Current surgical bioprostheses: Looking to the future.

The utilization of bioprostheses for surgical heart valve replacement has been increasing across all age groups. For patients, the appeal of the bioprosthetic valve rests with the avoidance of anticoagulation, fewer thrombotic and hemorrhagic events, and the increasing availability of transcatheter valve-in-valve interventions -both in the aortic and mitral positions- allowing for lower morbidity reinterventions. While improvements in valve hemodynamics and long-term durability have made bioprostheses a reasonable choice for a growing number of patients, challenges do remain. With increasing usage of bioprostheses, especially in younger patients, there will be an increase in the projected number of failing bioprosthetic valves. This trend will bring even more emphasis to maximizing long-term durability, optimizing anticoagulation, and promoting patient-level decision making around prosthesis choice.

Short-term remote ischemic preconditioning is not associated with improved blood pressure and exercise capacity in young adults.

We sought to determine whether a 9-day remote ischemic preconditioning (IPC) causes improvements in exercise performance, energetics, and blood pressure. Ten participants (mean age 24 ± 4 years) had no changes in aerobic capacity (preintervention: 38 ± 10 mL/(kg·min)(-1) vs. postintervention: 38 ± 10 mL/(kg·min)(-1)), blood pressure (preintervention: 112 ± 7/66 ± 6 mm Hg vs. postintervention: 112 ± 10/62 ± 5 mm Hg), cardiac phosphocreatinine-to-adenosine-triphosphate ratio (preintervention: 2.1 ± 0.5 vs. postintervention: 2.3 ± 0.4), and postexercise skeletal muscle phosphocreatine recovery (preintervention: 34 ± 11 s vs. postintervention: 31 ± 11 s). Short-term remote IPC may be ineffective in improving these outcomes.

Insulin resistance and inflammation are a cause of hyperglycemia after pediatric cardiopulmonary bypass surgery.

OBJECTIVES: Hyperglycemia is common after pediatric cardiopulmonary bypass (CPB) surgery and is attributed to a state of insulin resistance. We examined the role of CPB-induced inflammation on postoperative plasma glucose, insulin, and the glucose-to-insulin ratio, which was used as a marker of insulin resistance; a decrease in the ratio reflects increased resistance. METHODS: We conducted an ancillary study on a previously published randomized trial of children undergoing CPB surgery. Serial blood glucose, insulin, and cytokines were drawn after CPB and at selected intervals for up to 48 hours after surgery. The primary outcome was plasma insulin levels and glucose-to-insulin ratio. Glucose delivery and feeding status were monitored for potential modifying effects. RESULTS: The 299 children studied were predominantly male (55%) with a median age of 2.7 (interquartile range [IQR]: 0.5-6.5) years, and weight of 12.6 (IQR: 6.4-10.8) kg. Operations had a median Society of Thoracic Surgery-European Association for Cardio-Thoracic Surgery complexity score of 1 (IQR: 1-2) and CPB time of 82 (IQR: 58-122) minutes. Hyperglycemia occurred in 85% of subjects; odds of hyperglycemia peaked at 6 hours after CPB. Plasma glucose was associated with increased insulin and a lower glucose-to-insulin ratio. Increased interleukin (IL)-6 concentrations were associated with increased glucose (estimate [EST]: 0.55 (±0.13) mmol/L; P < .001) and insulin (EST: 1.14 (±0.12) µmol/L; P < .001) in linear regression adjusted for repeated measures. Paradoxically, increased cytokines were associated with an increased glucose-to-insulin ratio (EST: 0.21 (±0.03) mmol/µmol; P < .001). CONCLUSIONS: Hyperglycemia after pediatric CPB surgery is associated with hyperinsulinemia, which may reflect insulin resistance in some patients. Inflammation induced by CPB may play a causative role in insulin resistance.

Acute, delayed and chronic remote ischemic conditioning is associated with downregulation of mTOR and enhanced autophagy signaling.

