Educating Surgeons to Construct Valved Conduits: What Does It Take to Achieve Reproducible Results?

BACKGROUND: Despite the demonstrated utility of surgeon-fashioned polytetrafluoroethylene (PTFE) valved conduits, methods for educating surgeons to reproducibly construct these conduits are lacking. We present a surgeon education process and early outcomes for children receiving surgeon-fashioned PTFE valved conduits during the initial learning curve. METHODS: The educational curriculum included 4 hours of proctored instruction/supervised valve construction, followed by 2 hours of individual practice. A surgeon with prior mastery of the technique provided templated designs, videos, and follow-up consultation. A retrospective medical record review (2017-2022) described early outcomes and valve function for patients receiving surgeon-fashioned PTFE right ventricle-to-pulmonary artery conduits. RESULTS: Two surgeons were educated using the method described. Fifteen valved conduits were implanted in 14 patients (median patient age, 38 months; conduit size range, 10-24 mm). At discharge, no patient had more than mild stenosis or regurgitation, and 12 of 15 valves (80%) had none or trivial regurgitation. Median follow-up was 14 months (range, 1-52 months). At the last follow-up, median peak conduit gradient of the 15 valves was low (18 mm Hg), 1 (7%) had moderate stenosis, and 1 (7%) had mild-moderate regurgitation. Two conduits were replaced concomitantly during repair of associated lesions at 14 and 38 months (sizes 10 and 12 mm, respectively). There were no deaths and no infectious complications. CONCLUSIONS: Four hours of proctored surgeon education plus deliberate practice is an effective method for teaching valved PTFE conduit construction and is associated with excellent early valve function. This study provides educational methods and initial evidence of safety for congenital surgeons wishing to learn and adopt this technique.

Development of a Novel Society of Thoracic Surgeons Adult Congenital Mortality Risk Model.

BACKGROUND: Operative mortality risk models for adults with congenital heart disease (ACHD) undergoing cardiac operations are essential, given the growing population of these patients, yet they are currently unavailable. Existing adult Society of Thoracic Surgeons (STS) models exclude congenital procedures, whereas existing congenital models exclude operations for acquired disease. We aimed to develop an STS mortality risk model for ACHD patients undergoing cardiac operations. METHODS: Leveraging a comprehensive list of diagnostic and procedure codes, ACHD patients who underwent cardiac operations were identified from the STS Adult Cardiac Surgery Database (versions: v2.73, v2.81, and v2.9) between 2011 and 2019. The model was developed and validated in the ACHD population using a 60/40 development/validation split. Univariate analyses and clinical expertise informed the addition of ACHD-relevant procedure and diagnosis variables to existing STS adult risk model variables. Model performance was assessed overall and in 38 subgroups based on patient demographics, procedures, and diagnoses. RESULTS: Forty-seven procedure and diagnosis variables relevant to ACHD were added to existing STS adult risk model variables. The derived ACHD model for operative mortality was well calibrated within demographic, procedural, and diagnosis subgroups and the overall ACHD population, and discrimination in the validation cohort was excellent (C statistic, 0.815) compared with the model using only existing STS adult risk model variables (C statistic, 0.79; P < .0001). CONCLUSIONS: A novel, high-performing STS ACHD mortality risk model has been developed on the basis of contemporary patient data. The ACHD risk model represents an important expansion of the STS portfolio. Implementation with an online risk calculator is planned.

Predictors of Mediastinal Exploration While on Extracorporeal Membrane Oxygenation After Pediatric Cardiac Surgery.

