Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury.

Activation of invariant natural killer T (iNKT) cells and signaling through receptor for advanced glycation end products (RAGE) are known to independently mediate lung ischemia-reperfusion (IR) injury. This study tests the hypothesis that activation of RAGE specifically on iNKT cells via alveolar macrophage-produced high mobility group box 1 (HMGB1) is critical for the initiation of lung IR injury. A murine in vivo hilar clamp model was utilized, which demonstrated that RAGE(-/-) mice were significantly protected from IR injury. Treatment of WT mice with soluble RAGE (a decoy receptor), or anti-HMGB1 antibody, attenuated lung IR injury and inflammation, whereas treatment with recombinant HMGB1 enhanced IR injury in WT mice but not RAGE(-/-) mice. Importantly, lung dysfunction, cytokine production and neutrophil infiltration were significantly attenuated after IR in Jα18(-/-) mice reconstituted with RAGE(-/-) iNKT cells (versus WT iNKT cells). In vitro studies demonstrated that, after hypoxia-reoxygenation, alveolar macrophage-derived HMGB1 augmented IL-17 production from iNKT cells in a RAGE-dependent manner. These results suggest that HMGB1-mediated RAGE activation on iNKT cells is critical for initiation of lung IR injury and that a crosstalk between macrophages and iNKT cells via the HMGB1/RAGE axis mediates IL-17 production by iNKT cells causing neutrophil infiltration and lung IR injury.

Risk-stratified approach to hybrid transcatheter-surgical palliation of hypoplastic left heart syndrome.

We prospectively employed a risk-stratified approach to first-stage palliation of hypoplastic left heart syndrome. High-risk features included severe tricuspid insufficiency, severe right ventricular dysfunction, a severely restrictive or intact atrial septum, an ascending aortic diameter < or = 2 mm, late presentation, weight < 2 kg, or significant extracardiac issues, Infants without high-risk features underwent a Norwood procedure (with Sano modification), whereas infants with high-risk features underwent a hybrid procedure consisting of bilateral pulmonary artery banding, ductal stenting, and atrial septostomy or a Norwood/Sano. Operative survival for 10 infants without high-risk features undergoing a Norwood/Sano procedure was 90%. Operative survival for 5 infants with high-risk features undergoing hybrid palliation was 100%, compared to 29% in 7 infants with high-risk features undergoing the Norwood/Sano procedure. Although only short-term data are available, this hybrid palliative procedure may have a role for infants with hypoplastic left heart syndrome and high-risk features.

Surgical treatment of the failing heart.

Heart failure is one of the leading causes of hospitalization worldwide. Currently, most therapeutic strategies are aimed at resolving the acute exacerbation of failure, resulting in a high readmission rate. Despite significant advances in the medical treatment of heart failure, the results are far from perfect. Mortality remains high and hospitalization costly. Surgical management is still required for patients with end-stage heart failure. Unfortunately, its evolution has occurred in a less structured fashion. In addition to transplantation, strategies for the treatment of heart failure currently under investigation include implantation of pacemakers, left ventricular reconstruction, mitral valve repair, coronary revascularization, cardiomyoplasty and mechanical circulatory support. In the end however, the surgical management of patients with heart failure rests on the type of underlying cardiomyopathy. Hence, care must be taken to accurately diagnose these patients as either having dilated or ischemic cardiomyopathy.

Influence of graft ischemic time on outcomes following lung transplantation.

BACKGROUND: Reperfusion 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. METHODS: Data on 136 patients who had lung transplantation over a 10 year period was used for analysis. RESULTS: Cold 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. CONCLUSIONS: At 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.

A cost comparison of heart transplantation versus alternative operations for cardiomyopathy.

BACKGROUND: Heart transplantation is an established therapy for cardiomyopathy but is limited by organ shortage and expense. As a result, alternative operations have been proposed including coronary bypass, mitral valve repair, and left ventricular reconstruction. Because it is unknown whether alternative operations are less expensive than replacing the diseased heart, we compared in-hospital costs and early outcome of these operations with elective heart transplantation. METHODS: We compared clinical and financial data of 268 patients with ejection fraction less than 30% who underwent elective heart transplantation (n = 52, UNOS status 2 only), coronary bypass (n = 176), mitral repair (n = 15), or left ventricular reconstruction (n = 25). Data were evaluated for between-group differences, with p less than 0.05 as significant. RESULTS: Preoperative ejection fraction, although similar for heart transplantation (21.2% +/- 1.3%), coronary bypass (25.8% +/- 0.4%), mitral repair (22.9% +/- 1.5%), and left ventricular reconstruction (24.2% +/- 2.1%), was significantly different between the former two (p < 0.001). There was no difference in operative mortality: 5.8% (3 of 52), 3.4% (7 of 176), 6.7% (1 of 15), and 4.0% (1 of 25), respectively (p = 0.8). However, total hospital cost of heart transplantation was significantly greater than all others: $75,992 +/- $5,380, $25,008 +/- $1,446, $32,375 +/- $2,379, and $26,584 +/- $4,076, respectively (p < 0.001). Organ procurement expenses alone comprised 39.7% ($30,169) of total transplant cost. Kaplan-Meier survival analysis failed to show any survival difference between the various groups (p = 0.86) CONCLUSIONS: Compared with heart transplantation, alternative operations yield a comparable early outcome and long-term survival, and are markedly less expensive. The cost of transplantation, which is largely due to procurement expenses, is yet another reason to attempt alternative operations for cardiomyopathy whenever feasible.

