Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. METHODS: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. FINDINGS: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. INTERPRETATION: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. FUNDING: AstraZeneca.

Plain language summary of the TOPAZ-1 study: durvalumab and chemotherapy for advanced biliary tract cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary describing the results of a Phase III study called TOPAZ-1. The study looked at treatment with durvalumab (a type of immunotherapy) and chemotherapy to treat participants with advanced biliary tract cancer (BTC). Advanced BTC is usually diagnosed at late stages of disease, when it cannot be cured by surgery. This study included participants with advanced BTC who had not received previous treatment, or had their cancer come back at least 6 months after receiving treatment or surgery that aimed to cure their disease. Participants received treatment with durvalumab and chemotherapy or placebo and chemotherapy. The aim of this study was to find out if treatment with durvalumab and chemotherapy could increase the length of time that participants with advanced BTC lived, compared with placebo and chemotherapy. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took durvalumab and chemotherapy had a 20% lower chance of experiencing death at any point in the study compared with participants who received placebo and chemotherapy. The side effects experienced by participants were similar across treatment groups, and less than 12% of participants in either treatment group had to stop treatment due to treatment-related side effects. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, these results support durvalumab and chemotherapy as a new treatment option for people with advanced BTCs. Based on the results of this study, durvalumab is now approved for the treatment of adults with advanced BTCs in combination with chemotherapy by government organizations in Europe, the United States and several other countries.

Understanding the patient experience in hepatocellular carcinoma: a qualitative patient interview study.

PURPOSE: This study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development. METHODS: Patients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0-10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews. RESULTS: Interviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience. CONCLUSION: Patients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.

Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer.

BACKGROUND: Patients with advanced biliary tract cancer have a poor prognosis, and first-line standard of care (gemcitabine plus cisplatin) has remained unchanged for more than 10 years. The TOPAZ-1 trial evaluated durvalumab plus chemotherapy for patients with advanced biliary tract cancer. METHODS: In this double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease 1:1 to receive durvalumab or placebo in combination with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess overall survival. Secondary end points included progression-free survival, objective response rate, and safety. RESULTS: Overall, 685 patients were randomly assigned to durvalumab (n=341) or placebo (n=344) with chemotherapy. As of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. The hazard ratio for overall survival was 0.80 (95% confidence interval [CI], 0.66 to 0.97; P=0.021). The estimated 24-month overall survival rate was 24.9% (95% CI, 17.9 to 32.5) for durvalumab and 10.4% (95% CI, 4.7 to 18.8) for placebo. The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates were 26.7% with durvalumab and 18.7% with placebo. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. CONCLUSIONS: Durvalumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy and showed improvements versus placebo plus chemotherapy in prespecified secondary end points including progression-free survival and objective response rate. The safety profiles of the two treatment groups were similar. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03875235.)

Understanding Patient Experience in Biliary Tract Cancer: A Qualitative Patient Interview Study.

INTRODUCTION: Patients living with biliary tract cancer (BTC) experience a decline in health-related quality of life (HRQoL). This study aimed to obtain a comprehensive understanding of the patient experience of BTC-related signs/symptoms and the impacts of these on daily functioning and HRQoL. METHODS: Patients with BTC participated in qualitative semi-structured concept elicitation interviews. Signs/symptoms and impacts of BTC were initially explored by targeted literature searches and interviews with five clinicians. Patient interviews were transcribed and coded using qualitative research software. Concept saturation was assessed over five interview waves. A sign/symptom or impact was defined as "salient" if mentioned by ≥ 50% of patients, with a mean disturbance rating of ≥ 5 (0-10 scale). A conceptual model of the patient experience of BTC-related signs/symptoms and impacts was produced. RESULTS: Twenty-three patients from the USA (78% women; median age: 54 years), diagnosed as having early (n = 3), locally advanced (n = 11) or metastatic (n = 9) disease, were interviewed. Sixty-six signs/symptoms and 12 impacts were identified. Of these, 46 signs/symptoms and 8 impacts were not identified from the targeted literature or clinician interviews. Concept saturation was reached by the fourth of five interview waves. Fourteen disease-related signs/symptoms (including fatigue/lack of energy, abdominal pain, lack of appetite, insomnia and diarrhoea) and three impacts (physical, emotional and cognitive impacts) were deemed "salient". The conceptual model included 50 signs/symptoms and 12 impacts. CONCLUSION: Patients with BTC reported a range of signs/symptoms and impacts that negatively affect daily functioning and HRQoL.

