The miniaturized pediatric continuous-flow device: Preclinical assessment in the chronic sheep model.

BACKGROUND: The Infant Jarvik 2015 is an implantable axial-flow ventricular assist device (VAD) that has undergone the major evolutionary design modifications to improve hemocompatibility. This study was conducted in anticipation of data submission to the US Food and Drug Administration to obtain Investigational Device Exemption approval. METHODS: The VAD was implanted via a left thoracotomy in Barbado sheep (n = 10, 26 (19-34] kg). Anticoagulation was maintained with coumadin, with a target international normalized ratio of greater than the individual sheep's baseline values. The VAD was managed at the highest possible speed as clinically tolerable. Complete necropsy was performed at the end of the study. RESULTS: There were 2 early mortalities: tension pneumothorax (n = 1) and shower emboli of the fragmented myocardium (n = 1). The remaining 8 sheep (2 with 30-day and 6 with 60-day protocols) completed the anticipated study duration in excellent condition, with the 6 completing 60-day sheep showing appropriate weight gain during support. There were no signs of clinically significant hemolysis, with the final plasma-free hemoglobin of 2 (1-17) mg/dL. Necropsy showed old renal infarction in 7 sheep. Although thromboembolism can be the potential etiology, given the mild anticoagulation regimen, other sources of emboli were identified in 2 sheep (graft coating material and fragmented myocardium). Flow study demonstrated favorable increase in flow (up to 3.0 L/min) in proportion to change in pump speed. CONCLUSIONS: This study has demonstrated that the Infant Jarvik 2015 VAD is capable of maintaining its functionality for an extended period of time with minimal hemolysis.

Closing in on the PumpKIN Trial of the Jarvik 2015 Ventricular Assist Device.

The Infant Jarvik ventricular assist device (VAD; Jarvik Heart, Inc., New York, NY) has been developed to support the circulation of infants and children with advanced heart failure. The first version of the device was determined to have elevated hemolysis under certain conditions. The objective of this work was to determine appropriate modifications to the Infant Jarvik VAD that would result in acceptably low hemolysis levels. In vitro hemolysis testing revealed that hemolysis was related to the shape of the pump blade tips and a critical speed over which hemolysis would occur. Various design modifications were tested and a final design was selected that met the hemolysis performance goal. The new version was named the Jarvik 2015 VAD. Chronic in vivo tests, virtual fit studies, and a series of other performance tests were carried out to assess the device's performance characteristics. In vivo test results revealed acceptable hemolysis levels in a series of animals and virtual fit studies showed that the device would fit into children 8 kg and above, but could fit in smaller children as well. Additional FDA-required testing has been completed and all of the data are being submitted to the FDA so that a clinical trial of the Jarvik 2015 VAD can begin. Development of a Jarvik VAD for use in young children has been challenging for various reasons. However, with the hemolysis issue addressed in the Jarvik 2015 VAD, the device is well-poised for the start of the PumpKIN clinical trial in the near future.

The painfulness of active, but not sham, transcranial magnetic stimulation decreases rapidly over time: results from the double-blind phase of the OPT-TMS Trial.

BACKGROUND: Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) over several weeks is an FDA approved treatment for major depression. Although rTMS is generally safe when administered using the FDA guidelines, there are a number of side effects that can make it difficult for patients to complete a course of rTMS. Many patients report that rTMS is painful, although patients appear to accommodate to the initial painfulness. The reduction in pain is hypothesized to be due to prefrontal stimulation and is not solely explained by accommodation to the stimulation. METHODS: In a recent 4 site randomized controlled trial (using an active electrical sham stimulation system) investigating the antidepressant effects of daily left dorsolateral prefrontal rTMS (Optimization of TMS, or OPT-TMS), the procedural painfulness of TMS was assessed before and after each treatment session. Computerized visual analog scale ratings were gathered before and after each TMS session in the OPT-TMS trial. Stimulation was delivered with an iron core figure-8 coil (Neuronetics) with the following parameters: 10 Hz, 120% MT (EMG-defined), 4 s pulse train, 26 s inter-train interval, 3000 pulses per session, one 37.5 min session per day. After each session, procedural pain (pain at the beginning of the TMS session, pain toward the middle, and pain toward then end of the session) ratings were collected at all 4 sites. From the 199 patients randomized, we had usable data from 142 subjects for the initial 15 TMS sessions (double-blind phase) delivered over 3 weeks (142 × 2 × 15 = 4260 rating sessions). RESULTS: The painfulness of real TMS was initially higher than that of the active sham condition. Over the 15 treatment sessions, subjective reports of the painfulness of rTMS (during the beginning, middle and end of the session) decreased significantly 37% from baseline in those receiving active TMS, with no change in painfulness in those receiving sham. This reduction, although greatest in the first few days, continued steadily over the 3 weeks. Overall, there was a decay rate of 1.56 VAS points per session in subjective painfulness of the procedure in those receiving active TMS. DISCUSSION: The procedural pain of left, prefrontal rTMS decreases over time, independently of other emotional changes, and only in those receiving active TMS. These data suggest that actual TMS stimulation of prefrontal cortex maybe related to the reduction in pain, and that it is not a non-specific accommodation to pain. This painfulness reduction softly corresponds with later clinical outcome. Further work is needed to better understand this phenomenon and whether acute within-session or over time painfulness changes might be used as short-term biomarkers of antidepressant response.