Cardiac surgical patients requiring extracorporeal membrane oxygenation (ECMO) are at increased risk for hemorrhage due to necessary anticoagulation, in-situ cannulas, and disturbed hemostasis. We performed a retrospective, cross-sectional study of patients 0-18 years old in our cardiac intensive care unit (CICU) cannulated to ECMO within 48 h of cardiopulmonary bypass. The 69 patients included in the study were divided into three analysis groups based on serial chest tube output per hour: no bleeding (NB) on admission to the CICU (21/69, 30%), bleeding stopped (BS) with medical management (26/69, 38%), bleeding requiring emergent mediastinal exploration (BME) (22/69, 32%). The NB group had a more favorable coagulation profile upon admission to the CICU (PTT 53 s NB, 105 s BS, 83 s BME p < 0.001, ACT 169 s NB, 225 s BS, 211 s BME, p =0.013). Only chest tube output during the first three postcannulation hours remained associated with the need for mediastinal exploration by multivariable analysis. An average chest-tube output of 11.6 mL/kg/h during the first three hours had the highest percentage of patients classified correctly (84%) for requiring mediastinal exploration during their ECMO run (sensitivity 91%, specificity 81%).

Idiopathic Pericardial Effusions in Children: Workup and Final Diagnoses.

Pediatric idiopathic pericardial effusions are common and often have a prolonged clinical course. We hypothesized that these effusions have no standardized diagnostic workup, and ultimately have a final etiology not initially appreciated. To test these hypotheses, a hospital system-wide retrospective (1/1/1990-10/1/2019) cohort study of pericardial effusions in children (< 18 years) was conducted. Effusions were grouped by etiology and patients receiving an initial idiopathic diagnosis were further analyzed. Effusion size, diagnostic workup, final diagnosis, and time to resolution were abstracted. In total, 42/366 effusions were initially diagnosed as idiopathic. Workup was not standardized and included up to six laboratory tests including pericardial fluid analysis and infectious, metabolic, rheumatologic and thyroid workups. Treatment course involved 1 readmission in 24%, and > 1 readmission in 12%. Resolution of effusion occurred in 83% of patients within a median of 1 admission (range 1-4). Of those effusions initially deemed idiopathic, 12/42 (29%) were later found to have an underlying etiologic diagnosis including: autoimmune (7, 58%), neoplastic (2, 16%), infectious (2, 16%), and renal (1, 8%). Children initially diagnosed with idiopathic pericardial effusions have an underlying etiologic diagnosis 29% of the time, and a standardized workup may prevent delays in definitive diagnosis and treatment.

A Minimal Opioid Postoperative Management Protocol in Congenital Cardiac Surgery: Safe and Effective.

There is evidence that reducing opioid exposure in children undergoing cardiac surgery may enhance postoperative recovery. We aimed to describe a minimal opioid postoperative management protocol in children undergoing cardiac surgery and our early outcomes with this strategy. We reviewed the medical records of children (6 months-18 years) who underwent elective cardiac surgery through a median sternotomy with cardiopulmonary bypass at our institution between 2016 and 2018. All patients were managed postoperatively using a standardized protocol. 101 children (median age 5 years) were included and 85% were extubated in the operating room. Although most patients (96%) received opioids postoperatively, opioid requirements decreased steadily over time, with 88%, 58%, and 18% of children receiving opioids on postoperative day 1, 2, and 3, respectively; 41% received no opioids after postoperative day 1. The median cumulative opioid exposure was 0.25 morphine milligram equivalents per kg (interquartile range, 0.10-0.75). Greater than mild pain was rare (<10%) at each time point. The rates of operative mortality and major complication were 0% and 3%, respectively. The median postoperative length of stay was 3 days, and 13% required readmission within 30 days. Age, cardiopulmonary bypass time, and number of benzodiazepine doses were independently associated with cumulative opioid exposure. Any complication, chest tube time, and higher STAT Category were independently associated with prolonged postoperative length of stay. A minimal opioid postoperative management protocol can be safe and effective in children undergoing cardiac surgery. Future prospective studies are needed to determine optimal practice and patient selection.

Capturing Adult Congenital Heart Disease: Framework for Development of an Adult Congenital Heart Disease Mortality Risk Model.

