James J. Gangemi

Selective adenosine-A2A activation reduces lung reperfusion injury following transplantation

BACKGROUND The adenosine-A2A receptor on the neutrophil is responsible for several anti-inflammatory actions. We hypothesized that DWH-146e, a selective adenosine-A2A agonist, would reduce lung reperfusion injury following transplantation. METHODS We used an isolated, whole blood-perfused, ventilated rabbit lung model. Donor rabbits underwent lung harvest after pulmonary arterial PGE1 injection and Euro-Collins preservation solution flush, and lungs were preserved for 18 hours at 4 degrees C. Group I lungs (n = 9) served as control subjects. Group II lungs (n = 9) were reperfused with whole blood that was first passed through a leukocyte-depleting filter. In group III (n = 9), DWH-146e was added to the blood reperfusate (25 microg/kg) immediately before reperfusion and was administered throughout the reperfusion period (1 microg/kg/min). All lungs were reperfused for 30 minutes. RESULTS Arterial oxygenation in group II and group III was significantly higher than that of group I after 30 minutes of reperfusion (514.27 +/- 35.80 and 461.12 +/- 43.77 vs 91.41 +/- 20.58 mm Hg, p < .001). Pulmonary vascular resistance was significantly reduced in group III (22,783 +/- 357 dynes x s x cm(-5)) compared to both group II and group I (31,057 +/- 1743 and 36,911 +/- 2173 dynes x s x cm(-5), p < .001). Airway compliance was improved in groups II and III when compared to group I (1.68 +/- 0.08 and 1.68 +/- 0.05 vs 1.36 +/- 0.13, p = .03). Microvascular permeability in group III was reduced to 106.82 +/- 17.09 compared with 165.70 +/- 21.83 ng Evans blue dye per gram of tissue in group I (p = .05). Group III myeloperoxidase activity was 39.88 +/- 4.87 compared with 88.70 +/- 18.69 deltaOD/g/min in group I (p = .03); group II myeloperoxidase activity was 56.06 +/- 7.46. CONCLUSIONS DWH-146e reduced lung neutrophil sequestration and dramatically improved pulmonary graft function. Neutrophils are important components of the inflammatory cascade of reperfusion injury and their source may include both the circulating blood and the lung graft itself. Selective adenosine-A2A activation interrupts the neutrophil-mediated inflammatory response and reduces lung reperfusion injury following transplantation.

Cardiopulmonary bypass simulation at the Boot Camp

OBJECTIVE At Boot Camp, we evaluated a modular approach to skills mastery related to cardiopulmonary bypass and crisis scenarios. METHODS With 32 first-year cardiothoracic surgery residents divided into 4 groups, 4 consecutive hours were devoted to cardiopulmonary bypass skills by using a perfused nonbeating heart model, computer-controlled CPB simulator, and perfused beating heart simulator. Based on the cardiopulmonary bypass simulator, each resident was assessed by using a checklist rating score on cardiopulmonary bypass management and 1 crisis scenario. An overall cardiopulmonary bypass score was determined. Economy of time and thought was assessed (1 = unnecessary/disorganized to 5 = maximum economy). At the end of the session, residents completed a written examination. Residents rated the sessions on cannulation skills, cardiopulmonary bypass knowledge, and cardiopulmonary bypass emergency and crisis scenarios on a 5-point scale (5 = very helpful to 1 = not helpful). RESULTS Thirty residents completed cardiopulmonary bypass simulator exercises. For initiation and termination of cardiopulmonary bypass, most residents performed the tasks and sequence correctly. Some elements were not performed correctly. For instance, 3 residents did not verify the activated clotting time before cardiopulmonary bypass initiation. Four residents demonstrated inadequate communication with the perfusionist, including lack of assertiveness and unclear commands. In crisis scenarios management of massive air embolism (n = 8) was challenging and resulted in the most errors; poor venous drainage and high arterial line pressure scenarios were managed with fewer errors. For the protamine reaction scenario, all residents (n = 7) identified the problem, but in 3 cases heparin was not redosed before resuming cardiopulmonary bypass for right ventricular failure. The score for economy of time and thought was 3.83 ± 0.6 (range, 3-5). The score of the written examination was 90.0 ± 11.3 (range, 60-100), which did not correlate with the overall cardiopulmonary bypass score of 91.4 ± 7.1 (range, 80-100; r = 0.07). The session on acquiring aortic cannulation skills was rated 4.92, that for cardiopulmonary bypass knowledge was rated 4.96, and that for cardiopulmonary bypass crisis scenarios was rated 4.96. CONCLUSIONS This Boot Camp session introduced residents early in their training to aortic cannulation, principles and management of cardiopulmonary bypass, and crisis management. Based on a modular approach, technical skills and knowledge of cardiopulmonary bypass can be acquired and assessed by using simulations, but further work with more comprehensive educational modules and practice will accelerate the path to mastery of these critical skills.

