Scott D. Ross

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.

Reduced neutrophil infiltration protects against lung reperfusion injury after transplantation

BACKGROUND There is evidence that lung ischemia reperfusion injury is a result of the activation of components of the inflammatory cascade. However, the role of neutrophils in lung reperfusion injury continues to be a source of controversy. METHODS Using an isolated, whole blood-perfused, ventilated rabbit lung model, we sought to characterize the pattern of reperfusion injury and investigate the contribution of neutrophils to this injury. Donor rabbits underwent lung harvest after pulmonary arterial prostaglandin E1 injection and Euro-Collins preservation solution flush. Group I lungs (n = 8) were immediately reperfused without ischemic storage. Group II lungs (n = 8) were stored for 18 h at 4 degrees C before reperfusion. Group III lungs (n = 10) underwent 18 h of ischemic storage and were reperfused with whole blood that was first passed through a leukocyte-depleting filter. All lungs were reperfused for 2 h. RESULTS Arterial oxygenation in group III progressively improved, and was significantly higher than that of group II after 2 h of reperfusion (272.58+/-58.97 vs 53.58+/-5.34 mm Hg, p = 0.01). Both pulmonary artery pressure and pulmonary vascular resistance were significantly reduced in group III when compared with group II (27.85+/-1.45 vs 44.15+/-4.77 mm Hg, p = 0.002; and 30,867+/-2,323 vs 52,775+/-6,386 dynes x sec x cm(-5), p = 0.003, respectively). Microvascular permeability in group III lungs was reduced to 73.98+/-6.15 compared with 117.16+/-12.78 ng Evans blue dye/g tissue in group II (p = 0.005). Group III myeloperoxidase activity was 56.92+/-6.31 deltaOD/g/min compared with 102.84+/-10.41 delta0d/g/min in group II (p = 0.002). CONCLUSIONS Leukocyte depletion of the blood reperfusate protects against microvascular permeability and significantly improves pulmonary graft function. The neutrophil plays a major role in amplifying lung injury later during reperfusion, and this lung ischemia reperfusion injury may be reversed through the interruption of the inflammatory cascade and the interference with neutrophil infiltration.

Preservation of intercostal arteries during thoracoabdominal aortic aneurysm surgery: A retrospective study

OBJECTIVE The purpose of this article was to examine the influence of reimplantation of patent intercostal and lumbar arteries on the incidence of postoperative paraplegia/paraparesis in patients undergoing clamp-and-sew surgical repair of thoracoabdominal aortic aneurysms. METHODS Data from January 1987 through December 1997 were retrospectively collected on 132 patients. Ninety-one patients in group I underwent aneurysm repairs before January 1995 and did not undergo intercostal artery reimplantation. Group II included the more recent 41 patients who had vessels between the eighth thoracic intercostal and the second lumbar arteries reimplanted to the graft or preserved at the aortic anastomoses. RESULTS The operative mortality rate was 13.2% (12/91) in group I and 4.9% (2/41) in group II (P =.22). The incidence of postoperative paraplegia was significantly lower in the more recent cohort of patients (8.8% [8/91] in group I vs 0% [0/41] in group II, P =.05). The overall rate of spinal cord dysfunction was lowered from 9.9% (9/91) in group I to 2.4% (1/41) in group II (P =.17). However, a multivariable logistic regression analysis identified only aneurysm extent (Crawford type I and type II) as a predictor of less postoperative spinal cord injury (P =.08). The average aortic crossclamp time in group I was 30.3 +/- 11.5 (SD) minutes, and the time of aortic occlusion in group II was not significantly prolonged, with an average crossclamp time of 31.0 +/- 21.0 (SD) minutes (P =. 88). CONCLUSIONS An aggressive approach to maintain intercostal artery patency during clamp-and-sew repair of thoracoabdominal aortic aneurysms may effectively lower the incidence of spinal cord injury without prolonging aortic crossclamp time.