BACKGROUND: As a formative step toward development of adult congenital heart disease (ACHD) risk-adjusted metrics, we describe The Society of Thoracic Surgeons (STS) ACHD population, procedural frequency, and early mortality. METHODS: Adults (≥18 years) with CHD (2014-2019) were identified in the STS Adult Cardiac Surgery (ASCD) and the Congenital Heart Surgery (CHSD) Databases. After deduplication, variable mapping, data concatenation, and harmonization of preprocedure factors, procedures were grouped, and unadjusted mortality was catalogued for the overall cohort and the cohort excluding patients with an isolated bicuspid aortic valve (BAV). RESULTS: Among 171 186 ACSD and 18 281 CHSD records, 152 731 unique records met inclusion criteria. Twenty-eight congenital diagnoses accounted for 86% of the overall cohort, and prevalence of ACHD increased over the study time frame. ACHD patients underwent operations to treat both acquired and CHD. Most common procedures overall and after excluding isolated BAV were aortic valve replacement (AVR), ascending aortic surgery, and coronary artery bypass grafting (CABG). After excluding isolated BAV, major procedure combinations occurred in 46% (31% had 2 major procedures and 3% had ≥4), and the most prevalent combinations included AVR + CABG (n = 2352), AVR + subaortic stenosis repair (n = 1481), and AVR + ascending aortic surgery (n = 1239). Unadjusted 30-day mortality was procedure dependent, 2.8% overall and 3.6% with isolated BAV excluded. CONCLUSIONS: The ACHD surgical population is heterogenous, and patients undergo surgery for CHD-related and adult/acquired procedure combinations. Early mortality is variable and influenced by surgical complexity. Excluding isolated BAV patients and developing procedure-based ACHD mortality risk models may be ideal but will require empirically derived grouping and collaboration.

A shifting landscape: Practice patterns and outcomes of cystic fibrosis and non-cystic fibrosis pediatric lung transplantation.

BACKGROUND: New drugs may further decrease the need for lung transplant (LTx) in pediatric patients with cystic fibrosis (CF), but few studies highlight pediatric non-CF LTx characteristics and outcomes. METHODS: The ISHLT registry was used to report morbidity, graft failure, and survival for primary pediatric (<18 years) LTx performed 1990-2017. Recipient/donor characteristics and long-term outcomes were analyzed for CF and non-CF recipients. Survival was assessed using Kaplan-Meier curves. RESULTS: Of 2232 primary LTx, (43% in males), 918 (41%) were performed for non-CF indications; most commonly pulmonary hypertension (43%). Non-CF patients were younger (median age 11 vs. 15, p < .001), and more frequently on inotropes and/or extracorporeal membrane oxygenation (15% vs. 2.4%, p < .001) at transplant, compared to CF recipients. In-hospital major complications more commonly affected CF LTx recipients (57% vs. 48%, p = .003), but 30-day mortality was higher in the non-CF group (9% non-CF vs. 5% CF, p < .001). One-, five-, and ten-year mortality was 18%, 50%, and 65% for CF recipients, respectively, and 21%, 45%, and 58% for non-CF recipients (p = .01 at 10 years). Five-year survival was significantly better for non-CF females versus CF females (56% vs. 48%, p = .013), but was similar between groups for males (55% vs. 54%, p = .305). While age was a late outcomes risk factor, pulmonary hypertension and later transplants eras were protective. CONCLUSIONS: Early mortality is higher and late mortality is lower in non-CF LTx. Current non-CF LTx outcomes leave room for improvement. Further study is needed to evaluate the effects of center volume and pediatric-specific experience on outcomes.

Aortic Valve Replacement in Young and Middle-Aged Adults: Current and Potential Roles of TAVR.