BACKGROUND: Remote ischemic conditioning (RIC), induced by brief periods of limb ischemia has been shown to decrease acute myocardial injury and chronic responses after acute coronary syndromes. While several signaling pathways have been implicated, our understanding of the cardioprotection and its underlying mediators and mechanisms remains incomplete. In this study we examine the effect of RIC on pro-autophagy signaling as a possible mechanism of benefit. METHODS AND RESULTS: We examined the role of autophagy in the acute/first window (15 minutes after RIC), delayed/second window (24 hours after RIC) and chronic (24 hours after 9 days of repeated RIC) phases of cardioprotection. C57BL/6 mice (N = 69) were allocated to each treatment phase and further stratified to receive RIC, induced by four cycles of 5 minutes of limb ischemia followed by 5 minutes of reperfusion, or control treatment consisting solely of handling without transient ischemia. The groups included, group 1 (1W control), group 2 (1W RIC), group 3 (2W control), group 4 (2W RIC), group 5 (3W control) and group 6 (3W RIC). Hearts were isolated for assessment of cardiac function and infarct size after global ischemia using a Langendorff preparation. Infarct size was reduced in all three phases of cardioprotection, in association with improvements in post-ischemic left ventricular end diastolic pressure (LVEDP) and developed pressure (LVDP) (P<0.05). The pattern of autophagy signaling varied; 1W RIC increased AMPK levels and decreased the activation of mammalian target of rapamycin (mTOR), whereas chronic RIC was associated with persistent mTOR suppression and increased levels of autophagosome proteins, LC3II/I and Atg5. CONCLUSIONS: Cardioprotection following transient ischemia exists in both the acute and delayed/chronic phases of conditioning. RIC induces pro-autophagy signaling but the pattern of responses varies depending on the phase, with the most complete portfolio of responses observed when RIC is administered chronically.

Remote ischemic preconditioning in children undergoing cardiac surgery with cardiopulmonary bypass: a single-center double-blinded randomized trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) harnesses an innate defensive mechanism that protects against inflammatory activation and ischemia-reperfusion injury, known sequelae of cardiac surgery with cardiopulmonary bypass. We sought to determine the impact of RIPC on clinical outcomes and physiological markers related to ischemia-reperfusion injury and inflammatory activation after cardiac surgery in children. METHODS AND RESULTS: Overall, 299 children (aged neonate to 17 years) were randomized to receive an RIPC stimulus (inflation of a blood pressure cuff on the left thigh to 15 mm Hg above systolic for four 5-minute intervals) versus a blinded sham stimulus during induction with a standardized anesthesia protocol. Primary outcome was duration of postoperative hospital stay, with serial clinical and laboratory measurements for the first 48 postoperative hours and clinical follow-up to discharge. There were no significant baseline differences between RIPC (n=148) and sham (n=151). There were no in-hospital deaths. No significant difference in length of postoperative hospital stay was noted (sham 5.4 versus RIPC 5.6 days; difference +0.2; adjusted P=0.91), with the 95% confidence interval (-0.7 to +0.9) excluding a prespecified minimal clinically significant differences of 1 or 1.5 days. There were few significant differences in other clinical outcomes or values at time points or trends in physiological markers. Benefit was not observed in specific subgroups when explored through interactions with categories of age, sex, surgery type, Aristotle score, or first versus second half of recruitment. Adverse events were similar (sham 5%, RIPC 6%; P=0.68). CONCLUSIONS: RIPC is not associated with important improvements in clinical outcomes and physiological markers after cardiac surgery in children. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov. Unique identifier: NCT00650507.

Rate, associated factors and outcomes of recurrence of Kawasaki disease in Ontario, Canada.

BACKGROUND: Previous studies on recurrence of Kawasaki disease (KD) have mostly been limited to Japan, which has an incidence of KD 8-10-fold higher than North America. The aim of the present study was to determine the rate of KD recurrence for patients in Ontario, to identify factors potentially associated with increased odds of recurrence, and to compare the clinical course and outcomes of index and recurrent KD episodes. METHODS: Review was undertaken of all patients with recurrence of KD identified in Ontario, Canada, from 1995 to 2006. All patients with recurrence of KD (defined as at least three clinical signs of KD in addition to fever ≥ 5 days), presenting ≥ 14 days after the return to baseline from the index episode were included. RESULTS: A total of 1010 patients were followed for 5786 patient-years. During this period a total of 17 recurrent episodes in 16 patients were identified at a median of 1.5 years after the initial episode (2 weeks-5 years). Rate of recurrence of KD was 2.9 episodes/1000 patient-years, which is higher than the expected annual incidence of KD in the same age group (26.2/100,000 per year). No factors associated with increased risk of recurrence were identified, perhaps due to the small number of events. Clinical course and outcomes of the index and recurrent KD episodes were similar. CONCLUSIONS: A previous history of KD should increase the index of suspicion for future episodes of KD to allow for rapid recognition, treatment and to achieve optimal outcomes.