Spinal cord protection during aortic cross-clamping using retrograde venous perfusion

BACKGROUND Paraplegia remains a devastating complication following thoracic aortic operation. We hypothesized that retrograde perfusion of the spinal cord with a hypothermic, adenosine-enhanced solution would provide protection during periods of ischemia due to temporary aortic occlusion. METHODS In a rabbit model, a 45-minute period of spinal cord ischemia was produced by clamping the abdominal aorta and vena cava just below the left renal vessels and at their bifurcations. Four groups (n = 8/group) were studied: control, warm saline, cold saline, and cold saline with adenosine infusion. In the experimental groups, saline or saline plus adenosine was infused into the isolated cavae throughout the ischemic period. Clamps were removed and the animals to recovered for 24 hours before blinded neurological evaluation. RESULTS Tarlov scores (0 = paraplegia, 1 = slight movement, 2 = sits with assistance, 3 = sits alone, 4 = weak hop, 5 = normal hop) were (mean +/- standard error of the mean): control, 0.50 +/- 0.50; warm saline, 1.63 +/- 0.56; cold saline, 3.38 +/- 0.26; and cold saline plus adenosine, 4.25 +/- 0.16 (analysis of variance for all four groups, p < 0.00001). Post-hoc contrast analysis showed that cold saline plus adenosine was superior to the other three groups (p < 0.0001). CONCLUSION Retrograde venous perfusion of the spinal cord with hypothermic saline and adenosine provides functional protection against surgical ischemia and reperfusion.

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.

The Safety of Combined Cardiac and Vascular Operations: How Much is too Much?

OBJECTIVE The purpose of this study was to identify factors correlating with a poor outcome following combined cardiac and vascular procedures. METHODS We reviewed 45 consecutive patients undergoing combined cardiac and vascular operations. These included cardiac/CEA (n=27), cardiac/AAA (n=13), cardiac/AAA/one other vascular reconstruction (n=4), and cardiac/renal artery bypass (n=1). Group I included all patients with no morbidity or mortality (n=41) and Group II included patients who died or suffered significant morbidity (stroke, renal failure) (n=4). RESULTS Overall mortality was 4.4% (2/45). These two patients underwent cardiac surgery combined with two additional vascular procedures (cardiac/AAA/other). In patients undergoing cardiac/CEA or cardiac/AAA, there were no deaths and one stroke (contralateral to CEA). Group II had significantly decreased ejection fraction (39%+/-6% vs 52%+/-1%) and an increased number of procedures (2.75 vs 2.04). CONCLUSIONS Combined cardiac surgery and vascular reconstruction can be performed safely. However, multiple vascular reconstructions or the presence of decreased ejection fraction increased operative risk.

Reduced neutrophil infiltration protects against lung reperfusion injury after transplantation. Discussion

Background. There is evidence that lung ischemia reperfusion injury is a result of the activation of components of the inflammatory cascade. However, the role of neutrophils in lung reperfusion injury continues to be a source of controversy. Methods. Using an isolated, whole blood-perfused, ventilated rabbit lung model, we sought to characterize the pattern of reperfusion injury and investigate the contribution of neutrophils to this injury. Donor rabbits underwent lung harvest after pulmonary arterial prostoglandin E 1 injection and Euro-Collins preservation solution flush. Group I lungs (n = 8) were immediately reperfused without ischemic storage. Group II lungs (n = 8) were stored for 18 h at 4°C before reperfusion. Group III lungs (n = 10) underwent 18 h of ischemic storage and were reperfused with whole blood that was first passed through a leukocyte-depleting filter. All lungs were reperfused for 2 h. Results. Arterial oxygenation in group III progressively improved, and was significantly higher than that of group II after 2 h of reperfusion (272.58 ± 58.97 vs 53.58 ± 5.34 mm Hg, p = 0.01). Both pulmonary artery pressure and pulmonary vascular resistance were significantly reduced in group III when compared with group II (27.85 ± 1.45 vs 44.15 ± 4.77 mm Hg, p = 0.002; and 30,867 ± 2,323 vs 52,775 ± 6,386 dynes.sec.cm -5 , p = 0.003, respectively). Microvascular permeability in group III lungs was reduced to 73.98 ± 6.15 compared with 117.16 ± 12.78 ng Evans blue dye/g tissue in group II (p = 0.005). Group III myeloperoxidase activity was 56.92 ± 6.31 ΔOD/g/min compared with 102.84 ± 10.41 Δ0d/g/min in group II (p = 0.002). Conclusions. Leukocyte depletion of the blood reperfusate protects against microvascular permeability and significantly improves pulmonary graft function. The neutrophil plays a major role in amplifying lung injury later during reperfusion, and this lung ischemia reperfusion injury may be reversed through the interruption of the inflammatory cascade and the interference with neutrophil infiltration.