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: < or =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.

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.

A prospectus on tissue adhesives.

Tissue adhesives are common adjuncts in surgical practice. Fibrin sealants are the most prevalent adhesives today. Recently, new adhesives have been approved for use in the United States, including cyanoacrylates, albumin-based compounds, collagen-based compounds, glutaraldehyde glues, and hydrogels. This review summarizes all the available tissue adhesives, focusing on their current and prospective indications in the clinical forum.

An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusion.

BACKGROUND: We hypothesized that systemic ATL-146e, an adenosine A(2A) agonist, would decrease spinal cord reperfusion inflammatory stress and inhibit apoptosis and that these effects would correlate with improved neurologic functional outcome. METHODS: Thirty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group of animals (n = 14) received 0.06 microg/kg per minute of ATL-146e infused intravenously for 3 hours, beginning 15 minutes before reperfusion. A second group of animals (n = 16) underwent spinal cord ischemia with saline vehicle alone and served as ischemic controls. Animals (n = 9, 11) from each group survived for 48 hours and assessed for neurologic impairment with the Tarlov (0-5) scoring system. Four animals from each group were humanely killed at the end of the 3-hour treatment period, and the remainder killed after 48 hours' survival. In all animals, lumbar spinal cord tissue specimens were frozen for subsequent Western blot analysis of heat shock protein 70 (HSP 70), and for the p85 fragment of poly (ADP-ribose) polymerase (PARP). Neuronal viability indices were determined at 48 hours with hematoxylin and eosin staining. RESULTS: There was improvement in neurologic function in rabbits receiving ATL-146e (P <.001) compared with ischemic controls. At the end of the 3-hour treatment period there was a 46% (P <.05) decrease in HSP 70 expression in the ATL-146e group compared with the control group, but no difference in PARP expression. At 48 hours, there was no difference between control and ATL-146e groups in HSP 70 expression, but there was a 65% (P <.05) reduction in PARP in the spinal cords of animals that had received ATL-146e. There was a significant improvement in neuronal viability indices in animals receiving ATL-146e compared with ischemic controls (P <.05). CONCLUSIONS: Systemic ATL-146e infusion during reperfusion after spinal cord ischemia results in preservation of hindlimb motor function. There is evidence of decreased spinal cord inflammatory stress immediately after treatment with ATL-146e as indicated by reduced HSP 70 induction. Treatment with ATL-146e is associated with a reduction in neuronal apoptosis as suggested by a substantial decrease in the fragmentation of PARP at 48 hours. These results suggest that inflammation during reperfusion and subsequent apoptosis contribute to paralysis after restoration of blood flow to the ischemic spinal cord.

A technique for adequate coverage of the proximal suture line during abdominal aortic aneurysm repair.

The proximal suture line is a vulnerable area after abdominal aortic aneurysm repairs. This area has been implicated in various postoperative complications, such as pseudoaneurysm formation, graft-enteric fistula, and suture line disruption. We present a technique that provides safe and adequate coverage of this suture line by using the aneurysm sac. This technique is derived from the z-plasty technique used for scar revision. The technique is illustrated with detailed line drawings. None of the patients in whom we used this technique have had any complications related to the proximal suture line.

Adenosine analogue reduces spinal cord reperfusion injury in a time-dependent fashion.