Risk, clinical features, and outcomes of thrombosis associated with pediatric cardiac surgery.

BACKGROUND: Thrombosis, usually considered a serious but rare complication of pediatric cardiac surgery, has not been a major clinical and/or research focus in the past. METHODS AND RESULTS: We noted 444 thrombi (66% occlusive, 60% symptomatic) in 171 of 1542 surgeries (11%). Factors associated with increased odds of thrombosis were age <31 days (odds ratio [OR], 2.0; P=0.002), baseline oxygen saturation <85% (OR, 2.0; P=0.001), previous thrombosis (OR, 2.6; P=0.001), heart transplantation (OR, 4.1; P<0.001), use of deep hypothermic circulatory arrest (OR, 1.9 P=0.01), longer cumulative time with central lines (OR, 1.2 per 5-day equivalent; P<0.001), and postoperative use of extracorporeal support (OR, 5.2; P<0.001). Serious complications of thrombosis occurred with 64 of 444 thrombi (14%) in 47 of 171 patients (28%), and were associated with thrombus location (intrathoracic, 45%; extrathoracic arterial, 19%; extrathoracic venous, 8%; P<0.001), symptomatic thrombi (OR, 8.0; P=0.02), and partially/fully occluding thrombi (OR, 14.3; P=0.001); indwelling access line in vessel (versus no access line) was associated with lower risk of serious complications (OR, 0.4; P=0.05). Thrombosis was associated with longer intensive care unit (+10.0 days; P<0.001) and hospital stay (+15.2 days; P<0.001); higher odds of cardiac arrest (OR, 4.9; P<0.001), catheter reintervention (OR, 3.3; P=0.002), and reoperation (OR, 2.5; P=0.003); and increased mortality (OR, 5.1; P<0.001). Long-term outcome assessment was possible for 316 thrombi in 129 patients. Of those, 197 (62%) had resolved at the last follow-up. Factors associated with increased odds of thrombus resolution were location (intrathoracic, 75%; extrathoracic arterial, 89%; extrathoracic venous, 60%; P<0.001), nonocclusive thrombi (OR, 2.2; P=0.01), older age at surgery (OR, 1.2 per year; P=0.04), higher white blood cell count (OR, 1.1/10(9) cells per 1 mL; P=0.002), and lower fibrinogen (OR, 1.4/g/L; P=0.02) after surgery. CONCLUSIONS: Thrombosis affects a high proportion of children undergoing cardiac surgery and is associated with suboptimal outcomes. Increased awareness and effective prevention and detection strategies are needed.

Improved outcomes associated with intraoperative steroid use in high-risk pediatric cardiac surgery.

BACKGROUND: Corticosteroids are commonly administered perioperatively in pediatric cardiac surgery to reduce cardiopulmonary bypass induced inflammation. However, their effects on outcomes and potential for adverse events are not well defined. METHODS: A review was undertaken of cardiac operations between September 2004 and December 2007 carrying a comprehensive Aristotle score 10 or greater. A nonrandomized comparison was undertaken comparing those patients having received intraoperative methylprednisolone at anesthesia induction or in the bypass circuit prime with those who did not. To account for nonrandom assignment of steroid use, a propensity model was created to establish each patient's probability of having received steroids (∼150 variables evaluated, 17 in final model, c-stat 0.94, p < 0.001). Associations between postoperative outcomes and intraoperative steroid use were modeled in multivariable linear regression models adjusted for propensity score and relevant surgical characteristics. RESULTS: In 221 identified cases, 134 (61%) patients received intraoperative steroids; of these, 44 (33%) also received preoperative doses. In propensity-adjusted regression models, intraoperative steroid use was associated with lower chest tube volume loss in the first 24 postoperative hours (-5.3 mL/kg, p < 0.001), and shorter durations of stay in intensive care (-2.3 days, p < 0.001) and hospital (-4.1 days, p < 0.001). Use of an additional preoperative dose resulted in further improvements, especially a reduction in duration of mechanical ventilation (-1.7 days versus no steroids, -1.2 days versus intraoperative steroids only, p = 0.002). Steroids were not associated with increased postoperative lactate, creatinine, or glucose levels, or odds of infection. CONCLUSIONS: Intraoperative steroid use is associated with improved postoperative outcomes for children undergoing high-risk cardiac surgery, with further benefits associated with a preoperative dose.

