David C. Cassada

Influence of graft ischemic time on outcomes following lung transplantation

BACKGROUNDnReperfusion injury is the most common cause of early mortality following lung transplantation. Although cold graft ischemic time has been reported to influence this injury, some lung grafts with short ischemic times develop significant reperfusion injury, whereas other grafts with more prolonged ischemic times do not develop injury. Our hypothesis was that ischemic time did not significantly influence reperfusion injury or other outcomes following lung transplantation.nnnMETHODSnData on 136 patients who had lung transplantation over a 10 year period was used for analysis.nnnRESULTSnCold graft ischemic time > or = 6 hours did not increase the risk of reperfusion injury, acute rejection, cytomegalovirus infection, bacterial or fungal pneumonia, bronchiolitis obliterans syndrome, 1-month mortality, 1-year mortality, or 5-year mortality compared with ischemic times of either < 4 hours or 4 to 6 hours. The incidence of reperfusion injury was at least 20% for each time group.nnnCONCLUSIONSnAt least 20% of all patients will develop reperfusion injury regardless of cold graft ischemic time. Prolonged ischemic times up to 8 hours do not result in a significant increase in adverse short-term, intermediate, or long-term outcomes. Cautious extension of ischemic time beyond the current target of 4 to 6 hours may be warranted for geographic expansion of the donor lung pool.

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

BACKGROUNDnATL-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.nnnMETHODSnTwenty 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.nnnRESULTSnThere 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).nnnCONCLUSIONnSystemic 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.

BACKGROUNDnThe 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.nnnMETHODSnTwenty-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.nnnRESULTSnSystemic 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.nnnCONCLUSIONSnIntravenous 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.

The role of pharmacology in spinal cord protection during thoracic aortic reconstruction

Surgery of the thoracic aorta continues to have a significant risk of neurologic complication. Several strategies to minimize this risk are emerging. Pharmacologic protection from these complications continues to be researched, but at this point few medications are being used clinically. This article reviews the pathophysiology of ischemic spinal cord injury and summarizes the investigational pharmacology that may prevent these serious complications.

Pyrrolidine dithiocarbamate reduces lung reperfusion injury.

BACKGROUNDnThe inflammatory cascade has emerged as the primary mediator of reperfusion injury. Nuclear factor kappaB (NF-kappaB) is a rapid response transcription factor that activates genes responsible for the mediators of inflammation. Heat shock protein 70 (HSP70) has been shown to protect against lung injury. We hypothesized that the antioxidant pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB and upregulator of HSP70, would decrease lung injury after ischemia and reperfusion.nnnMETHODSnUsing our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest followed by 10-h storage (4 degrees C) and blood reperfusion for 30 min. Group I lungs (n = 5) served as controls. In group II lungs (n = 5), both lung and blood donors received PDTC (100 mg/kg) intravenously 30 min before harvest. NF-kappaB activity was evaluated with electrophoretic mobility shift assay, and Western blot was performed for HSP70.nnnRESULTSnGroup II demonstrated superior pulmonary function. Although HSP70 expression was somewhat elevated in group II lungs, NF-kappaB binding activity was not different between the groups.nnnCONCLUSIONSnPDTC improves pulmonary function after ischemia and reperfusion in an isolated rabbit lung model. The improved function correlates with elevated HSP70 expression during initial reperfusion, independent of NF-kappaB activity.

Controlled perfusion decreases reperfusion injury after high-flow reperfusion.

INTRODUCTIONnSome investigators have suggested that high pulmonary artery flow rates increase the risk of severe reperfusion injury after lung transplantation. We hypothesized that controlling the initial flow rate and pulmonary artery pressure would decrease the severity of lung dysfunction in the setting of high-flow reperfusion.nnnMETHODSnUsing our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest, 4-hour storage (4 degrees C), and blood reperfusion. We measured pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio. Group 1 (control, n = 8) underwent reperfusion at 60 ml/min for 30 minutes. Group 2 (high flow, n = 8) underwent reperfusion at 120 ml/min for 30 minutes. Group 3 (controlled flow, n = 8) underwent initial reperfusion at 60 ml/min for 5 minutes, followed by reperfusion at 120 ml/min for 25 minutes.nnnRESULTSnGroup 1 had significantly improved pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio measurements compared with groups 2 and 3 after 30 minutes of reperfusion. However, Group 3 had improved pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio measurements compared with Group 2.nnnCONCLUSIONSnHigh-flow reperfusion results in severe reperfusion injury after lung transplantation. Controlled reperfusion using a low initial flow rate decreases the severity of reperfusion injury associated with high-flow rates.