Allopurinol use during pediatric acute lymphoblastic leukemia maintenance therapy safely corrects skewed 6-mercaptopurine metabolism, improving inadequate myelosuppression and reducing gastrointestinal toxicity.

BACKGROUND: Inadequate myelosuppression during maintenance therapy for acute lymphoblastic leukemia (ALL) is associated with an increased risk of relapse. One mechanism is skewed metabolism of 6-mercaptopurine (6MP), a major component of maintenance therapy, which results in preferential formation of the hepatotoxic metabolite (6-methyl mercaptopurine [6MMP]) with low levels of the antileukemic metabolite, 6-thioguanine nucleotides (6TGN). Allopurinol can modify 6MP metabolism to favor 6TGN production and reduce 6MMP. METHODS: Patients in maintenance were considered for allopurinol treatment who had the following features: (a) Grade ≥3 hepatotoxicity; (b) Grade ≥2 nonhepatic gastrointestinal (GI) toxicity; or (c) persistently elevated absolute neutrophil count (ANC) despite >150% protocol dosing of oral chemotherapy. RESULTS: From 2013 to 2017, 13 ALL patients received allopurinol: nine for hepatotoxicity, five for inadequate myelosuppression, and three for nonhepatic GI toxicity (four met multiple criteria). Allopurinol was well tolerated, without significant adverse events. Allopurinol resulted in a significant decrease in the average 6MMP/6TGN ratio (mean reduction 89.1, P = .0001), with a significant increase in 6TGN (mean 550.4, P = .0008) and a significant decrease in 6MMP (mean 13 755, P = .0013). Patients with hepatotoxicity had a significant decrease in transaminase elevation after starting allopurinol (alanine transaminase [ALT] mean decrease 22.1%, P = .02), and all with nonhepatic GI toxicity had improved symptoms. Those with inadequate myelosuppression had a significant increase in the time with ANC in goal (mean increase 26.4%, P = .0004). CONCLUSIONS: Allopurinol during ALL maintenance chemotherapy is a safe, feasible, and effective intervention for those who have altered metabolism of 6MP causing toxicity or inadequate myelosuppression.

International recommendations for electrocardiographic interpretation in athletes.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

International criteria for electrocardiographic interpretation in athletes: Consensus statement.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

International Recommendations for Electrocardiographic Interpretation in Athletes.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On February 26-27, 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

One size does not fit all: the influence of age at surgery on outcomes following Norwood operation.

BACKGROUND: Given our large catchment area that often results in later presentation age, we sought to understand our institutional outcomes for the Norwood operation in the context of published data. Specifically, we studied whether operative and late death post-Norwood are dependent on age at operation. METHODS: Retrospective review of 105 consecutive infants undergoing Norwood (2004-2011) at our institution. Patients were divided into those undergoing Norwood ≤ 7 days of age (N = 43; 41%) and those undergoing Norwood > 7 days of age (N = 63; 59%). Operative mortality (≥30 days), interstage mortality (between Norwood and superior bidirectional Glenn), STS-mortality (operative death + in-hospital death), and late mortality, occurring any time following hospital discharge were compared among groups. Multivariable factors for mortality at each time-point were compared using logistic regression models. RESULTS: Underlying diagnosis was HLHS in 67 (64%) with the remainder (N = 38; 36%) being other single ventricle variants. Median age at surgery was 8 days (range 1-63 days) and mean weight at surgery was 3.2 ± 0.6 kg. Pulmonary blood flow was provided by a right ventricle-pulmonary artery conduit in 94% (N = 99). Overall operative survival was 92%, with 73% (N = 66) undergoing bidirectional Glenn. Median age was higher for operative survivors compared to non-survivors (12 days vs. 5 days; P = 0.036), with operative mortality higher for infants ≤7 days at Norwood compared to infants >7 days at Norwood (14% vs. 3%; P = 0.04). After censoring for in-hospital death, age ≤ 7 days was also associated with increased risk for late death (26% vs. 5%; P = 0.005). CONCLUSIONS: In contrast to other institutional series, infants at our center undergoing Norwood operation at an earlier age have worse outcomes. Adoption of published practice patterns could lead to different local outcomes because of intangible center-specific effects, underscoring the principle that results from one institution may not be generalizable to others. Targeted center-specific internal review, if possible, should precede externally recommended changes in practice.

Acute-onset choreiform movements in a previously healthy 4-year-old patient.