BACKGROUND: Contemporary practice patterns and outcomes for aortic valve replacement (AVR) among young and middle-aged adults are unknown given guideline modifications for surgical AVR (SAVR) and increasing transcatheter AVR (TAVR) acceptance. This study describes SAVR and TAVR use and outcomes using The Society of Thoracic Surgeons (STS) National Databases. METHODS: Adults 18 to 55 years of age in the Congenital Heart Surgery Database (CHSD) and the Adult Cardiac Surgery Database (ACSD) who underwent SAVR or TAVR from 2013 to 2018 were included. Perioperative characteristics and early outcomes were described by valve type. Multivariable regression identified determinants of death, length of hospital stay, and a composite end point of renal failure, persistent neurologic deficit, readmission, and reoperation. RESULTS: The study analyzed 1580 unique CHSD and 44,173 ACSD operations, 16% of which were performed in patients with congenital heart disease. Valve use included the following: TAVR, 1%; mechanical, 42%; bioprosthetic, 55%; autograft, 0.6%; homograft, 1.2%; and Ozaki, 0.4%. Over time, TAVR volumes increased by 167%. The 30-day mortality was as follows: TAVR, 3.8%; mechanical, 3.2%; bioprosthetic, 3.7%; autograft, 0.6%; homograft, 9%; and Ozaki, 3.4%. Stroke rate was lower for isolated SAVR vs isolated TAVR (0.9% vs 2.4%; P = .002). In multivariable analyses, mortality risk was lower with mechanical valves, congenital morbidity risk was higher with TAVR, and length of stay was shorter with TAVR. CONCLUSIONS: TAVR is increasingly used for adults younger than 55 years of age. Given the uniformly excellent results with SAVR, including both mortality and morbidity-particularly regarding stroke, our data favor SAVR in this population, but a prospective trial is needed. Ongoing efforts to harmonize variables and outcomes definitions between the ACSD and CHSD are valuable.

Blood pressure measurements during intraoperative pediatric scoliosis surgery.

BACKGROUND: Intraoperative hypotension is frequently encountered during surgery and it can be associated with adverse outcomes. Blood pressure monitoring is critical during surgery, but there are no universally agreed upon standards for interpreting values of hypotension and no consensus regarding interventions. MATERIAL AND METHODS: We performed a retrospective chart review of pediatric patients who underwent idiopathic scoliosis surgery by a single surgeon. We used the arterial line for all measures. Intraoperative hypotension was defined as 20% decrease of the baseline systolic blood pressure (SBP), 30% decrease of baseline SBP, or mean arterial pressure less than 60 mmHg. Use of vasopressor agents was also recorded and correlated with blood pressure definitions. RESULTS: Seventy idiopathic scoliosis patients were retrospectively evaluated. There was a significant correlation between the three measures of hypotension. Sixty percent of the patients received vasopressors. There was a significant correlation between a drop of mean arterial pressure to less than 60 mmHg and the use of the ephedrine. We did not find any changes on neuromonitoring measures during the case and there were no intraoperative or one-month postoperative complications. CONCLUSIONS: Blood pressure is only one of the measures anesthesiologists look to for good perfusion during surgery. Pediatric anesthesiologists and orthopedics agree in trying tight blood pressure control during surgery to decrease blood loss, but what the exact definition of that blood pressure number is, is still unclear. We propose that using mean arterial pressure less than 60 mmHg is perhaps a better definition. We provide recommendations for future studies.

Right Ventricular Dominance Is Associated With Inferior Outcomes After the Extracardiac Fontan.

BACKGROUND: Investigations of ventricular dominance and outcomes after the Fontan procedure have shown conflicting results. This may be due to the inclusion of multiple modifications of the Fontan or the omission of recently identified complications of the procedure. We examined the association between right ventricular dominance (RVD) and morbidity/mortality in a contemporary cohort following the extracardiac (EC) Fontan. METHODS: We studied all pediatric patients at our center who underwent a predominantly fenestrated EC Fontan from 2004 to 2016. Outcomes assessed were freedom from (1) Fontan failure (death, takedown, listing for transplantation) and (2) complication (arrhythmia requiring medication, postoperative pacemaker, or implantable cardioverter defibrillator requirement, stroke, thrombosis in the Fontan circuit, protein losing enteropathy, plastic bronchitis, New York Heart Association class >2). We defined the perioperative period as occurring before hospital discharge or within 30 days of the Fontan. RESULTS: A total of 137 patients (median age: 34 months, 62% male, 60% RVD) underwent the EC Fontan. Median duration of follow-up was 5.8 years (interquartile range: 2.4-9.0). Freedom from any event was 82.5% (RVD = 77%, LVD = 91%, χ2(1) = 5.03, P = .025) and RVD was associated with reduced event-free survival (hazard ratio: 2.94, P = .02). No confounders were identified. In the perioperative period, RVD was associated with reduced complication-free survival (P = .004). After this period, RVD was associated with reduced failure-free survival (P = .003). CONCLUSIONS: In this contemporary, single-center cohort of EC Fontan patients, RVD was associated with inferior outcomes.

