Deborah Ridout

Delayed diagnosis of congenital heart disease worsens preoperative condition and outcome of surgery in neonates

Objectives: To assess whether the route by which neonatal congenital heart disease (CHD) is first recognised influences outcome after surgery. Methods: Surgical neonates admitted to a tertiary cardiac unit between March 1999 and February 2002 were retrospectively reviewed with analysis of risk factors for outcome. Three routes to initial recognition of CHD were compared: antenatal diagnosis, detection on the postnatal ward, and presentation after discharge to home. Outcome measures were mortality and duration of perioperative ventilation. Results: 286 neonates had cardiac surgery with a median duration of ventilation of 101 h and in-hospital mortality of 12%. Recognition of CHD was antenatal in 20%, on the postnatal ward in 55% and after discharge to home in 25%. Multiple regression analyses, including the cardiac diagnosis, associated problems and other risk factors, indicated that severe cardiovascular compromise on admission to the cardiac unit was significantly related to mortality and prolonged ventilation. Considered in isolation, the route to recognition of heart disease did not influence mortality or ventilation time. Route to initial recognition did, however, influence the patient’s condition on admission to the cardiac unit. Cardiovascular compromise and end organ dysfunction were least likely when recognition was antenatal and most common when presentation followed discharge to home. Conclusion: The setting in which neonatal CHD is first recognised has an impact on preoperative condition, which in turn influences postoperative progress and survival after surgery. Optimal screening procedures and access to specialist care will improve outcome for neonates undergoing cardiac surgery.

Mineral Metabolism and Vascular Damage in Children on Dialysis

Cardiovascular disease is increasingly recognized as a life-limiting problem in young patients with chronic kidney disease, but there are few studies in children that describe its determinants. We studied the association of intact parathyroid hormone (iPTH) levels and their management on vascular structure and function in 85 children, ages 5-18 years, who had received dialysis for > or =6 months. Compared to controls, dialysis patients had increased carotid intima-media thickness and pulse-wave velocity. All vascular measures positively correlated with serum phosphorus levels, while carotid intima-media thickness and cardiac calcification score also correlated with iPTH levels. Patients with mean time-integrated iPTH levels less than twice the upper limit of normal (n = 41) had vascular measures that were comparable to age-matched controls, but those with iPTH levels greater than twice the upper limit of normal (n = 44) had greater carotid intima-media thickness, stiffer vessels, and increased cardiac calcification than controls. Patients with increased carotid intima-media thickness had stiffer vessels and a greater prevalence of cardiac calcification. There was a strong dose-dependent correlation between vitamin D and all vascular measures, and calcium intake from phosphate binders weakly correlated with carotid intima-media thickness. In conclusion, both iPTH level and dosage of vitamin D are associated with vascular damage and calcification in children on dialysis.

New-Onset Heart Failure Due to Heart Muscle Disease in Childhood A Prospective Study in the United Kingdom and Ireland

Background— We undertook the first prospective, national, multicenter study to describe the incidence and outcome of heart muscle disease–induced heart failure in children. Methods and Results— Data were collected on patients admitted to a hospital through 2003 with a first episode of heart failure in the absence of congenital heart disease. All 17 pediatric cardiac centers in the United Kingdom and Ireland participated. Follow-up data were obtained to a minimum of 1 year. The incidence was 0.87/100 000 population <16 years (n=104; 53 girls; 95% confidence interval 0.71 to 1.05 per 100 000). Median age at presentation was 1 year, with 82% in New York Heart Association class III to IV. Causes of heart failure included dilated cardiomyopathy (50 idiopathic, 8 familial), probable myocarditis (23), occult arrhythmia (7), anthracycline toxicity (5), metabolic disease (4), left ventricular noncompaction (3), and other (4). Overall 1-year survival was 82%, and event (death or transplantation)-free survival was 66%. Regression analysis showed older age and reduced systolic function on admission echocardiogram increased the event risk. Only 8% of event-free survivors (n=69) remained in New York Heart Association class III to IV, but 35 required readmission during the study period, and all but 8 remained on medication. Conclusions— This first national prospective study of new-onset heart failure in children has shown an incidence of 0.87/100 000. Multivariable analysis of survival data indicates a better outcome for younger children and for those with better systolic function at presentation, but overall, one third of children die or require transplantation within 1 year of presentation.

Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy

Objective To assess the current use of glucocorticoids (GCs) in Duchenne muscular dystrophy in the UK, and compare the benefits and the adverse events of daily versus intermittent prednisolone regimens. Design A prospective longitudinal observational study across 17 neuromuscular centres in the UK of 360 boys aged 3–15 years with confirmed Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off) prednisolone for a mean duration of treatment of 4 years. Results The median loss of ambulation was 12 years in intermittent and 14.5 years in daily treatment; the HR for intermittent treatment was 1.57 (95% CI 0.87 to 2.82). A fitted multilevel model comparing the intermittent and daily regiments for the NorthStar Ambulatory Assessment demonstrated a divergence after 7 years of age, with boys on an intermittent regimen declining faster (p<0.001). Moderate to severe side effects were more commonly reported and observed in the daily regimen, including Cushingoid features, adverse behavioural events and hypertension. Body mass index mean z score was higher in the daily regimen (1.99, 95% CI 1.79 to 2.19) than in the intermittent regimen (1.51, 95% CI 1.27 to 1.75). Height restriction was more severe in the daily regimen (mean z score −1.77, 95% CI −1.79 to −2.19) than in the intermittent regimen (mean z score −0.70, 95% CI −0.90 to −0.49). Conclusions Our study provides a framework for providing information to patients with Duchenne muscular dystrophy and their families when introducing GC therapy. The study also highlights the importance of collecting longitudinal natural history data on patients treated according to standardised protocols, and clearly identifies the benefits and the side-effect profile of two treatment regimens, which will help with informed choices and implementation of targeted surveillance.

Healthcare-associated infection in pediatric patients on extracorporeal life support: The role of multidisciplinary surveillance.

Objective: To describe the use of a multidisciplinary approach to sepsis surveillance and evaluate impact on outcome. Design: Prospective clinical study or clinical audit cycle. Setting: Tertiary pediatric extracorporeal membrane oxygenation (ECMO) center. Patients: Patients were 215 children supported with ECMO January 1999 to December 2004. Interventions: A multidisciplinary team met monthly to evaluate cases of bloodstream infection and mediastinitis, review trends, and update unit policies. Changes in practice were made at the end of 2001 in order to address a perceived high rate of sepsis: a) reeducation; b) introduction of electively preprimed ECMO circuits; and c) preference for neck rather than chest cannulation in cardiac patients. Prophylactic antibiotics were used from preprocedure for 24 hrs only throughout the study. Measurements and Main Results: Over the entire study period, 39 children had 47 septic episodes, with a rate of 24.9 per 1000 ECMO days. Multiple logistic regression analyses indicated that infection was associated with duration of ECMO support (odds ratio 1.24; 95% confidence interval 1.15, 1.35 per day) and case type: Closed vs. open chest was protective in cardiac patients (odds ratio 0.08; 95% confidence interval 0.01, 0.50). Infection increased the odds of death by 2.01 (95% confidence interval 1.00, 4.05), but this effect was less important than case type and ECMO days. After policy changes were implemented, there was a reduction in sepsis from 29.3 to 20.1 episodes per 1000 ECMO days. There was reduced sepsis in respiratory patients: neonates from 28.0 to 6.6 and pediatric patients from 42.4 to 16.9 episodes per 1000 ECMO days. Despite policy changes, sepsis remained a problem in cardiac patients with open sternum: 65.1 per 1000 ECMO days. Conclusions: ECMO support is a high-risk setup for nosocomial infection, in particular for cardiac patients with open sternum for whom antibiotic prophylaxis is justified. Multidisciplinary surveillance offers an excellent approach for quality improvement in this challenging field.