BACKGROUND: We hypothesized that inflammation during spinal cord reperfusion worsens ischemic injury. ATL-146e, an adenosine A(2A) agonist with known anti-inflammatory properties, was used to test this hypothesis at varied intervals to determine the time course of reperfusion injury. METHODS: Forty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group (n = 14 animals) received 0.06 microg/kg/min systemic ATL-146e over 3 hours, beginning after 30 minutes of ischemic time. A second group (n = 6 animals) received ATL-146e over 1.5 hours. A third group (n = 3 animals) received ATL-146e over 1 hour, and a fourth group (n = 17 animals) received saline solution. All animals were assessed at 48 hours for hind limb motor function (Tarlov scale, 0-5). RESULTS: Animals that received ATL-146e for 3 hours (Tarlov score, 4.3 +/- 0.22; P <.001) or 1.5 hours (Tarlov score, 2.7 +/- 0.6; P <.05) had improved neurologic outcomes compared with rabbits that received saline solution (Tarlov score, 0.6 +/- 0.29). Animals that received ATL-146e for 1 hour (Tarlov score, 0.7 +/- 0.8) were not significantly different from those animals that received saline solution. CONCLUSIONS: Systemic ATL-146e, given during reperfusion, results in time-dependent improvement in spinal cord function after ischemia. This implies that the mechanism of spinal reperfusion injury includes leukocyte-mediated inflammation at a critical post-ischemic time interval.

Epidermal growth factor receptor up-regulation is associated with lung growth after lobectomy.

BACKGROUND: We hypothesized that compensatory lung growth after lobectomy is characterized by a combination of cellular hyperplasia and hypertrophy and that up-regulation of epidermal growth factor receptor (EGFR) is involved in these processes. METHODS: Age-matched mature pigs were divided into four groups. The control group (group C) did not have operation. Two groups underwent left upper lobectomy and were studied 2 weeks (group L2) or 3 months (group L3) later. The last group underwent a sham left thoracotomy, and the left lower lobe was harvested 2 weeks later for EGFR analysis. Left lower lobes were studied using wet weight, cell proliferation index through immunostaining for 5-bromo-2'-deoxyuridine, morphometry, and Western blot analysis for EGFR. Content of protein and DNA (deoxyribonucleic acid) in the lung tissue was also determined. RESULTS: Left lower lobe weights were elevated in both groups L2 and L3 compared with group C. We noted a significant rise in the proliferation index, with a concomitant increase in EGFR expression, in group L2 compared with group C. In group L3, there was an increase in the protein to DNA ratio compared with group C. CONCLUSIONS: We conclude that compensatory lung growth after lobectomy comprises an early increase in the cell proliferation index (ie, cellular hyperplasia) and a late increase in the protein to DNA ratio (ie, cellular hypertrophy). The early proliferative phase is associated with EGFR up-regulation.

CT findings following the cabrol composite graft procedure.

PURPOSE: Insertion of a composite graft and reimplantation of the coronary arteries through an intermediate Dacron tube (Cabrol composite graft procedure) has been used to treat ascending aortic aneurysms and dissections. The CT findings after the Cabrol composite graft procedure have not been previously described. METHOD: Retrospective review of 12 postoperative CT and CT angiography (CTA) studies both in the immediate postoperative period as well as during long-term follow-up was conducted. RESULTS: The Cabrol composite graft procedure produces typical CT findings consisting of a coronary conduit separate from the aortic graft. The presence of perigraft flow can be normal or abnormal depending on the time point of its occurrence and the extent of its hemodynamic consequences. CONCLUSION: Knowledge of the typical CT and CTA findings following a Cabrol composite graft procedure is essential for the correct interpretation of these studies.

Cardiac reoperation in the intensive care unit.

BACKGROUND: At our institution, cardiac reoperations are routinely performed in the cardiac intensive care unit, as opposed to taking these patients back to the operating room. Our hypothesis was that reoperation in a cardiac intensive care unit does not increase sternal infection rate. METHODS: A retrospective analysis was performed on 6,908 adult patients undergoing cardiac operation over a 9-year period. Excluding those in cardiac arrest, 340 (4.9%) patients underwent reoperation in the cardiac intensive care unit, of which 289 survived (85%). RESULTS: Of the 289 patients who survived reoperation in the intensive care unit, 6 developed wound infections that required operative debridement (2.1%), which was not significantly different from those patients not requiring reoperation (1.9%, 121 of 6,497, p = 0.70). Hospital charges for a 2-hour reoperation in the intensive care unit and operating room are approximately $1,972/patient and $5,832/patient, respectively. CONCLUSIONS: Reoperation in the intensive care unit does not increase wound infection rate compared to those without reoperation. Decreased charges, avoiding transport of potentially unstable patients, quicker time to intervention, and convenience are advantages of reoperation in an intensive care unit.

Lung transplant reperfusion injury involves pulmonary macrophages and circulating leukocytes in a biphasic response.