National Practice Patterns and Early Outcomes of Aortic Valve Replacement in Children and Teens.

BACKGROUND: Several options exist for aortic valve replacement (AVR) in children and teens, but contemporary practice patterns and outcome data are lacking. We describe national AVR practice patterns and early outcomes. METHODS: Children (aged 1 to 18 years) in The Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing AVR from 2000 to 2016 were included. Preoperative characteristics, operative data, and outcomes were described. To evaluate practice patterns, centers were assigned tertiles by aortic valve surgical volume. Statistical comparisons included Mann-Whitney U statistic, Kruskal-Wallis, χ2 test, and gamma testing. RESULTS: In total, 3446 operations (46% children aged 1 to 12 years; 54% teens aged 12 to 18 years) were included. Preoperative risk factors were present in 23%, and 46% had a prior sternotomy. Valve utilization included autograft (64% child, 37% teen), mechanical (19% child, 35% teen), bioprosthetic (8% child, 20% teen), and homograft (9% child, 7% teen). Autografts were utilized more often for teenage girls than for teenage boys (odds ratio 1.3, 95% confidence interval: 1.05 to 1.66, P < .05). Overall, inpatient mortality and major complications affected 1% and 10%, respectively, and these rates were highest for homografts (5%, P < .001, and 13%, P < .05). Autograft utilization varied widely across centers (10th to 90th percentile: 21% to 71% of total AVR volume). More autografts were utilized at high-volume centers vs low- or medium-volume centers (53% ± 2.3% vs 46% ± 2.6%, P < .001). CONCLUSIONS: Practice patterns for AVR in children and teens vary across centers, age groups, and sexes. Although early outcomes were similar across valve types, homografts had higher morbidity and mortality. Valve choice was related to aortic valve surgical volume. Further efforts are needed to understand and optimize AVR practice patterns and long-term outcomes.

Preclinical performance of a pediatric mechanical circulatory support device: The PediaFlow ventricular assist device.

OBJECTIVES: The PediaFlow (HeartWare International, Inc, Framingham, Mass) is a miniature, implantable, rotodynamic, fully magnetically levitated, continuous-flow pediatric ventricular assist device. The fourth-generation PediaFlow was evaluated in vitro and in vivo to characterize performance and biocompatibility. METHODS: Supported by 2 National Heart, Lung, and Blood Institute contract initiatives to address the limited options available for pediatric patients with congenital or acquired cardiac disease, the PediaFlow was developed with the intent to provide chronic cardiac support for infants as small as 3 kg. The University of Pittsburgh-led Consortium evaluated fourth-generation PediaFlow prototypes both in vitro and within a preclinical ovine model (n = 11). The latter experiments led to multiple redesigns of the inflow cannula and outflow graft, resulting in the implantable design represented in the most recent implants (n = 2). RESULTS: With more than a decade of extensive computational and experimental efforts spanning 4 device iterations, the AA battery-sized fourth-generation PediaFlow has an operating range of 0.5 to 1.5 L/min with minimal hemolysis in vitro and excellent hemocompatibility (eg, minimal hemolysis and platelet activation) in vivo. The pump and finalized accompanying implantable components demonstrated preclinical hemodynamics suitable for the intended pediatric application for up to 60 days. CONCLUSIONS: Designated a Humanitarian Use Device for "mechanical circulatory support in neonates, infants, and toddlers weighing up to 20 kg as a bridge to transplant, a bridge to other therapeutic intervention such as surgery, or as a bridge to recovery" by the Food and Drug Administration, these initial results document the biocompatibility and potential of the fourth-generation PediaFlow design to provide chronic pediatric cardiac support.

