Jennifer Rutledge

Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues

Many of the applications of liposomes drug-delivery systems have been limited by their short circulation half-lives as a result of rapid uptake into the reticuloendothelial (mononuclear phagocyte) system. We have recently described liposomes formulations with long circulation half-lives in mice (Allen, T.M. and Chonn, A. (1987) FEBS Lett. 223, 42-46). A study of the principal factors important to the attainment of liposomes with prolonged circulation half-lives is presented in this manuscript. Liposomes with the longest circulation half-lives, in mice, had compositions which mimicked the outer leaflet of red blood cell membranes (egg phosphatidylcholine/sphingomyelin/cholesterol/ganglioside GM1, molar ratio 1:1:1:0.14). Several other gangliosides and glycolipids were examined, but none could substitute for GM1 in their ability to prolong circulation half-lives. However, other negatively charged lipids with bulky headgroups, i.e., sulfatides and phosphatidylinositol, had some effect in prolonging circulation half-lives, but GM1 was clearly superior in this regard. Bilayer rigidity, imparted by sphingomyelin or other high-phase-transition lipids, acted synergistically with the negatively charged components, especially GM1, in extending circulation times. Circulation half-lives of liposomes increased with decreasing size, but even larger (0.2-0.4 microns) liposomes of the optimum formulations had significantly prolonged half-lives in circulation. Uptake of liposomes into tissues other than liver and spleen increased with increasing circulation times of the liposomes for i.v. and for i.p. injections. Liposomes appeared to move from the circulation into the carcass between 6 and 24 h post-injection. Our ability to achieve significant prolongation in circulation times of liposomes makes possible a number of therapeutic applications of liposomes which, until now, have not been achievable.

An Increased Incidence of Conduit Endocarditis in Patients Receiving Bovine Jugular Vein Grafts Compared to Cryopreserved Homograft for Right Ventricular Outflow Reconstruction

BACKGROUND We compared the outcome of patients receiving bovine jugular vein grafts versus cryopreserved homografts for right ventricular outflow tract reconstruction. METHODS Between 2000 and 2012, 379 conduits (244 bovine jugular vein grafts, 135 homografts) were implanted in 298 patients (median age 50 months) with a median follow-up of 3.4 years. RESULTS Freedom from reoperation at 1, 5, and 7 years was 96.3%, 79.3%, and 64.2% after bovine jugular vein graft and 94.6%, 75.7%, and 68.6% after homograft insertion (p = 0.086). There were 24 cases of endocarditis, 23 associated with bovine jugular vein grafts (9.4%) and 1 associated with a homograft (0.7%; p < 0.001) at median follow-up of 44 months (range, 15 days to 10 years) after conduit implantation. After endocarditis, 15 of 24 conduits were replaced. Three patients had recurrent endocarditis in the revised conduit. Multivariate logistic regression analysis showed age less than 3 years and endocarditis to be significant risk factors associated with conduit replacement. Age more than 3 years and bovine jugular vein grafts were significant risk factors for graft endocarditis. Patients more than 3 years of age at bovine jugular vein graft implantation had significantly lower freedom from reoperation (p = 0.01). CONCLUSIONS Compared with homograft conduits, the use of bovine jugular vein grafts for right ventricular outflow tract reconstruction was associated with a significantly higher incidence of bacterial endocarditis and conduit deterioration in older children at our institution. That may influence decision making regarding conduit choice for right ventricular outflow tract reconstruction. Patients and practitioners should be aware of the late risks of bacterial endocarditis after bovine jugular vein graft implantation.

Antithrombotic strategies in children receiving long-term Berlin Heart EXCOR ventricular assist device therapy

BACKGROUND Thromboembolic events while receiving ventricular assist device (VAD) support remain a significant cause of morbidity and mortality despite standard anti-coagulation and anti-platelet therapies. The use of bivalirudin and epoprostenol infusions as an alternate anti-thrombotic (AT) regimen in pediatric VAD patients was reviewed. METHODS This was a retrospective record review of 6 pediatric patients (aged ≤17 years) at 2 institutions treated with bivalirudin and epoprostenol infusions while being supported with the Berlin Heart EXCOR (Berlin Heart GmbH, Berlin, Germany) VAD. RESULTS Six patients (age, 0.8-14 years; weight, 6.7-29.7 kg) were treated. Diagnoses included cardiomyopathy in 2 and congenital heart disease in 4. VAD support was left VAD in 2 and bi-VAD in 4, with duration of support of 21 to 155 days. Three patients required extracorporeal membrane oxygenation before VAD support. Bivalirudin/epoprostenol was used after recurrent thromboses on conventional medication in 3 patients, heparin-induced thrombocytopenia in 2, and in 1 patient considered high risk with a prosthetic mitral valve. The bivalirudin dose was titrated to partial thromboplastin time (PTT) of 1.5- to 2-times baseline (0.1-0.8 mg/kg/hour); the epoprostenol dose was 2 to 10 ng/kg/min. Additional anti-platelet agents included acetylsalicylic acid, dipyridamole, and clopidogrel in 5 patients each. No bleeding complications occurred. One patient sustained a cerebrovascular infarct on therapy, with subsequent complete recovery. No other complications occurred. Five patients underwent successful transplantation, and 1 patient died of multisystem organ failure. CONCLUSIONS This report provides data on estimated safety and efficacy of bivalirudin and epoprostenol as an AT strategy in pediatric patients on extended VAD support. The short drug half-life and predictable AT response facilitated conversion to standard AT regimens at the time of transplantation (heparin-induced thrombocytopenia-negative patients). These agents should be considered for management of pediatric VAD patients when standard regimens fail.

