Robin Kaye

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 × 1012 vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of ∼8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression*.

Validation of the Bispectral Index Monitor for Measuring the Depth of Sedation in Children

The Bispectral Index (BIS) is an empirically calibrated number derived from adult electroencephalograph data that correlates with the depth of sedation in adults. We tested the hypothesis that the BIS score is a valid measure of the depth of pediatric sedation in a study designed to avoid limitations of a previously published report. BIS values from 96 healthy ASA physical status I–II children aged 1–12 yr undergoing sedation were continually recorded and electronically transferred to a computer. Two independent observers blinded as to BIS score evaluated sedation using the Observer’s Assessment of Alertness/Sedation (OAA/S) and the University of Michigan Sedation Scale (UMSS) at 3–5 min intervals. There was a significant correlation between BIS and UMSS and between BIS and OAA/S by both the Spearman’s rank correlation test and by prediction probability (P < 0.001). In children <6 yr, there was a significant correlation between BIS and the clinical sedation scores for subgroups undergoing invasive and noninvasive procedures (P < 0.001). There was also good agreement between the 2 independent observers who assessed clinical sedation scores (kappa = 0.51, P < 0.001). We conclude that the BIS monitor is a quantitative, nondisruptive and easy to use depth of sedation monitor in children.

Evaluation of ultrasound-guided radial artery cannulation in children

Objective: To compare ultrasound (US)-guided radial artery cannulation with the traditional palpation technique. Design: Prospective randomized study. Setting: Operating room in a tertiary care pediatric center. Patients: One hundred fifty-two children under 18 yrs of age requiring radial artery cannulation. Interventions: Patients were randomized to either 1) palpation or 2) US guidance technique for radial artery cannulation. Measurements and Main Results: The primary end point of the study was the time taken for attempted cannulation by the first operator at the first site. Secondary end points included the number of attempts at arterial cannulation, the number of cannulae used, and the need for additional assistance from another anesthesiologist. Eighty and 72 children were randomized to the palpation and the US-guided groups, respectively. There were no statistically significant differences in age, gender, weight, and systolic blood pressure between the two study groups. The designated first operator (20 pediatric subspecialty trainees and eight consultant anesthesiologists) had previous experience in US-guided arterial cannulation in <10 cases, with 94% having experience in <5 cases. Although the radial artery was eventually cannulated in all patients, the designated operator was successful at the first site of cannulation in only 66% and 69% in the palpation and US groups, respectively. There were no statistically significant differences between the groups in time to successful cannulation, total number of attempts, number of successful cannulations during the first attempt, or in the number of cannulae used for catheterization. Conclusions: US guidance did not facilitate faster cannulation of the radial artery in children in our study.

CT-Guided Percutaneous Steroid Injection for Management of Inflammatory Arthropathy of the Temporomandibular Joint in Children

OBJECTIVE The purposes of this study were to retrospectively review an injection technique, to develop a grading system for evaluation of imaging findings, and to report preliminary outcome related to percutaneous CT-guided steroid injection into the temporomandibular joints of children with inflammatory arthropathy. CONCLUSION CT-guided steroid injection into the temporomandibular joint of children with inflammatory arthropathy results in clinical and imaging improvement in a substantial proportion of children treated.

CT-guided percutaneous lung biopsy in children

PURPOSE To describe techniques and evaluate outcomes of computed tomography (CT)-guided percutaneous lung biopsy in children. MATERIALS AND METHODS Between April 1992 and June 2003, 64 patients (32 male, 32 female) with a mean age of 10.8 years (0.6-20 years) were referred for 75 lung biopsies. Most biopsies were performed for suspected malignancy (n = 24; 32%) or to distinguish posttransplantation lymphoproliferative disorder from fungal infection in immunocompromised patients (n = 17; 23%). All children referred to the pediatric interventionalists in two childrens hospitals for CT-guided biopsy of parenchymal or pleural-based lesions in the thorax were studied. Prospectively gathered procedural data were reviewed for medical history and indications for procedure, admission status, type of anesthesia, technical approach (core vs aspiration biopsy), procedural modifications, lesion size, number of passes required, and immediate complications. Medical records were retrospectively reviewed for diagnostic outcome, impact on patient management, and delayed complications. RESULTS Procedures were performed under deep sedation whenever possible (n = 61; 81%) with use of a coaxial core biopsy technique (n = 56; 75%), a fine needle aspiration biopsy technique (n = 15; 20%), or both (n = 4; 5%). Mean lesion diameters were 2.5 cm (range, 1-10 cm) in the core biopsy group and 1.0 cm (range, 0.5-1.7 cm) in the aspiration biopsy group. Sixty-four biopsies (85%) were diagnostic. There was one major complication (1.3%), a tension pneumothorax treated with intraprocedural placement of a chest tube. CONCLUSION Percutaneous CT-guided lung biopsy is a safe and accurate diagnostic procedure in children that obviates open surgical biopsy in most patients.