Management of innominate artery injury in the setting of bovine arch anomaly

Blunt injury to the aortic arch vessels is rare and can be life-threatening. Historically urgent repair of these injuries is emphasized. We describe the initial nonoperative management of a blunt injury to the brachiocephalic trunk in the setting of bovine arch anomaly, followed by delayed surgical management.

Mechanical characteristics of lyophilized human saphenous vein valves

PURPOSEnWe investigated the mechanical characteristics of lyophilized human saphenous vein valves to determine their suitability for use as allogeneic transplants to treat chronic venous insufficiency.nnnMETHODSnFresh cadaveric veins were lyophilized in vacuum bottles within 24 hours of harvest and were stored at room temperature. The veins were reconstituted in saline solution and then were placed in an in vitro flow circuit for evaluation. At varied flow rates, pressures proximal and distal to valves during prograde and retrograde flow were measured. Valve closure times were determined with Doppler examination and spectral analysis. The valves were also stressed to 350 mm Hg on a separate apparatus.nnnRESULTSnAll pressures proximal and distal to the valves remained less than 10 mm Hg during prograde flow. A pressure gradient developed immediately on the reversal of flow. Pressure as high as 200 mm Hg applied against the closed valves was not transmitted beyond the valve. Valve closure times had a mean of 0.31 +/- 0.03 seconds and 0.21 +/- 0.01 seconds for the Doppler examination and spectral analysis, respectively. All valves withstood stress pressures to 350 mm Hg.nnnCONCLUSIONSnThe in vitro mechanical characteristics of the valves of lyophilized veins are similar to known values for normal in vivo valves.

Carotid Arteriography Impacts Carotid Stenosis Management

Recent literature advocates carotid endarterectomy on duplex alone. The authors hypothesized that carotid angiography adds information that alters clinical management in a substantial number of patients compared to the use of carotid duplex examination alone. The records of 182 consecutive patients who underwent carotid artery duplex and subsequent carotid/cerebral angiography for suspected carotid artery stenosis between January 1998 and April 1999 were reviewed retrospectively. Carotid artery duplex examinations were stratified based on stenosis: <39%, 40% to 59%, 60% to 79% (moderate), 80% to 99% (severe), 100%. Carotid stenosis on angiograms was determined by NASCET criteria. New information found at angiography included vertebral, subclavian, or arch atherosclerosis, intracranial pathosis, or a change in duplex stenosis category to a degree of stenosis not requiring surgery. Clinical importance was attributed to angiograms that altered the patients management plan. Angiography provided additional information in 53% (97/182) of patients. Vertebral disease was found in 25.1%, subclavian disease in 16.4%, intracranial disease in 15.3%, aortic arch disease in 3.3%. Patient treatment was altered in 30% (55/182). Angiographic findings downgraded the stenosis to medical therapy in 20.9% (38/182). The surgical plan was influenced in 5.5% (10/182). Nine intracranial aneurysms were discovered. Carotid angiography was essential for vascular bypass surgery planning in 3.3% (6/182). Angioplasty was performed in 2.2% (4/182). The accurate determination of stenosis is critical in determining optimal treatment of patients with carotid artery stenosis. Routine carotid angiography remains valuable in the clinical treatment of these patients.

Analysis of airway function of immature whole lung transplants versus mature lobar transplants

For the pediatric patient with end-stage lung disease in need of transplantation, two potential donor options currently exist: size-matched immature whole lungs or reduced-size mature lobes. To determine which of these options provides superior long-term function, we studied airway mechanics in a chronic porcine model of pediatric lung transplantation. Three groups of animals were studied: the first group underwent left upper lobectomy at 9 +/- 1 weeks of age (innervated left lower lobes). These animals served as controls. A second group of 9-week-old animals received an immature whole left lung allograft from age-matched donors. The third group received a reduced-size mature left lower lobe from 6-month-old donors. Measurements of dynamic airway resistance, pulmonary compliance, and functional residual capacity of the isolated lobes or lungs, and of the nonoperated right lungs, were recorded 12 +/- 1 weeks later, and mean values were calculated for each group. Results showed that transplantation of an immature whole lung resulted in abnormal dynamic airway resistance to airflow, which was not seen in the mature lobar transplants. In addition, compliance was impaired most significantly in the immature whole lung transplants. We conclude that in this experimental model of pediatric lung transplantation, transplantation of a mature lobar segment results in superior long-term airway function when compared with immature whole lung transplants.