Predictors of Poor Outcomes in Pediatric Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides respiratory and hemodynamic support to pediatric patients in severe cardiac failure. We aim to identify risk factors associated with poorer outcomes in this population. METHODS: A retrospective chart review was conducted of pediatric patients requiring VA-ECMO support for cardiac indications at our institution from 2004 to 2015. Data were collected on demographics, indication, markers of cardiac output, ventricular assist device (VAD) insertion, heart transplantation, or left atrial (LA) decompression. Univariate Cox proportional hazards models were used to calculate hazard ratios (HRs) for variables associated with the composite primary outcome of transplant-free survival (TFS). RESULTS: Of the 68 reviewed patients, 65% were male, 84% were white, 38% had a prior surgery, 13% had a prior transplant, 10% had a prior ECMO support, and 87.5% required vasoactive support within six hours of cannulation. The ECMO indications included congenital heart disease repaired >30 days prior (12%), cardiomyopathy (41%), posttransplant rejection (7%), and cardiorespiratory failure (40%). The TFS was 54.5% at discharge and 47.7% at one year. Predictors of transplant and/or death include epinephrine use (hazard ratio [HR] = 2.269, P = .041), elevated lactate (HR = 1.081, P = 0005), and elevated creatinine (HR = 1.081, P = .005) within six hours prior to cannulation. Sixteen (23.6%) patients underwent LA decompression. Placement of VAD occurred in 16 (23.5%) patients, for which nonwhite race (HR = 2.94, P = .034) and prior ECMO (HR = 3.42, P = .053) were the only identified risk factors. CONCLUSIONS: Need for VA-ECMO for cardiac support carries high inpatient morbidity and mortality. Epinephrine use and elevated lactate and creatinine were associated with especially poor outcomes. Patients who survived to discharge had good short-term follow-up results.

Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass.

OBJECTIVES: To determine the relationship between the production of cell-free plasma hemoglobin and acute kidney injury in infants and children undergoing cardiopulmonary bypass for cardiac surgery. DESIGN: Prospective observational study. SETTING: Twelve-bed cardiac ICU in a university-affiliated children's hospital. PATIENTS: Children were prospectively enrolled during their preoperative outpatient appointment with the following criteria: greater than 1 month to less than 18 years old, procedures requiring cardiopulmonary bypass, no preexisting renal dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma and urine were collected at baseline (in a subset), the beginning and end of cardiopulmonary bypass, and 2 hours and 24 hours after cardiopulmonary bypass in 60 subjects. Levels of plasma hemoglobin increased during cardiopulmonary bypass and were associated (p < 0.01) with cardiopulmonary bypass duration (R = 0.22), depletion of haptoglobin at end and 24 hours after cardiopulmonary bypass (R = 0.12 and 0.15, respectively), lactate dehydrogenase levels at end cardiopulmonary bypass (R = 0.27), and change in creatinine (R = 0.12). Forty-three percent of patients developed acute kidney injury. There was an association between plasma hemoglobin level and change in creatinine that varied by age (overall [R = 0.12; p < 0.01]; in age > 2 yr [R = 0.22; p < 0.01]; and in < 2 yr [R = 0.03; p = 0.42]). Change in plasma hemoglobin and male gender were found to be risk factors for acute kidney injury (odds ratio, 1.02 and 3.78, respectively; p < 0.05). CONCLUSIONS: Generation of plasma hemoglobin during cardiopulmonary bypass and male gender are associated with subsequent renal dysfunction in low-risk pediatric patients, especially in those older than 2 years. Further studies are needed to determine whether specific subgroups of pediatric patients undergoing cardiopulmonary bypass would benefit from potential treatments for hemolysis and plasma hemoglobin-associated renal dysfunction.

Dual chamber stent prevents organ malperfusion in a model of donation after cardiac death.