Reliability of Conditioned Pain Modulation: a Systematic Review

Abstract A systematic literature review was undertaken to determine if conditioned pain modulation (CPM) is reliable. Longitudinal, English language observational studies of the repeatability of a CPM test paradigm in adult humans were included. Two independent reviewers assessed the risk of bias in 6 domains; study participation; study attrition; prognostic factor measurement; outcome measurement; confounding and analysis using the Quality in Prognosis Studies (QUIPS) critical assessment tool. Intraclass correlation coefficients (ICCs) less than 0.4 were considered to be poor; 0.4 and 0.59 to be fair; 0.6 and 0.75 good and greater than 0.75 excellent. Ten studies were included in the final review. Meta-analysis was not appropriate because of differences between studies. The intersession reliability of the CPM effect was investigated in 8 studies and reported as good (ICC = 0.6-0.75) in 3 studies and excellent (ICC > 0.75) in subgroups in 2 of those 3. The assessment of risk of bias demonstrated that reporting is not comprehensive for the description of sample demographics, recruitment strategy, and study attrition. The absence of blinding, a lack of control for confounding factors, and lack of standardisation in statistical analysis are common. Conditioned pain modulation is a reliable measure; however, the degree of reliability is heavily dependent on stimulation parameters and study methodology and this warrants consideration for investigators. The validation of CPM as a robust prognostic factor in experimental and clinical pain studies may be facilitated by improvements in the reporting of CPM reliability studies.

Postconditioning protects against human endothelial ischaemia–reperfusion injury via subtype-specific KATP channel activation and is mimicked by inhibition of the mitochondrial permeability transition pore

AIMS Intermittent early reperfusion (ischaemic postconditioning; PostC) reduces ischaemia-reperfusion (IR) injury. Using an in vivo model of endothelial IR injury in humans, we sought to determine the role of K(ATP) channels in PostC and whether inhibition of the mitochondrial permeability transition pore (mPTP) at the onset of reperfusion protected against endothelial IR injury. METHODS AND RESULTS Endothelial function (EF) in healthy volunteers was assessed using vascular ultrasound to measure the percentage increase in the diameter of the brachial artery in response to reactive hyperaemia [flow-mediated dilatation (FMD)]. In resistance vessels, venous occlusion plethysmography was used to measure the dilator response to acetylcholine (ACh) [area under ACh dose-response curve (ACh AUC)]. Measurements were made before and after IR injury. Ischaemic postconditioning consisted of three 10 s cycles of alternating ischaemia and reperfusion in the first minute of reperfusion. Oral glibenclamide and glimepiride were used to determine the role of K(ATP) channel subtypes in PostC. Intra-arterial cyclosporine was used to determine the role of mPTP in endothelial IR injury. Ischaemia-reperfusion reduced EF in the brachial artery (FMD 7.1 ± 0.9% pre-IR, 2.8 ± 0.4% post-IR; P < 0.001) and resistance vessels [ACh AUC (×10(4)) 2.1 ± 0.4 pre-IR, 1.5 ± 0.2 post-IR; P < 0.05]. Ischaemic postconditioning preserved EF in the brachial artery [FMD 6.8 ± 0.9% (P < 0.001 vs. post-IR)] and resistance vessels [ACh AUC (×10(4)) 1.9 ± 0.2 (P < 0.001 vs. post-IR)]. Protection by PostC was abolished by glibenclamide in the brachial artery [FMD 3.3 ± 0.2% (P < 0.001 vs. post-IR + PostC)] and in resistance vessels [ACh AUC (×10(4)) 1.1 ± 0.2 (P < 0.001 vs. post-IR + PostC)], whereas glimepiride had no effect. Cyclosporine preserved EF after IR injury in the resistance vessels [ACh AUC (×10(4)) 1.4 ± 0.2 post-IR vs. 2.2 ± 0.3 post-IR + cyclosporine; P < 0.05]. CONCLUSION Protection by PostC against endothelial IR injury in humans depends on K(ATP) channel activation and is mimicked by inhibition of the mPTP at reperfusion.

