Mark A. Law

Efficient, long-term hepatic gene transfer using clinically relevant HDAd doses by balloon occlusion catheter delivery in nonhuman primates.

Helper-dependent adenoviral vectors (HDAd) are devoid of all viral coding sequences and are thus an improvement over early generation Ad because they can provide long-term transgene expression in vivo without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic intravenous injection, and this unfortunately results in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver HDAd into the liver of nonhuman primates. Briefly, a balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. HDAd was injected directly into the occluded liver via a percutaneously placed hepatic artery catheter. Compared to systemic vector injection, this approach resulted in substantially higher hepatic transduction efficiency using clinically relevant low vector doses and was accompanied by mild-to-moderate acute but transient toxicities. Transgene expression was sustained for up to 964 days. These results suggest that our minimally invasive method of delivery can significantly improve the vectors therapeutic index and may be a first step toward clinical application of HDAd for liver-directed gene therapy.

Pulmonary artery stents: Long-term follow-up†

Objectives: Determine the long‐term outcomes of branch pulmonary artery (PA) stents. Background: PA stents in congenital heart disease effectively relieve stenoses in the short‐term. Published long‐term data are limited. Methods: Patients enrolled in an FDA IDE protocol from 1989–92 were included. Clinical follow‐up and catheterization data were evaluated. Patients were included if >5 year follow‐up data was available or if mortality occurred following the initial procedure. Results: There were five deaths: four due to progression of their underlying heart disease, and one from a complication during a follow‐up catheterization. Clinical data for 43 surviving patients demonstrated 39 patients (91%) are in NYHA class I or II. Seven patients underwent surgical intervention during the follow‐up period (five RV‐PA conduit, two Fontan revisions), but none addressed PA stenosis. Final repeat catheterizations were performed in 36 patients (55 stents) 7.2 ± 4.3 years post stent insertion with 1.2 ± 0.9 further procedures with stent dilations. In this subgroup, the minimum vessel diameter increased from 4.7 ± 1.8 to 13.4 ± 2.4 mm (P < 0.001), and the pressure gradient improved from 41 ± 25 to 9 ± 11 mm Hg (P < 0.001). Higher initial gradient and smaller balloons were associated with a final stent diameter of <14 mm (P = 0.030 and 0.046). Jailed vessels occurred in 49% of stents with abnormal angiographic flow in 18/55. Six repeat catheterizations resulted in complications, including the one procedural death. Conclusion: Stents implants for PA stenoses provide effective improvement in vessel caliber in the long‐term. Although repeat interventions are necessary, this procedure reduces RV pressure and provides an important alternative to surgery for residual PA obstruction.

Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors

Helper-dependent adenoviral vectors (HDAd) have been shown to mediate a considerably longer duration of transgene expression than first-generation adenoviral vectors. We have previously shown that transgene expression from HDAd-transduced hepatocytes can persist at high levels for up to 2.6 years in nonhuman primates following a single-vector administration. Because duration of transgene expression and long-term toxicity are critical for risk:benefit assessment, we have continued to monitor these animals. We report here that transgene expression has persisted for the entire observation period of up to 7 years for all animals without long-term adverse effects. However, in all cases, transgene expression level slowly declined over time to less than 10% of peak values by the end of the observation period but remained 2.3-111-fold above baseline values. These results will provide important information for a more informed risk:benefit assessment before clinical application of HDAd.

Stent fractures in congenital heart disease

To describe incidence, characteristics, predictive factors, and sequelae of stent fractures in congenital heart disease.

Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery.

Objective: To describe our experience with low-dose arginine vasopressin infusions (0.0003 U/kg/min) initiated in the operating room after the Norwood procedure or arterial switch operation. Design: Retrospective cohort study of 37 consecutive neonates. Setting: Pediatric cardiovascular intensive care unit in a tertiary hospital. Subjects: Nineteen patients that received low-dose arginine vasopressin infusion instituted in the operating room (arginine vasopressin+) were compared to 18 patients that did not receive early arginine vasopressin infusion (arginine vasopressin–). Interventions: None. Results: When comparing arginine vasopressin+ and arginine vasopressin− in the first 24 hrs after cardiovascular intensive care unit admission, there was no difference in demographic variables, heart rate, blood pressure, central venous pressure, maximum lactate, maximum arterial and central venous saturation difference, urine output, chest tube output, or peritoneal drain output. Mean fluid resuscitation in the first 24 hrs was significantly lower in the arginine vasopressin+ group compared to the arginine vasopressin− group (182 ± 61 mL/kg vs. 223 ± 53 mL/kg, p = .03). The arginine vasopressin+ group also reached median net negative cumulative fluid balance sooner (55 hrs: interquartile range 45, 74 vs. 76 hrs: interquartile range 69, 92; p = .02). Median maximum inotrope score in the first 24 hrs was significantly lower in arginine vasopressin+ (9: interquartile range 5, 12.5 vs. 16.5: interquartile range 10.3, 22.1; p = .02). There was a nonsignificant trend toward shorter duration of mechanical ventilation and cardiovascular intensive care unit length of stay in the arginine vasopressin+ group. The lowest serum sodium in the first 48 hrs was significantly lower in arginine vasopressin+ (132 vs. 137 mmol/L, p = .01). Conclusion: Low-dose arginine vasopressin infusion initiated in the operating room after complex neonatal cardiac surgery was associated with decreased fluid resuscitation and catecholamine requirements in the first 24 postoperative hours.