BACKGROUND: The paradigm for donation after cardiac death subjects donor organs to ischemic injury. A dual-chamber organ perfusion stent would maintain organ perfusion without affecting natural cardiac death. A center lumen allows uninterrupted cardiac blood flow, while an external chamber delivers oxygenated blood to the visceral vessels. METHODS: A prototype organ perfusion stent was constructed from commercial stents. In a porcine model, the organ perfusion stent was deployed, followed by a simulated agonal period. Oxygenated blood perfused the external stent chamber. Organ perfusion was compared between controls (n = 3) and organ perfusion stent (n = 6). Finally, a custom, nitinol, dual chamber organ perfusion stent was fabricated using a retrievable "petal and stem" design. RESULTS: Endovascular organ perfusion stent deployment achieved visceral isolation without adverse impact on cardiac parameters. Visceral oxygen delivery was 4.8-fold greater compared with controls. During the agonal period, organs in organ perfusion stent-treated animals appeared well perfused in contrast with the malperfused controls. A custom nitinol and polyurethane organ perfusion stent was recaptured easily with simple sheath advancement. CONCLUSION: An organ perfusion stent maintained organ perfusion during the agonal phase in a porcine model of donation after cardiac death organ donation without adversely affecting cardiac function. Ultimately, the custom retrievable design of this study may help resolve the critical shortage of donor organs for transplant.

Surfactant Administration During Pediatric Extracorporeal Membrane Oxygenation.

Administering surfactant during pediatric extracorporeal membrane oxygenation (ECMO) may influence important clinical variables but has been insufficiently described. Ninety-six courses of ECMO from our center were retrospectively assessed, and 89 surfactant doses were identified during 37 ECMO courses. Surfactant administration was associated with a respiratory indication for ECMO and increased durations of ECMO and positive pressure ventilation. Hospital survival was 64.9% (24) in surfactant-treated ECMO courses and 72.9% (43) otherwise (p = 0.41). Dynamic compliance of the respiratory system (Cdyn; shown as least squares mean [standard error] in ml/cm H2O/kg by mixed-effects modeling) increased significantly from 0.34 (0.03) before surfactant to 0.40 (0.03) within 12 hours (p = 0.023) and to 0.45 (0.03) within 24 hours (p < 0.001) of surfactant administration. Other mechanical ventilator parameters, ECMO settings, and arterial blood gas results did not differ significantly after surfactant administration. Among surfactant recipients, significantly increased Cdyn was observed in the nonsurgical group (n = 20) but not in the cardiac surgery group (n = 17). In conclusion, respiratory system compliance is increased after surfactant administration and noncardiac surgical patients may preferentially benefit from this therapy. Surfactant administration was associated with longer durations of mechanical support, but not with unfavorable mortality.

In vivo PEG modification of vascular surfaces for targeted delivery.

OBJECTIVE: Thrombosis and restenosis remain problematic for many intravascular procedures. Previously, it has been demonstrated that modifying an injured vascular surface with a protein-reactive polymer could block undesirable platelet deposition. As an added benefit, it would be advantageous if one could target therapeutics to the injured site. This study investigates a site-specific delivery system to target microspheres to vascular surfaces modified with a reactive polyethylene glycol tagged with biotin. METHODS: Rabbit femoral arteries were injured with a 2F embolectomy catheter. Modification of the vascular surface was achieved using a channeled balloon catheter or small-diameter tube. Microspheres were injected intravenously through catheterization of the ear vein. Polymer modification on the injured surface and delivery of microspheres was quantified using epifluorescence microscopy at 0, 24, 48, and 72 hours. RESULTS: Polymer modification of the vascular surface could be achieved using a channeled drug delivery catheter or small-diameter tube with similar results. Maximum polymer coverage occurred at 0 hours and decreased to 85% maximal at 24 hours, 72% at 48 hours, and 67% at 72 hours. The initial number of microspheres per mm(2) binding to modified, injured arteries was 304 versus 141 for the unmodified, damaged control (P < .01). At subsequent times, the number of adherent microspheres to modified, injured arteries decreased by 50%, 70%, and 84% at 24, 48, and 72 hours, respectively; while nonspecific binding to unmodified, injured arteries quickly decreased by 93%. Initial microsphere binding to modified, healthy arteries was 153 microspheres/mm(2) as opposed to 26 microspheres/mm(2) for the unmodified, healthy controls (P < .01). CONCLUSIONS: Chemical modification of injured vessels following intravascular procedures can be readily accomplished in vivo to create a substrate for targeted delivery systems. As a proof of concept, targeted microspheres preferentially adhered to polymer-modified surfaces as opposed to injured, unmodified, or healthy vascular surfaces.