A comparison of pain measures in newborn infants after cardiac surgery

&NA; Accurate pain assessment tools to evaluate pain in critically ill neonates in the postoperative period are lacking. Therefore, we compared a number of potentially useful indices of pain in critically ill neonates following cardiac surgery. Eighty‐one full‐term infants were studied during the first 48 postoperative hours and the following indices were measured: heart rate, mean arterial blood pressure, heart‐rate variability, urinary and plasma cortisol, and 4 composite pain measurement scales: Children’s and Infants’ Postoperative Pain Scale (CHIPPS), CRIES, COMFORT, and Premature Infant Pain Profile (PIPP). Regression models were used to investigate relationships between individual pain indices or composite pain assessment scales with respect to procedural intensity and opioid dose and plasma levels. COMFORT score performed best, with a 27% difference in score between procedures causing tissue damage and those that did not (P < 0.001). COMFORT score and the high‐frequency component of heart‐rate variability showed inverse correlations with opioid dose and plasma levels over the first 48 hours postoperatively, but after accounting for clinical variables, only COMFORT score remained significant (eg, 52% of variance in morphine level at 24 hours, P < 0.001). The factor structure of the COMFORT score revealed that both behavioural and physiological variables account for a significant proportion of the variance (45% and 15%, respectively; P < 0.001). Plasma concentrations of cortisol increased postoperatively but urinary cortisol excretion did not change significantly. Of the pain indices studied, the COMFORT score performed best, with both behavioural and physiological components providing significant contributions. The COMFORT score explains the largest amount of variance related to analgesia dose and plasma levels in critically ill neonates after cardiac surgery.

The impact of mechanical ventilation time before initiation of extracorporeal life support on survival in pediatric respiratory failure: a review of the Extracorporeal Life Support Registry.

Objective: To evaluate the relationship between duration of mechanical ventilation before the initiation of extracorporeal life support and the survival rate in children with respiratory failure. Extracorporeal life support has been used as a rescue therapy for >30 yrs in children with severe respiratory failure. Previous studies suggest patients who received >7–10 days of mechanical ventilation were not acceptable extracorporeal life support candidates as a result of irreversible lung damage. Design: A retrospective review encompassing the past 10 yrs of the International Extracorporeal Life Support Organization Registry (January 1, 1999, to December 31, 2008). Setting: Extracorporeal Life Support Organization Registry database. Patients: A total of 1325 children (≥ 30 days and ⩽ 18 yrs) met inclusion criteria. Interventions: None. Measurements and Main Results: The following pre-extracorporeal life support variables were identified as independently and significantly related to the chance of survival: 1) >14 days of ventilation vs. 0–7 days was adverse (odds ratio, 0.32; p < .001); 2) the presence of a cardiac arrest was adverse (odds ratio, 0.56; p = .001); 3) pH per 0.1-unit increase was protective (odds ratio, 1.15; p < .001); 4) oxygenation index, per 10-unit increase was adverse (odds ratio, 0.95; p = .002); and 5) any diagnosis other than sepsis was related to a more favorable outcome. Patients requiring >7–10 or >10–14 days of pre-extracorporeal life support ventilation did not have a statistically significant decrease in survival as compared with patients who received 0–7 days. Conclusions: There was a clear relationship between the number of mechanical ventilation days before the initiation of extracorporeal life support and survival. However; there was no statistically significant decrease in survival until >14 days of pre-extracorporeal life support ventilation was reached regardless of underlying diagnosis. We found no evidence to suggest that prolonged mechanical ventilation should be considered as a contraindication to extracorporeal life support in children with respiratory failure before 14 days.

Chronic kidney disease in children following lung and heart-lung transplantation

Abstract:  CKD is a major co‐morbidity in pediatric lung transplant recipients. We report the prevalence of renal impairment post‐lung transplant at a single center, using a modified, age‐adjusted eGFR for the best approximation of true GFR, and investigated associations and possible predictors of decline in renal function post‐transplant. Renal function was assessed by eGFR pre‐transplant, three and 12 months post‐transplant, and at last follow‐up. Decline in renal function was analyzed as percentage fall in eGFR in two phases (0–3 and 3–12). Furthermore, we investigated impact of gender, age, pre‐transplant diagnosis and renal function, transplant type, early post‐transplant dialysis, and tacrolimus trough levels on decline in eGFR using multivariate analysis. Over a five‐yr period, 30 transplants were performed. Mean eGFR pretransplant was 117 mL/min/1.73 m2 (s.d. 35) with mean decline in eGFR during the first three months post‐transplant of 33% (s.d. 31, p < 0.001). Thereafter, mean decline in eGFR was 8% (s.d. 18, p = 0.02). None of the factors assessed were significantly associated with decline in eGFR post‐transplant. In conclusion, many children have decline in renal function following lung transplantation, particularly early post‐transplant. Unlike in adults, we were unable to detect any predictors of renal impairment in pediatric lung transplant recipients.