Ultrasound-guided femoral vein catheterization in neonates with cardiac disease*.

Objective: To describe a novel technique for real-time, ultrasound-guided femoral vein catheterization in neonates with cardiac disease, and to compare it to a contemporaneous cohort of neonates undergoing femoral vein central venous line placement via landmark technique. Design: Retrospective cohort study of data extracted from a quality improvement database. Setting: Pediatric cardiac intensive care unit and cardiovascular operating room in pediatric tertiary hospital. Patients: One hundred fifteen neonates (mean weight, 3.07 ± 0.41 kg) with cardiac disease who underwent femoral central venous line attempts from January 2009 to September 2011. Measurements and Main Results: Study populations were similar in age, weight, and Risk Adjustment for Congenital Heart Surgery-1 category, but differed in intubation status (32% vs. 100%, ultrasound vs. landmark, p < .0001). Central venous line success rate was superior in the ultrasound group: 72 of the 76 (94.7%) vs. 31 of the 39 (79.5%), p = .02. Ultrasound group also had a superior first (75% vs. 30.8 %) and second attempt success rate (90.8% vs. 51.3%), p value for both < .0001. Inadvertent arterial puncture occurred less frequently in the ultrasound group: four of the 76 (5.3%) vs. nine of the 39 (23.1%), p = .01. There was a trend toward more venous thrombosis in the landmark group, 16 of the 39 (41%) vs. 18 of the 76 (23.7%), p = .08. Among all 115 subjects, there was a very strong association between greater than two central venous line attempts and the odds of being diagnosed with a deep venous thrombosis (odds ratio, 9.3; 95% confidence interval 3.5–24.8) and the odds of suffering an inadvertent femoral arterial puncture during the central venous line event (odds ratio, 8.8; 95% confidence interval 10.6–730). Conclusions: This novel long-axis real-time ultrasound technique facilitates placement of femoral vein central venous line in critically ill neonates with cardiac disease at a higher rate of success with fewer attempts and lower occurrence of complications when compared with the landmark technique.

Successful continuous renal replacement therapy using two single-lumen catheters in neonates and infants with cardiac disease

BackgroundAcute kidney injury (AKI) frequently occurs in neonates and infants after cardiopulmonary bypass (CPB) and may require renal replacement therapy (RRT). Peritoneal dialysis (PD) is the RRT modality of choice in neonates with AKI after CPB, but continuous renal replacement therapy (CRRT) may be necessary if PD is ineffective or contraindicated. Vascular access is challenging in this population, in part, due to small central vein size that may preclude placement. The risk of malfunction or morbidity associated with standard dialysis catheters may be excessive in neonates with congenital heart disease. We describe a unique approach to vascular access for CRRT in six small patients with AKI.Case-Diagnosis/TreatmentThis is a retrospective review of six patients with fluid overload and AKI that received CRRT because PD was contraindicated. In all cases, CRRT was performed via two hemostasis valve sheaths placed into separate veins for dialysis access and return. The low-resistance sheaths provided excellent blood flow with normalization of metabolic derangements and significant fluid removal (median negative 167xa0ml/kg at 72xa0h). Mean circuit life before the first change was 55.2u2009±u200930.4xa0h.ConclusionsThe use of two small single-lumen catheters in separate veins enables consistent and effective hemodiafiltration in neonates and infants with challenging vascular access.

Transcatheter Pulmonary Valve Implantation: A Comprehensive Systematic Review and Meta‐Analyses of Observational Studies

Background Transcatheter pulmonary valve implantation is approved for the treatment of dysfunctional right ventricle to pulmonary artery conduits. However, the literature is limited because of a small patient population, and it does not reflect changing procedural practice patterns over the last decade. Methods and Results A comprehensive search of Medline and Scopus databases from inception through August 31, 2016 was conducted using predefined criteria. We included studies reporting transcatheter pulmonary valve implantation in at least 5 patients with a follow‐up duration of 6 months or more. In 19 eligible studies, 1044 patients underwent transcatheter pulmonary valve implantation with a pooled follow‐up of 2271 person‐years. Procedural success rate was 96.2% (95% confidence intervals [CI], 94.6–97.4) with a conduit rupture rate of 4.1% (95% CI, 2.5–6.8) and coronary complication rate of 1.3% (95% CI, 0.7–2.3). Incidence of reintervention was 4.4 per 100 person‐years overall (95% CI, 3.0–5.9) with a marked reduction in studies reporting ≥75% prestenting (2.9 per 100 person‐years [95% CI, 1.5–4.3] versus 6.5/100 person‐years [95% CI, 4.6–8.5]; P<0.01). Pooled endocarditis rate was 1.4 per 100 person‐years (95% CI, 0.9–2.0). Conclusions Our study provides favorable updated estimates of procedural and follow‐up outcomes after transcatheter pulmonary valve implantation. Widespread adoption of prestenting has improved longer‐term outcomes in these patients.