Adenosine A2A analogue improves neurologic outcome after spinal cord trauma in the rabbit.

BACKGROUND ATL-146e, an adenosine A2A agonist, reduces paralysis after spinal cord ischemia-reperfusion. We hypothesized that systemic ATL-146e could improve neurologic outcome after blunt spinal cord trauma. METHODS Twenty rabbits survived a thoracic spinal cord impact of 30 g-cm. One group received 0.06 microg/kg/min ATL-146e for the first 3 hours after impact (A2A group), whereas a second group received saline carrier (T/C group). Neurologic outcome was measured using the Tarlov scale (0-5). Histologic sections from the A2A and T/C groups were compared for neuronal viability. RESULTS There was significant improvement in Tarlov scores of A2A animals compared with T/C animals at 12 hours (p = 0.007), with a trend toward improvement at 36 (p = 0.08) and 48 (p = 0.09) hours after injury. There was decreased neuronal attrition in A2A animals (p = 0.06). CONCLUSION Systemic ATL-146e given after spinal cord trauma results in improved neurologic outcome. Adenosine A2A agonists may hold promise as a rapidly acting alternative to steroids in the early treatment of the spinal cord injured patient.

Systemic adenosine A2A agonist ameliorates ischemic reperfusion injury in the rabbit spinal cord.

BACKGROUND The adenosine A2A agonist ATL-146e (4-[3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxytetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester) has been shown to prevent reperfusion injury in multiple organ systems through inhibition of activated leukocyte-endothelial interaction. We hypothesized that systemic ATL-146e could reduce spinal cord reperfusion injury after aortic clamping. METHODS Twenty-six rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group received intravenous ATL-146e for 3 hours during reperfusion. A second cohort received only vehicle and served as controls. Animals were assessed at 24 and 48 hours using the Tarlov (0 to 5) scoring system for hind limb function. To evaluate neuronal attrition, immunostaining of lumbar spinal cord sections was performed using anti-SMI 33 antibody against neurofilament. RESULTS Systemic ATL-146e was tolerated without hemodynamic lability. Animals that received ATL-146e had significantly improved neurologic outcomes 24 and 48 hours after spinal cord ischemia (p < 0.001). There was preservation of neuronal architecture in the ventral horn of spinal cord sections from animals receiving ATL-146e compared with control animals. CONCLUSIONS Intravenous ATL-146e given during reperfusion is tolerated without hemodynamic lability, and results in substantially improved spinal cord function after ischemia by preservation of ventral horn neurons.

Hypothermic retrograde venous perfusion with adenosine cools the spinal cord and reduces the risk of paraplegia after thoracic aortic clamping