Fast-track extubation after modified Fontan procedure

OBJECTIVE In 2007, we introduced a policy to plan to extubate all patients after a modified Fontan procedure in the operating room. Our objective was to review the feasibility, safety, and clinical outcomes of this approach. METHODS Patients who underwent a modified Fontan operation between May 2004 and May 2010 were reviewed. RESULTS Ninety-seven patients underwent a modified Fontan operation (mean age, 3.9 ± 2.2 years; mean weight, 15.1 ± 5.0 kg); 46 patients (47%) were extubated in the operating room (group A). Nineteen patients were extubated in the intensive care unit within 24 hours (group B), and 32 patients had delayed extubation (group C). The 3 groups were not significantly different with respect to preoperative characteristics. Twenty-four hours postoperatively, group A had a lower mean central venous pressure compared with patients in group B or C (13 vs 14 vs 17 mm Hg, respectively, P < .001); a higher base excess (0.4 vs -1.3 vs -3.4, P < .001); a lower fluid balance (234 vs 514 vs 730 mL, P < .001); and a lower inotrope score (4.6 vs 6.7 vs 10.8, P < .001). Group C had a longer median intensive care unit length of stay (2 vs 3 vs 6 nights, P = .01), kept their chest tubes longer (8 vs 9 vs 15 days, P = .001), and had a longer median hospital length of stay (9 vs 11 vs 21 days, P = .001). CONCLUSIONS Extubation in the operating room after a modified Fontan procedure seems feasible. This approach is associated with improved early postoperative hemodynamics, earlier time to chest tube removal, and shorter intensive care unit and hospital lengths of stay.

The profile of the systemic inflammatory response in children undergoing ventricular assist device support

OBJECTIVES Serum C-reactive protein (CRP) has been used as a systemic inflammatory response (SIR) marker in the critical ill, including children after cardiopulmonary bypass surgery. Ventricular assist devices (VAD) have been increasingly used as a bridge support to heart transplantation in children. We aimed to examine the profiles of CRP in children receiving VAD support. METHODS Charts of 13 children receiving Berlin Heart EXCOR(®) from 2005 to 2009 were reviewed. The data obtained prior to and during VAD support included: CRP, white blood cells, inotropes and steroid use, VAD mode and duration of VAD support. Ten patients received left VAD (LVAD) and 3 biventricular VAD (BiVAD). RESULTS The median duration of VAD support was 59 days (ranged 3-678 days). Pre-VAD CRP was 35 ± 51 mg/l and increased to 109 ± 59 mg/l on days 1-3 after the VAD implantation (P = 0.01), then gradually decreased to 28 ± 28 mg/l by 4 months and normalized by 5 months (P < 0.0001). CRP was higher in BiVAD than in LVAD patients throughout the study period (P = 0.003). CRP positively correlated with the doses of the epinephrine and norepinephrine and the monocyte counts, and negatively correlated with the lymphocyte count. The lymphocyte count was 2.5 ± 0.4 x 10(9)/l prior to implantation, and decreased to 2.1 ± 1.3 x 10(9)/l on days 1-3 (P = 0.5) and then to 0.6 ± 0.1 x 10(9)/l by 6 months (P = 0.08). It tended to be lower in BiVAD patients (P = 0.06). CONCLUSIONS SIR exists in children prior to VAD support. VAD implantation is associated with a significant and prolonged increase in CRP and a decrease in lymphocyte count, indicating a suppressed immune function, being more pronounced in BiVAD patients.