The outcome of pulmonary artery stents following surgical manipulation

Background: Pulmonary artery (PA) stents are utilized to treat branch pulmonary stenosis (BPS). Often patients with PA stents undergo subsequent cardiac surgery for other indications, and the stents can be manipulated during the procedure. Objective: The purpose of this study was to evaluate the outcome of branch PA stenoses following surgical manipulation of previously implanted PA stents and to determine factors associated with future reintervention. Methods: Catheterization data, operative reports, and clinical summaries were reviewed on patients with PA stents placed between September 1989 and December 2006 undergoing subsequent cardiac surgery. Surgical manipulation was recorded as removed, trimmed, or longitudinally transected, and patched. Those that were not manipulated were defined as untouched. Results: 459 patients had branch PA stents placed. About 54 patients, with 70 stents in branch PAs. subsequently had further cardiac surgery. The median age of stent placement was 7.5 (0.5–32.4) years with a median age of surgery of 12.7 (5.1–39.6) years. Surgical manipulation was performed in 23 (33%) PAs and 47 (66%) stents were untouched. Stent removal occurred in 11 (16%), with transecting longitudinally and patching in 5 (7%), and trimming in 7 (10%). Comparing the surgical manipulation and the untouched groups, there was no difference in median age of stent placement [7.2 (0.5–30.2) versus 7.6 (1.8–32.4) years, p = 0.40], wt [21.0 (5.3–86.5) versus 24.7 (9.0–96.0) kg, p = 0.42], or residual catheterization gradient across the stent [3 (0–59) versus 4 (0–50) mmHg, p = 0.81]. Catheter reintervention (stent n = 6 or balloon dilation n = 14) on the previously stented PAs was similar between the surgically manipulated (median 7.5 years) and untouched groups (median 11.5 years) (p = 0.31). In multivariate analysis, the factors associated with future catheter reintervention were having the stent transected longitudinally and patched (p = 0.003) and a lower weight (p = 0.006) at the time of stent placement. Conclusions: Surgical stent manipulation is often performed in patients who have PA stents. Surgical manipulation does not alter the need for future reintervention and catheter re‐intervention may be more likely when the stents are transected longitudinally and patched.

Balloon Angioplasty for the Treatment of Left Innominate Vein Obstruction Related Chylothorax after Congenital Heart Surgery

OBJECTIVEnChylothorax complicates the postoperative course of patients after congenital heart surgery. Innominate vein thrombosis and stenosis have been associated with postoperative chylothorax. Revascularization and angioplasty can be accomplished using transcatheter techniques. We report our experience with this procedure for the management of postoperative chylothorax.nnnDESIGNnThis is a retrospective case series of patients who underwent catheter revascularization and/or angioplasty of the innominate vein following cardiac surgery at our institution from January 1, 2008 through April 9, 2014.nnnSETTINGnThe cardiovascular intensive care unit and cardiac catheterization laboratory at the University of Alabama at Birmingham and Benjamin Russell Hospital for Children in Birmingham, Alabama were used as settings for the study.nnnPATIENTSnOut of 112 patients with postoperative chylothorax, 7 (6.3%) underwent transcatheter dilation of the innominate vein for occlusion/stenosis. The median age of the cohort was 1 month (15 days-6 years); median weight was 3u2009kg (2.7-22.2). Diagnosis was made a median 8 days (2-20) and persisted for a median of 24 days (9-44). Most patients failed medical management (low fat diet, nothing by mouth, and/or octreotide).nnnRESULTSnCardiac catheterization occurred at a median 9 days (2-29) after chylothorax diagnosis. Median chest tube output on the day prior to procedure was 63 (12-149) cc/kg/day and decreased to 23 (0-64) cc/kg/day 2 days postprocedure (P = .01). Effusions resolved in a median of 5 days (1-16). There were no clinical complications postcatheterization. All patients who have undergone repeat angiography have maintained patency of the innominate vein. There was no mortality. Complications from chylothorax included prolong hospitalization, hyponatremia, hypoproteinemia, coagulopathy, lymphopenia, and infection.nnnCONCLUSIONSnInnominate vein occlusion and stenosis associated with chylous effusion are amenable to transcatheter revascularization and/or angioplasty, consistently leading to improvement, if not full resolution of chylothorax.