OBJECTIVE We evaluated the utility of retrograde venous perfusion to cool the spinal cord and protect neurologic function during aortic clamping. We hypothesized that hypothermic adenosine would preserve the spinal cord during ischemia. METHODS Six swine (group I) underwent thoracic aortic occlusion for 30 minutes at normothermia. Group II animals underwent spinal cooling by retrograde perfusion of the paravertebral veins with hypothermic (4 degrees C) saline solution during aortic occlusion. The spinal cords of group III animals were cooled with a hypothermic adenosine solution in a similar fashion. Intrathecal temperature was monitored and somatosensory evoked potentials assessed the functional status of spinal pathways. RESULTS Spinal cooling without systemic hypothermia significantly improved neurologic Tarlov scores in group III (4.8 +/- 0.2) and group II (3.8 +/- 0.4) when compared with group I scores (1.3 +/- 0.6) (P <.001). Furthermore, 5 of the 6 animals in group III displayed completely normal neurologic function, whereas only one animal in group II and no animals in group I did (P =.005). Somatosensory evoked potentials were lost 10.6 +/- 1.4 minutes after ischemia in group I. In contrast, spinal cooling caused rapid cessation of neural transmission with loss of somatosensory evoked potentials at 6.9 +/- 1.2 minutes in group II and 7.0 +/- 0.8 minutes in group III (P =.06). Somatosensory evoked potential amplitudes returned to 85% of baseline in group III and 90% of baseline in group II compared with only 10% of baseline in group I (P =.01). CONCLUSIONS We conclude that retrograde cooling of the spinal cord is possible and protects against ischemic injury and that adenosine enhances this effect. The efficacy of this method may be at least partly attributed to a more rapid reduction in metabolic and electrical activity of the spinal cord during ischemia.

Retrograde Perfusion With a Sodium Channel Antagonist Provides Ischemic Spinal Cord Protection

BACKGROUND Neuronal voltage-dependent sodium channel antagonists have been shown to provide neuroprotection in focal and global cerebral ischemic models. We hypothesized that retrograde spinal cord venous perfusion with phenytoin, a neuronal voltage-dependent sodium channel antagonist, would provide protection during prolonged spinal cord ischemia. METHODS In a rabbit model, spinal cord ischemia was induced for 45 minutes. Six groups of animals were studied. Controls (group I, n = 8) received no intervention during aortic cross-clamping. Group II (n = 8) received systemic phenytoin (100 mg). Group III (n = 4) received systemic phenytoin (200 mg). Group IV (n = 8) received retrograde infusion of room temperature saline (22 degrees C) only. Group V (n = 8) and group VI (n = 9) received retrograde infusion of 50 mg and 100 mg of phenytoin, respectively, (infusion rate: 0.8 mL x kg(-1) x min(-1) during the ischemic period). Mean arterial blood pressure was monitored continuously. Animals were allowed to recover for 24 hours before assessment of neurologic function using the Tarlov scale. RESULTS Tarlov scores (0 = complete paraplegia, 1 = slight lower limb movement, 2 = sits with assistance, 3 = sits alone, 4 = weak hop, 5 = normal hop) were as follows (mean +/- SEM): group I, 0.50 +/- 0.50; group II, 0.25 +/- 0.46; group IV, 1.63 +/- 0.56; group V, 4.13 +/- 0.23; and group VI, 4.22 +/- 0.22 (p < 0.0001 V, VI versus I, II, IV by analysis of variance). No differences in mean arterial blood pressure were observed. All animals in group III became profoundly hypotensive and died before the conclusion of the 45-minute ischemic time. CONCLUSIONS Retrograde venous perfusion of the spinal cord with phenytoin, a voltage-sensitive sodium channel blocker, is safe and provides significant protection during prolonged spinal cord ischemia.

Coarctation of the Aorta - The Current State of Surgical and Transcatheter Therapies

Aortic coarctation represents a distinct anatomic obstruction as blood moves from the ascending to the descending aorta and can present in a range of ages from infancy to adulthood. While it is often an isolated and discrete narrowing, it can also be seen in the more extreme scenario of severe arch hypoplasia as seen in the hypoplastic left heart syndrome or in conjunction with numerous other congenital heart defects. Since the first description of an anatomic surgical repair over sixty years ago, an evolution of both surgical and transcatheter therapies has occurred allowing clinicians to manage and treat this disease with excellent results and low morbidity and mortality. This review focuses on the current state of both transcatheter and surgical therapies, paying special attention to recent data on long-term follow-up of both approaches. Further, current thoughts will be explored about future therapeutic options that attempt to improve upon historical long-term outcomes.