Percutaneous gastrostomy tube placement in patients with ventriculoperitoneal shunts

Objective. The purpose of this study is to determine the risk of CNS and/or peritoneal infection in children with ventriculoperitoneal shunts in whom a percutaneous gastrostomy tube is placed. Materials and methods. We placed 205 gastrostomy or gastrojejunostomy tubes from January of 1991 to December 1996. Twenty-three patients (10 boys, 13 girls) had ventriculoperitoneal shunts at the time of placement. All shunts were placed at least 1 month prior to placement of the gastrostomy tube. The patients ranged in age from 8 months to 16 years with a mean age of 6 years, 9 months. Patient weight ranged from 2 kg to 60 kg. All 23 children required long-term nutritional support due to severe neurologic impairment. No prophylactic antibiotics were given prior to the procedure. Of the patients, 21/23 had a 14-F Sacks-Vine gastrostomy tube with a fixed terminal retention device inserted, using percutaneous fluoroscopic antegrade technique. Two of the 23 patients had a Ross 14-F Flexi-flo gastrostomy tube which required a retrograde technique due to a small caliber esophagus in these children. Results. All 23 children had technically successful placements of percutaneous gastrostomy (7) or gastrojejunostomy (16) tubes. Of the children, 21/23 (91 %) had no complications from the procedure. Two of 23 (9 %) patients demonstrated signs of peritonitis after placement of their gastrostomy tubes and subsequently had shunt infections. In both, children CSF culture grew gram-positive cocci. The antegrade technique was used in both children who developed peritonitis. Conclusion. Our study indicates children with ventriculoperitoneal shunts who undergo percutaneous gastrostomy are at greater risk for infection and subsequent shunt malfunction. Therefore, we recommend prophylactic antibiotic therapy to cover for skin and oral flora.

Transhepatic insertion of vascular dialysis catheters in children : a safe, life-prolonging procedure

Introduction. Central venous catheters (CVC) have been inserted percutaneously since 1989. This technique has been adapted for transhepatic insertion of large-bore catheters in children with occluded central veins. Materials and methods. Three children aged 5, 11, and 12 years required hemodialysis or plasmaphoresis for treatment of life-threatening conditions. All central veins were occluded, thus transhepatic insertion of a large-bore catheter was necessary. All children underwent successful placement using a combination of ultrasound guidance and fluoroscopy. No complications occurred. Discussion. Transhepatic insertion of large-bore catheters can be performed safely in children. Catheter removal should be accompanied by track embolization to prevent exsanguinating hemorrhage. Conclusion. Transhepatic insertion of dialysis catheters is a safe alternative in children with occluded central veins.

May-Thurner syndrome (iliac vein compression) and thrombosis in adolescents.

May–Thurner syndrome refers to anatomic compression of the left iliofemoral vein by the overriding right iliac artery. We report three adolescents who presented to our pediatric hospital with iliac vein thrombosis and were diagnosed with May–Thurner syndrome. Each received catheter‐directed thrombolysis followed by balloon angioplasty to restore flow. Two patients had endovascular stents placed. The procedures were well tolerated, without major complications. Additional thrombophilic risk factors were identified in each patient. Though uncommon, pediatric hematologists should consider May–Thurner syndrome in adolescents who present with a left lower extremity thrombosis. Aggressive therapy may be warranted due to the risk of post‐thrombotic syndrome. Pediatric Blood Cancer 2006;47:834–838.

Aortic and renal artery thrombosis in a neonate: recovery with thrombolytic therapy.

Abstract. This report describes a neonate with acute renal failure associated with extensive aortic and bilateral renal artery thrombosis attributed to inadequate breastfeeding and severe dehydration. Dialytic and general supportive care, together with concurrent anticoagulation, and continuous aggressive intrathrombic instillation of urokinase for 5 days resulted in near-complete thrombolysis. Renal functional recovery began 11 days after the onset of anuria. Despite ischemic atrophy of the left kidney, renal function and blood pressure were normal on follow-up. Thus, in neonates thrombolytic therapy may positively impact survival and recovery of renal function even in the setting of prolonged ischemic renal injury.

Pseudoaneurysm in children: diagnosis and interventional management

Pseudoaneurysms (PAn) are uncommon in adults and even less common in children. They are most often encountered after iatrogenic arterial injury. Presentation may be substantially delayed after the iatrogenic event, and diagnosis can be difficult, especially when the PAn occurs in an unexpected location. Treatment of PAn has evolved during the last two decades from a reliance on surgical resection to US-guided compression, coil embolization, covered stents, and stent-graft exclusion. More recently, direct percutaneous US-guided thrombin injection has been used in the treatment of PAn. We present three cases of successful PAn thrombosis by US-guided percutaneous thrombin injection in children, one of the epigastric artery and two of the femoral artery.