Parental anxiety associated with Kawasaki disease in previously healthy children.

OBJECTIVE: The objective of this study was to explore the lived experience of parents of children diagnosed with Kawasaki disease (KD) and to identify factors associated with increased levels of parental anxiety. STUDY DESIGN: Three focus groups were conducted including 25 parents of 17 patients with KD, seven (41%) of whom had coronary artery complications. A conceptual model was developed to depict parental experiences and illustrate the key issues related to heightened anxiety. RESULTS: Themes identified included anxiety related to the child's sudden illness and delay in obtaining a correct diagnosis because of the lack of health care providers' awareness and knowledge regarding KD. Parents were frustrated by the lack of information available in lay language and the limited scientific knowledge regarding the long-term consequences of the disease. Parents also reported positive transformations and different perspective toward challenges in life. However, the parents of children with coronary artery complications expressed persistent anxiety even years after the acute phase of the illness due to the uncertainty of the long-term prognosis. CONCLUSIONS: There remains a critical need for richly textured research data on the perspective and experience of families of children with KD.

Post-transplant lymphoproliferative disorder in pediatric heart transplant recipients.

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) is a major cause of morbidity and mortality after pediatric heart transplantation. METHODS: Heart transplant recipients at The Hospital for Sick Children, Toronto, from 1990 to May 2008, were reviewed. Competing risk hazard analysis was used to model the natural history of the disease. Patients were matched for gender and duration of follow-up to identify potential covariates associated with increased risk of PTLD. RESULTS: A total of 173 heart transplant recipients (42% <1 year old) were reviewed. Twenty-three developed PTLD at a median of 4 years post-transplantation. After transplantation, PTLD affected 9%, 15% and 28% at 3, 5 and 10 years, respectively. Freedom from death or PTLD recurrence was 72%, 58% and 50% at 1, 3 and 5 years, respectively, after PTLD diagnosis. Higher maximum Epstein-Barr viral (EBV) load (hazard ratio [HR]: 2.6, p = 0.004) and longer duration of induction therapy (HR: 1.7, p = 0.02) were associated with increased risks of PTLD. Higher cumulative cyclosporine doses over the first year post-transplantation were associated with increased risks of PTLD (HR: 1.2 per 1 mg/kg/day equivalent, p = 0.03), but higher tacrolimus doses were not (p = 0.38). Patients on cyclosporine at 6 months post-transplantation were at higher risk of PTLD than those on tacrolimus (HR: 5.2, p = 0.003). The use of anti-viral prophylaxis in patients with high EBV load may provide some protection (HR: 7.6 vs 15.4 with no anti-viral, p = 0.02). CONCLUSIONS: PTLD is a major concern in pediatric heart transplant recipients and is associated with high morbidity/mortality. Exposure to EBV and higher intensity of immunosuppression seems to be associated with increased risk.

Transition to adult health care for adolescents and young adults with congenital heart disease: perspectives of the patient, parent and health care provider.