OBJECTIVE: Both donor pulmonary macrophages and recipient circulating leukocytes may be involved in reperfusion injury after lung transplantation. By using the macrophage inhibitor gadolinium chloride and leukocyte filters, we attempted to identify the roles of these two populations of cells in lung transplant reperfusion injury. METHODS: With our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest followed by 18-hour cold storage and 2-hour blood reperfusion. Measurements of pulmonary artery pressure, lung compliance, and arterial oxygenation were obtained. Group I (n = 8) served as a control. Group II (n = 8) received gadolinium chloride at 14 mg/kg 24 hours before lung harvest. Group III (n = 8) received leukocyte-depleted blood reperfusion by means of a leukocyte filter. RESULTS: The gadolinium chloride group had significantly improved arterial oxygenation and pulmonary artery pressure measurements compared with control subjects and an improved arterial oxygenation compared with the filter group after 30 minutes of reperfusion. After 120 minutes of reperfusion, however, the filter group had significantly improved arterial oxygenation and pulmonary artery pressure measurements compared with the control group and an improved arterial oxygenation compared with the gadolinium chloride group. CONCLUSIONS: Lung transplant reperfusion injury occurs in two phases. The early phase is mediated by donor pulmonary macrophages and is followed by a late injury induced by recipient circulating leukocytes.

Retinoic acid enhances lung growth after pneumonectomy.

BACKGROUND: We sought to identify the role of retinoic acid (RA) upon lung growth. RA has a role in perinatal lung development, and we hypothesized that exogenous RA would enhance postpneumonectomy compensatory lung growth. METHODS: Utilizing the postpneumonectomy rat model, we studied the impact of RA upon contralateral lung growth. Adult Sprague-Dawley rats were divided into three groups. Group S underwent a sham left thoracotomy, group P underwent left pneumonectomy, and group R underwent left pneumonectomy with administration of exogenous RA (0.5 microg/g/day intraperitoneally). We then quantitated right lung growth after 10 and 21 days. Lung weight and volume were expressed as a ratio to the final body weight (lung weight and volume indices, LWI and LVI). Epidermal growth factor receptor (EGFR) expression was quantitated using Western blot analysis. Cellular proliferation index (CPI) was determined using BrdU immunostaining. RESULTS: LWI, LVI, CPI, and EGFR expression at 21 days were significantly higher in group R versus S and P. At the 10-day interval, both LWI and LVI were significantly higher in group R versus S and P. CONCLUSIONS: RA administration markedly enhances lung growth after pneumonectomy, as evidenced by increases in LWI, LVI, and CPI. Upregulation of EGFR expression was associated with these effects.

Early intervention after severe oxygenation index elevation improves survival following lung transplantation.

BACKGROUND: Reperfusion injury and technical problems following lung transplantation may result in life-threatening pulmonary dysfunction that requires intervention with either extracorporeal membrane oxygenation or reoperation. Early intervention in these patients could prevent complications associated with delayed or emergent intervention and may improve survival. The oxygenation index [(mean airway pressure x percent of inspired oxygen)/partial pressure of arterial oxygen] provides a rapid assessment of pulmonary function in the critical phase of reperfusion. Our hypothesis was that the oxygenation index could be used as an early predictor for severe respiratory failure requiring acute intervention. METHODS: Analysis of 136 consecutive lung transplant operations revealed 18 patients (reperfusion injury in 16 and technical complications in 2) with an oxygen index of > or = 30. Of those patients with reperfusion injury, 9 had fibrotic lung disease, 4 had obstructive lung disease, and 3 had primary pulmonary hypertension. RESULTS: Patients undergoing transplantation for fibrotic lung diseases were more likely to develop severe reperfusion injury (oxygenation index > or = 30) compared to patients with obstructive lung diseases (9 of 42 or 21% vs 4 or 80 or 5%, p = 0.005). The 5 patients with early intervention (< or = 2 hours) after an oxygenation index elevation above 30 had significantly improved survival compared to the 13 with no or late intervention (80% vs 15% survival, p = 0.02). CONCLUSION: Oxygenation index elevation > or = 30 following lung transplantation is an early predictor of severe respiratory failure requiring acute intervention. Early intervention in these patients improves survival.

Pulmonary macrophages are involved in reperfusion injury after lung transplantation.

BACKGROUND: Reperfusion injury is a perplexing cause of early graft failure after lung transplantation. Although recipient neutrophils are thought to have a role in the development of reperfusion injury, some researchers have shown that neutrophils are not involved in its earliest phase. Intrinsic donor pulmonary macrophages may be responsible for this early phase of injury. Using the macrophage inhibitor gadolinium chloride, we attempted to investigate the role of pulmonary macrophages in reperfusion injury after lung transplantation. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest followed by 18-hour storage (4 degrees C) and blood reperfusion for 30 minutes. Group I served as a control. Group II received gadolinium chloride at 7 mg/kg 24 hours before harvest. Group III received gadolinium chloride at 14 mg/kg 24 hours before harvest. RESULTS: Group III had significantly improved arterial oxygenation and pulmonary artery pressures compared with groups I and II after 30 minutes of reperfusion. CONCLUSIONS: The earliest phase of reperfusion injury after lung transplantation involves donor pulmonary macrophages.