We report the case of 4-year-old male with sinus venous thrombosis leading to bilateral thalamic and basal ganglia strokes presenting as generalized choreiform movements. Acute-onset chorea in the pediatric population is most commonly associated with Sydenham chorea, which is a manifestation of acute rheumatic fever. Chorea is a much less commonly noted sign of stroke, and when it occurs, it typically presents as hemichorea. Given the unlikely presentation, rapid and appropriate imaging was the key to diagnosis.

Combined heart-kidney transplant improves post-transplant survival compared with isolated heart transplant in recipients with reduced glomerular filtration rate: Analysis of 593 combined heart-kidney transplants from the United Network Organ Sharing Database.

OBJECTIVE: Criteria for simultaneous heart-kidney transplant (HKTx) recipients are unclear. We characterized the evolution of combined HKTx in the United States over time compared with isolated heart transplantation (HTx) and determined factors maximizing post-transplant survival. We focused on whether a threshold estimated glomerular filtration rate (eGFR) could be identified that justified combined transplantation. METHODS: A supplemented United Network Organ Sharing Dataset identified HTx and HKTx recipients from 2000 to 2010. eGFR was calculated for HTx and recipients were grouped into eGFR quintiles. Time-related mortality was compared among recipients, with multivariable factors sought using Cox proportional hazard regression models. RESULTS: We identified 26,183 HTx recipients, of whom 593 were HKTx recipients. HTx increased modestly over time (3.6%), whereas prevalence of HKTx increased dramatically (147%). Risk-unadjusted survival was similar among HTx recipients (8.4 ± 0.04 years) and HKTx recipients (7.7 ± 0.2 years) (P = .76). Isolated HTx recipients in the lowest eGFR quintile had decreased survival (P < .001), but those in the third eGFR quintile had superior survival, suggesting a benefit in this subgroup. HTx recipients in the lowest eGFR quintile (eGFR less than mean 37 mL/minute) had worse survival than combined HKTx recipients (7.1 ± 0.07 vs 7.7 ± 0.2; P < .001). Multivariable factors for increased mortality among HTx recipients included lower eGFR, higher recent panel reactive antibody score, older age, African American race, diabetes, longer ischemic time, and certain diagnoses. CONCLUSIONS: Performance of combined HKTx is increasing out of proportion to isolated HTx. eGFR is an important determinant of improved HTx survival. Combined HKTx recovers post-transplant survival in patients with eGFR <37 mL/minute and can be recommended in this subgroup.

Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children.

BACKGROUND: Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. METHODS AND RESULTS: This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1-435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death. CONCLUSIONS: Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.

Increased extracorporeal membrane oxygenation center case volume is associated with improved extracorporeal membrane oxygenation survival among pediatric patients.

OBJECTIVE: We sought to examine the relationship between extracorporeal membrane oxygenation center case volume and survival in pediatric patients requiring extracorporeal membrane oxygenation support. METHODS: Pediatric patients (≤ 20 years) undergoing extracorporeal membrane oxygenation cannulation were identified using the Healthcare Cost and Utilization Project Kids' Inpatient Database for 2000 to 2009. Annual hospital extracorporeal membrane oxygenation volume tertiles were <15 patients/year (low volume), 15 to 30 patients/year (medium volume), and >30 patients/year (high volume). Cases of extracorporeal membrane oxygenation were segregated by indication into cardiac and noncardiac groups. Cases of cardiac extracorporeal membrane oxygenation were mapped to Risk Adjustment for Congenital Heart Surgery categories to adjust for case complexity. Weighted multivariable logistic and linear regression models identified determinants of in-hospital mortality. RESULTS: Overall, 3867 cases of extracorporeal membrane oxygenation were identified, yielding a national estimate of 6333 ± 495 cases. Extracorporeal membrane oxygenation was used with nearly equivalent prevalence across volume tertiles for all Risk Adjustment for Congenital Heart Surgery categories, suggesting that patient selection for extracorporeal membrane oxygenation was fairly uniform. A higher annual extracorporeal membrane oxygenation volume tertile was associated with reduced in-hospital mortality (P = .01) within nearly all Risk Adjustment for Congenital Heart Surgery categories. After adjustment for Risk Adjustment for Congenital Heart Surgery category and other patient variables, lower extracorporeal membrane oxygenation volume remained an important determinant of in-hospital death (odds ratio, 1.75; 95% confidence interval, 1.03-2.94; P = .03). CONCLUSIONS: Higher extracorporeal membrane oxygenation case volume is associated with improved hospital survival in pediatric cardiac extracorporeal membrane oxygenation patients. The results of this study may support the paradigm of regionalized centers of excellence for managing pediatric cardiac extracorporeal membrane oxygenation patients.