BACKGROUND: Pediatric institutions play a large role in preparing young adults with congenital heart disease to transition to adult care. OBJECTIVE: To determine the perspectives of patients, parents and providers on transition preparation. METHODS: Patients aged nine to 18 years with congenital heart defects and their respective parent(s) participated in semistructured interviews. Health care providers completed a self-administered survey. RESULTS: A total of 23 patients, 22 parents and 45 health care providers were enrolled in the study. Only 36% of patients demonstrated a clear understanding of transition and its implications for their cardiac care. Parents were extensively involved in care activities, with 95% accompanying their child to visits at the clinic, 68% staying with their child for the entire visit and 45% administering their medication. Children more knowledgeable about their diagnosis demonstrated a better understanding about their transition to adult care (100% versus 7%, respectively; P<0.01) and were more likely to communicate directly with their providers than those who were less or not knowledgeable (88% versus 33%, respectively; P=0.03). Nurses were more likely than physicians to view increased parental involvement in care activities as a barrier to transition preparation (37% versus 5%, respectively; P=0.02). CONCLUSIONS: A lack of clear role expectations indicates a need for the pediatric health care setting to adapt appropriately to address the shifting needs of adolescent and young adult patients and their families. A formalized approach to transition preparation for adolescents with congenital heart disease needs to emphasize comprehensive education. A delegation of explicit responsibilities and the clear definition of roles for parents, providers and patients are necessary to provide young adults with the resources and support necessary to achieve a successful transition to adult care.

Kawasaki disease at the extremes of the age spectrum.

OBJECTIVE: We sought to determine outcomes of Kawasaki disease (KD) and to explore factors associated with poor clinical outcomes for patients diagnosed outside the age range of 1 to 4 years. METHODS: A retrospective review of data for all patients seen between January 1990 and April 2007 was performed. Patients were stratified into 5 groups on the basis of age at diagnosis. RESULTS: A total of 1374 patients were identified; 61 (4%) were <6 months of age at diagnosis, 114 (8%) 6 months to <1 year, 854 (62%) 1 to 4 years, 258 (19%) 5 to 9 years, and 87 (6%) >9 years. Patients <1 year of age and those >9 years of age were more likely to have coronary artery abnormalities than were patients diagnosed between 1 and 4 years of age. Patients diagnosed between the ages of 5 and 9 years were at the lowest risk. Patients at both extremes of the age spectrum were more likely to present with <4 of the classic KD features, but only those <6 months or >5 years of age were at increased risk of being diagnosed >12 days after illness onset. Patients <6 months of age had lower albumin levels, and those <1 year of age had higher white blood cell and platelet counts, all of which are known predictors of coronary artery abnormalities. Patients >9 years of age were less likely to receive intravenous immunoglobulin treatment. CONCLUSION: Outcomes for children diagnosed with KD at either extreme of the age spectrum are suboptimal, although the associated factors are different.

Spectrum and management of hypertriglyceridemia among children in clinical practice.

OBJECTIVES: The prevalence and identification of hypertriglyceridemia in youths will likely will increase in the future as a consequence of childhood obesity and increased screening for dyslipidemias. We sought to review our clinical experience with hypertriglyceridemia, evaluate factors associated with increased triglyceride levels, and review treatment options to provide guidance for management. METHODS: Clinical review of data for all patients who had > or =1 elevated triglyceride level (>4 mmol/L [>350 mg/dL]) while being monitored in a specialized lipid disorders clinic was performed. RESULTS: The study population consisted of 76 patients with 761 clinic visits. Hypertriglyceridemia was secondary to lifestyle factors for 13 patients. The rest had primary hypertriglyceridemia, with 32 patients having familial combined hypertriglyceridemia and hypercholesterolemia (type II), 25 patients having primary hypertriglyceridemia (type IV), 4 patients having familial lipase deficiency (type I), and 2 patients having hyperlipoproteinemia E2/E2 phenotype (type III). Triglyceride levels were highest in type I and III hypertriglyceridemia (>10 mmol/L [>900 mg/dL]), followed by type IV and adiposity-related hypertriglyceridemia (>4 mmol/L [>350 mg/dL]) and finally type II familial combined hypertriglyceridemia and hypercholesterolemia (>2 mmol/L [>180 mg/dL]). A total of 34 patients received 37 trials of drug therapy as part of triglyceride level management (bile acid-binding resins, n = 12; fibrates, n = 19; statins, n = 6). Triglyceride levels were found to decrease over time with the use of fibrates, to increase with the use of bile acid-binding resins, and not to change with the use of statins. CONCLUSIONS: Lifestyle modifications remain the primary therapeutic avenue for the management of pediatric hypertriglyceridemia. We propose an algorithm for the management of this heterogeneous population to guide clinicians in their treatment decisions.