Uniquely shaped cardiovascular stents enhance the pressure generation of intravascular blood pumps

OBJECTIVE Advances in the geometric design of blood-contacting components are critically important as the use of minimally invasive, intravascular blood pumps becomes more pervasive in the treatment of adult and pediatric patients with congestive heart failure. The present study reports on the evaluation of uniquely shaped filaments and diffuser blades in the development of a protective stent for an intravascular cavopulmonary assist device for patients with a single ventricle. METHODS We performed numeric modeling, hydraulic testing of 11 stents with an axial flow blood pump, and blood bag experiments (n = 6) of the top-performing stent geometries to measure the levels of hemolysis. A direct comparison using statistical analyses, including regression analysis and analysis of variance, was completed. RESULTS The stent geometry with straight filaments and diffuser blades that extended to the vessel wall outperformed all other stent configurations. The pump with this particular stent was able to generate pressures of 2 to 32 mm Hg for flow rates of 0.5 to 4 L/min at 5000 to 7000 RPM. A comparison of the experimental performance data to the numeric predictions demonstrated an excellent agreement within 16%. The addition of diffuser blades to the stent reduced the flow vorticity at the pump outlet. The average and maximum normalized index of hemolysis level was 0.0056 g/100 L and 0.0064 g/100 L, respectively. CONCLUSIONS The specialized design of the stents, which protect the vessel wall from the rotating components of the pump, proved to be advantageous by further augmenting the pressure generation of the pump, reducing the flow vorticity at the pump outlet, and enhancing flow control.

Face-to-Face Handoff: Improving Transfer to the Pediatric Intensive Care Unit After Cardiac Surgery

The goal was to develop and implement a comprehensive, primarily face-to-face handoff process that begins in the operating room and concludes at the bedside in the intensive care unit (ICU) for pediatric patients undergoing congenital heart surgery. Involving all stakeholders in the planning phase, the framework of the handoff system encompassed a combination of a formalized handoff tool, focused process steps that occurred prior to patient arrival in the ICU, and an emphasis on face-to-face communication at the conclusion of the handoff. The final process was evaluated by the use of observer checklists to examine quality metrics and timing for all patients admitted to the ICU following cardiac surgery. The process was found to improve how various providers view the efficiency of handoff, the ease of asking questions at each step, and the overall capability to improve patient care regardless of overall surgical complexity.

Short and long-term outcomes for bidirectional glenn procedure performed with and without cardiopulmonary bypass.

BACKGROUND The bidirectional Glenn (BDG) procedure is most commonly used as staged palliation for complex cyanotic congenital heart defects. The benefits of a BDG procedure without the use of cardiopulmonary bypass (CPB) remain mixed within reported series. The purpose of this study was to compare short- and long-term outcomes for performance of a BDG procedure with and without the use of CPB. METHODS From 2001 to 2010, 106 patients underwent a BDG procedure. Patients were stratified into CPB (n = 72; age = 202 days) and non-CPB (n = 34; age = 182 days) groups. Primary outcomes included operative mortality and postoperative complications as well as differences in long-term Kaplan-Meier survival. RESULTS Median follow-up was 30 months. Preoperative patient characteristics were similar among patients despite the use of CPB. The most frequent indications for a BDG procedure were hypoplastic left heart syndrome (HLHS) (35.8%) and tricuspid atresia (TA) (17.9%). Median perfusion time was 73 minutes for CPB patients. Overall mortality was 0.9% and no deaths occurred among non-CPB patients (0.0% versus 1.4%; p > 0.99). Similarly, no significant differences existed between non-CPB patients and CPB patients with respect to overall complication rates (11.8% versus 18.1%; p = 0.57) or postoperative length of stay (7.0 [5.0-12.0] versus 7.0 [5.0-11.0] days; p = 0.38). Furthermore, 1-, 3-, and 5-year survival was high and similar between groups. CONCLUSIONS The BDG procedure can be performed with no significant differences in operative mortality, morbidity, or use of resources, with or without CPB support. Long-term survival after the BDG procedure is high with both strategies. Performance of an off-pump BDG procedure should be considered a safe alternative to the conventional use of CPB for appropriately selected patients.