Prospective trial of a pediatric ventricular assist device.

BACKGROUND: Options for mechanical circulatory support as a bridge to heart transplantation in children with severe heart failure are limited. METHODS: We conducted a prospective, single-group trial of a ventricular assist device designed specifically for children as a bridge to heart transplantation. Patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.7 m(2); cohort 2, 0.7 to <1.5 m(2)), with 24 patients in each group. Survival in the two cohorts receiving mechanical support (with data censored at the time of transplantation or weaning from the device owing to recovery) was compared with survival in two propensity-score-matched historical control groups (one for each cohort) undergoing extracorporeal membrane oxygenation (ECMO). RESULTS: For participants in cohort 1, the median survival time had not been reached at 174 days, whereas in the matched ECMO group, the median survival was 13 days (P<0.001 by the log-rank test). For participants in cohort 2 and the matched ECMO group, the median survival was 144 days and 10 days, respectively (P<0.001 by the log-rank test). Serious adverse events in cohort 1 and cohort 2 included major bleeding (in 42% and 50% of patients, respectively), infection (in 63% and 50%), and stroke (in 29% and 29%). CONCLUSIONS: Our trial showed that survival rates were significantly higher with the ventricular assist device than with ECMO. Serious adverse events, including infection, stroke, and bleeding, occurred in a majority of study participants. (Funded by Berlin Heart and the Food and Drug Administration Office of Orphan Product Development; ClinicalTrials.gov number, NCT00583661.).

Arterial switch operation in the first hours of life using autologous umbilical cord blood.

BACKGROUND: In this study, we analyzed our clinical experience performing the arterial switch operation in the first hours of life using autologous umbilical cord blood transfusion (AUCBT). The safety and efficiency of AUCBT was assessed and compared with surgery with the use of homologous blood transfusion. METHODS: Between September 2009 and February 2011, 61 neonates underwent ASO at our institution. Patients were enrolled and allocated to two groups with different modalities of management strategies for neonates with dextrotransposition of the great arteries. RESULTS: The groups were similar in diagnoses, birth weight, cardiopulmonary bypass protocol, and surgical technique, excepting timing of surgery and blood management strategy. Preoperative mean hematocrit did not differ significantly between the groups (45% versus 45%). Mean hematocrit was significantly lower in the study group than in the control group during cardiopulmonary bypass (24% versus 31%). The hematocrit progressively increased in the study group to 38% on the first postoperative day. Serum lactate levels were higher in the study group till the second day after surgery. There were no significant differences in postoperative clinical profiles. There were no hospital deaths and no AUCBT-related side effects in our study. CONCLUSIONS: The arterial switch operation can be performed in the first hours of life with AUCBT. Therefore, AUCBT is a safe and an efficient alternative to homologous blood in neonatal open heart surgery. During the study, we also identified positive economic effects associated with this approach.

A Comprehensive Intervention Associated With Reduced Surgical Site Infections Among Pediatric Cardiovascular Surgery Patients, Including Those With Delayed Closure.

BACKGROUND: Surgical site infections (SSIs) cause significant morbidity and mortality in patients undergoing cardiovascular (CV) surgery. Following an increase in SSIs in this population, driven by a high rate in those with delayed closure, we implemented an intervention to reduce these infections and assessed the intervention using both population- and patient-level analyses. METHODS: An intervention drawing from existing guidelines and targeting preoperative preparation of the patient, prophylactic antibiotics, and postoperative incision care was implemented. Special attention was paid to standardizing the care of the incision of patients with delayed closure. National Healthcare Safety Network criteria were used to prospectively identify SSIs. Population-level intervention effect was assessed using interrupted time series. To assess intervention adherence and effect in our patient population, retrospective chart review was performed on a cohort of patients undergoing cardiac procedures pre- and postintervention. Multivariate analysis was used to assess risk of SSI at the patient level. RESULTS: Timely preoperative prophylactic antibiotic dosing increased from 60% preintervention to 92% postintervention, and redosing during prolonged surgeries increased from 5% to 79% (both, P < .001). At the population-level, a decrease of 6.7 infections per 100 surgeries per 6 months was observed directly following the intervention (P = .002). The SSI rate decreased from 40% to 0.8% (P < .001) in patients with delayed closure and from 4.3% to 1.8% (P = .02) in patients with immediate closure. In multivariate analyses, surgery prior to the intervention was the strongest predictor for SSI (incidence rate ratio, 3.98; 95% confidence interval, 1.59 to 9.97). CONCLUSIONS: Our intervention decreased SSIs in pediatric CV surgery patients, particularly those with delayed closures.