Platelet activation after implantation of the Levitronix PediVAS in the ovine model.

The Levitronix PediVAS is an extracorporeal magnetically levitated pediatric ventricular assist system with an optimal flow rate range of 0.3-1.5 L/min. The system is being tested in preclinical studies to assess hemodynamic performance and biocompatibility. The PediVAS was implanted in nine ovines for 30 days using either commercially available cannulae (n = 3) or customized Levitronix cannulae (n = 6). Blood biocompatibility in terms of circulating activated platelets was measured by flow cytometric assays to detect P-selectin. Platelet activation was further examined after exogenous agonist stimulation. Platelet activation increased after surgery and eventually returned to baseline in animal studies where minimal kidney infarcts were observed. Platelet activation remained elevated for the duration of the study in animals where a moderate number of kidney infarcts with or without thrombotic deposition in the cannulae were observed. When platelet activation did return to baseline, platelets appropriately responded to agonist stimulation, signifying conserved platelet function after PediVAS implant. Platelet activation returned to baseline in the majority of studies, representing a promising biocompatibility result for the Levitronix PediVAS.

Platelet activation in ovines undergoing sham surgery or implant of the second generation PediaFlow pediatric ventricular assist device.

The PediaFlow pediatric ventricular assist device (VAD) is a magnetically levitated turbodynamic pump under development for circulatory support of small children with a targeted flow rate range of 0.3-1.5 L/min. As the design of this device is refined, ensuring high levels of blood biocompatibility is essential. In this study, we characterized platelet activation during the implantation and operation of a second generation prototype of the PediaFlow VAD (PF2) and also performed a series of surgical sham studies to examine purely surgical effects on platelet activation. In addition, a newly available monoclonal antibody was characterized and shown to be capable of quantifying ovine platelet activation. The PF2 was implanted in three chronic ovine experiments of 17, 30, and 70 days, while surgical sham procedures were performed in five ovines with 30-day monitoring. Blood biocompatibility in terms of circulating activated platelets was measured by flow cytometric assays with and without exogenous agonist stimulation. Platelet activation following sham surgery returned to baseline in approximately 2 weeks. Platelets in PF2-implanted ovines returned to baseline activation levels in all three animals and showed an ability to respond to agonist stimulation. Late-term platelet activation was observed in one animal corresponding with unexpected pump stoppages related to a manufacturing defect in the percutaneous cable. The results demonstrated encouraging platelet biocompatibility for the PF2 in that basal platelet activation was achieved early in the pump implant period. Furthermore, this first characterization of the effect of a major cardiothoracic procedure on temporal ovine platelet activation provides comparative data for future cardiovascular device evaluation in the ovine model.

Mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation.

Mesenchymal stem cell (MSC) therapy has demonstrated applications in vascular regenerative medicine. Although blood vessels exist in a mechanically dynamic environment, there has been no rigorous, systematic analysis of mechanical stimulation on stem cell differentiation. We hypothesize that mechanical stimuli, relevant to the vasculature, can differentiate MSCs toward smooth muscle (SMCs) and endothelial cells (ECs). This was tested using a unique experimental platform to differentially apply various mechanical stimuli in parallel. Three forces, cyclic stretch, cyclic pressure, and laminar shear stress, were applied independently to mimic several vascular physiologic conditions. Experiments were conducted using subconfluent MSCs for 5 days and demonstrated significant effects on morphology and proliferation depending upon the type, magnitude, frequency, and duration of applied stimulation. We have defined thresholds of cyclic stretch that potentiate SMC protein expression, but did not find EC protein expression under any condition tested. However, a second set of experiments performed at confluence and aimed to elicit the temporal gene expression response of a select magnitude of each stimulus revealed that EC gene expression can be increased with cyclic pressure and shear stress in a cell-contact-dependent manner. Further, these MSCs also appear to express genes from multiple lineages simultaneously which may warrant further investigation into post-transcriptional mechanisms for controlling protein expression. To our knowledge, this is the first systematic examination of the effects of mechanical stimulation on MSCs and has implications for the understanding of stem cell biology, as well as potential bioreactor designs for tissue engineering and cell therapy applications.