Spectral analysis of the heart sounds in children with and without pulmonary artery hypertension

BACKGROUND Pulmonary artery hypertension (PAH) is difficult to recognize clinically. Digital stethoscopes offer an opportunity to re-evaluate the diagnosis of PAH. We hypothesized that spectral analysis of heart sound frequencies using recordings from a digital stethoscope would differ between children with and without PAH. METHODS We recorded heart sounds using a digital stethoscope from 27 subjects (12 males) with a median age of 7 years (3 months to 19 years) undergoing simultaneous cardiac catheterization. 13 subjects had a mean pulmonary artery pressure (mPAp)<25 mm Hg (8-24 mm Hg). 14 subjects had a mPAp≥25 mm Hg (25-97 mm Hg). We applied the fast Fourier transform, power spectral analysis, separability testing, and linear discriminant analysis with leave-one-out cross-validation to the heart sounds recorded from the cardiac apex and 2nd left intercostal space (LICS) to examine the frequency domain. The significance of the results was determined using a t-test and rank-sum test. RESULTS The relative power of the frequencies 21-22 Hz of the heart sounds recorded at the 2nd LICS was decreased significantly in subjects mPAp≥25 mm Hg versus<25 mm Hg. CONCLUSIONS Heart sound signals of patients with PAH contain significantly less relative power in the band 21-22 Hz compared to subjects with normal PAp. Information contained in the frequency domain may be useful in diagnosing PAH and aid the development of auscultation based techniques for diagnosing PAH. In the future, utilizing the diagnostic information contained in heart sounds recordings may require analysis of both the time and frequency domains.

Percutaneous coronary intervention for extrinsic coronary compression after pulmonary valve replacement

Coronary artery compression is a rare and potentially fatal complication after pulmonary valve replacement. This report describes myocardial infarction from extrinsic left main coronary artery compression after pulmonary valve replacement in a 10‐y‐old boy. He was successfully treated with percutaneous coronary intervention.

ABH‐glycan microarray characterizes ABO subtype antibodies: fine specificity of immune tolerance after ABO‐incompatible transplantation

Organ transplantation from ABO blood group–incompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century‐old assay used clinically, does not discriminate subtype‐specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO‐glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor‐specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO‐compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens—the only ABH antigen subtypes expressed in heart tissue—were absent, demonstrating the fine specificity of B cell tolerance to donor/graft blood group antigens. In contrast to the hemagglutination assay, the ABO‐glycan microarray allows detailed characterization of donor‐specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection.

Occlusion of a large expanding saphenous vein bypass graft aneurysm with percutaneously injected ethylene-vinyl alcohol copolymer.

A 63-year-old man with prior coronary artery bypass graft surgery (9 years prior) was incidentally diagnosed with a saphenous vein graft (SVG) aneurysm during investigation of an abdominal aortic aneurysm. Computed tomographic scan demonstrated expansion of the SVG aneurysm from 2.3 to 4.5 cm

Detection of Heart Sounds in Children with and without Pulmonary Arterial Hypertension―Daubechies Wavelets Approach

Background Automatic detection of the 1st (S1) and 2nd (S2) heart sounds is difficult, and existing algorithms are imprecise. We sought to develop a wavelet-based algorithm for the detection of S1 and S2 in children with and without pulmonary arterial hypertension (PAH). Method Heart sounds were recorded at the second left intercostal space and the cardiac apex with a digital stethoscope simultaneously with pulmonary arterial pressure (PAP). We developed a Daubechies wavelet algorithm for the automatic detection of S1 and S2 using the wavelet coefficient ‘D 6’ based on power spectral analysis. We compared our algorithm with four other Daubechies wavelet-based algorithms published by Liang, Kumar, Wang, and Zhong. We annotated S1 and S2 from an audiovisual examination of the phonocardiographic tracing by two trained cardiologists and the observation that in all subjects systole was shorter than diastole. Results We studied 22 subjects (9 males and 13 females, median age 6 years, range 0.25–19). Eleven subjects had a mean PAP < 25 mmHg. Eleven subjects had PAH with a mean PAP ≥ 25 mmHg. All subjects had a pulmonary artery wedge pressure ≤ 15 mmHg. The sensitivity (SE) and positive predictivity (+P) of our algorithm were 70% and 68%, respectively. In comparison, the SE and +P of Liang were 59% and 42%, Kumar 19% and 12%, Wang 50% and 45%, and Zhong 43% and 53%, respectively. Our algorithm demonstrated robustness and outperformed the other methods up to a signal-to-noise ratio (SNR) of 10 dB. For all algorithms, detection errors arose from low-amplitude peaks, fast heart rates, low signal-to-noise ratio, and fixed thresholds. Conclusion Our algorithm for the detection of S1 and S2 improves the performance of existing Daubechies-based algorithms and justifies the use of the wavelet coefficient ‘D 6’ through power spectral analysis. Also, the robustness despite ambient noise may improve real world clinical performance.