Direct optical measurement of intraoperative myocardial oxygenation during congenital heart surgery.

This study demonstrates use of novel technology to measure cellular oxygenation during corrective congenital heart surgery. Cellular oxygenation was measured using a custom-designed optical probe placed on the free wall of the right ventricle. Cellular oxygenation, determined from myoglobin saturation, was calculated using multiwavelength analysis. Timing of bypass, aortic cross-clamp, infusion of cardioplegic solution, and length of intensive care unit (ICU) stay were recorded. Baseline cellular oxygenation was approximately 50% just before aortic cross-clamp and decreased to approximately 20% during cardioplegia. Cellular oxygenation remained low throughout cardioplegia and returned toward baseline after bypass. In four cases, cellular oxygenation did not return as quickly to baseline as in the other three cases. Among the four patients demonstrating slow recovery, the average ICU length of stay was 2.25 days compared with an average stay of 1.33 days for those patients exhibiting rapid cellular oxygenation recovery (p = 0.06). The slow recovery group had an average cross-clamp time of 40.1 ± 28.4 minutes, compared with 26.0 ± 8.5 minutes for the fast recovery group (p = 0.34). This study demonstrates for the first time that myocyte cellular oxygenation can be measured intraoperatively during cardiac surgery. Measurement of cellular oxygenation may be useful for improving myocardial preservation techniques.

Predictors of ECMO support in infants with tachycardia-induced cardiomyopathy.

The development of tachycardia-induced cardiomyopathy (TIC) is related to the rate and duration of supraventricular tachycardia (SVT). Infants may be more susceptible to TIC because early symptoms might be unrecognized. Extracorporeal membrane oxygenation (ECMO) may improve outcome in patients with SVT and TIC; however, clinical predictors of infants who require ECMO support have not been determined. The purpose of this study was to identify predictors of the need for ECMO in infants with SVT and TIC. Sixteen infants <6 months of age who experienced resolution of TIC following control of arrhythmia were identified. Three patients (19%) required ECMO support. Comparisons were made between patients who required ECMO and those who did not. The groups were similar with respect to age at presentation, type of SVT, rate of SVT, and degree of ventricular dysfunction. However, patients requiring ECMO had increased median M-mode-derived left ventricular end diastolic dimension (LVED) z-score when compared to the medically managed patents (+2.8 vs. 0.0, P = 0.009). No patient in the medically managed group had an LVED z-score >2.3. Infants presenting with SVT and TIC with LVED z-score >2 are at increased risk for requiring ECMO support and early use of ECMO should be considered.

Bridging children of all sizes to cardiac transplantation: the initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device.

BACKGROUND: Beginning in 2000 and accelerating in 2004, the Berlin Heart EXCOR (Berlin Heart Inc Woodlands, TX) became the first pediatric-specific ventricular assist device (VAD) applied throughout North America for children of all sizes. This retrospective study analyzed the initial Berlin Heart EXCOR pediatric experience as a bridge to transplantation. METHODS: Between June 2000 and May 2007, 97 EXCOR VADs were implanted in North America at 29 different institutions. The analysis is limited to 73 patients (75%) from 17 institutions, for which retrospective data were available. RESULTS: Median age and weight at VAD implant were 2.1 years (range, 12 days-17.8 years) and 11 kg (range, 3-87.6 kg), respectively. The primary diagnoses were dilated cardiomyopathy in 42 (58%), congenital heart disease in 19 (26%), myocarditis in 7 (10%), and other cardiomyopathies in 5 (7%). Pre-implant clinical condition was critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), or other in 2 (3%). Extracorporeal membrane oxygenation was used as a bridge to EXCOR in 22 patients (30%). Device selection was left VAD (LVAD) in 42 (57%) and biventricular assist devices (BiVAD) in 31 (43%). The EXCOR bridged 51 patients (70%) to transplant and 5 (7%) to recovery. Mortality on the EXCOR was 23% (n = 17) overall, including 35% (11 of 31) in BiVAD vs 14% (6 of 42) in LVAD patients (p = 0.003). Multivariate analysis showed younger age and BiVAD support were significant risk factors for death while on the EXCOR. CONCLUSIONS: This limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The prospective investigational device evaluation trial presently underway will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation.