with postoperative clinical outcome. Design: Retrospective case series. Setting: Pediatric Cardiac ICU at the Royal Brompton Hospital. Patients: Neonates undergoing surgery for congenital heart disease. Those undergoing ductus arteriosus ligation alone were excluded. Children with coexisting noncardiac morbidity were excluded. Outcome variables included prevalence of postoperative complications (including sepsis, delayed chest closure, renal impairment, and necrotizing enterocolitis), duration of ventilation, intensive care stay, postoperative mortality, and mortality at 1 year after surgery. Interventions: None. Analysis of patient data only. Measurements and Main Results: Two hundred forty-eight neonates fulfilled the entry criteria. Median (interquartile range) age was 7 days (2–15 d), median (interquartile range) weight was 3.3 kg (2.91–3.6 kg), and median weight-for-age z score was –0.77 (–1.44 to 0.01). Twenty-eight children (11%) had a weight-for-age z score of less than –2. There was no evidence that children with lower weight-for-age z score had less severe surgery as measured by the Risk Adjustment for Congenital Heart Surgery 1 score. In multivariable regression analysis, the weight-for-age z at admission had strong correlation with the number of days free of respiratory support (invasive and noninvasive ventilation) at 28 days (p < 0.0001) and with all-cause mortality at 1 year (p = 0.001). Conclusions: Poor nutritional status as measured by weight-for-age z is associated with adverse short- and long-term outcomes in neonates undergoing surgery for congenital heart disease.

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase.

Objectives:Myocardial failure, leading to inotrope-unresponsive shock, is the predominant cause of death in meningococcal and other forms of septic shock. Proinflammatory cytokines released in septic shock are known to have myocardial depressant effects. We previously showed that interleukin 6 is a major myocardial depressant factor in children with meningococcal septicemia. In the current study, we aimed to investigate the mechanisms by which interleukin 6 induces myocardial failure in meningococcal sepsis and to identify potential novel therapeutic targets. Design:Laboratory-based study. Setting:University hospital and laboratories. Patients:Children with a clinical diagnosis of meningococcal septic shock. Methods:We studied interleukin 6-induced signaling events, both in vitro using isolated rat ventricular cardiac myocytes as a model of myocardial contractility and in whole blood from children with meningococcal sepsis. Interventions:None. Measurements and Main Results:We demonstrated involvement of Janus kinase 2, phosphatidylinositol 3-kinase, Akt, and p38 mitogen-activated protein kinase in interleukin 6-induced negative inotropy in isolated cardiac myocytes. Inhibition of p38 mitogen-activated protein kinase not only reversed interleukin 6-induced myocardial depression in both rat and human myocytes, but restored inotrope responsiveness. Cardiomyocytes transduced with dominant-negative p38 mitogen-activated protein kinase showed no interleukin 6-induced myocardial depression. To investigate p38 mitogen-activated protein kinase in vivo, we profiled global RNA expression patterns in peripheral blood of children with meningococcal septicemia. Transcripts for genes mapping to the p38 mitogen-activated protein kinase pathway showed significantly altered levels of abundance with a high proportion of genes of this pathway affected. Conclusions:Our findings demonstrate an integral role of the p38 mitogen-activated protein kinase pathway in interleukin 6-mediated cardiac contractile dysfunction and inotrope insensitivity. Dysregulation of the p38 mitogen-activated protein kinase pathway in meningococcal septicemia suggests that this pathway may be an important target for novel therapies to reverse myocardial dysfunction in patients with meningococcal septic shock who are not responsive to inotropic support.