Stewart M. Long

Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome.

BACKGROUND Bronchiolitis obliterans syndrome (BOS) is the most common cause of long-term morbidity and mortality after lung transplantation. Our hypothesis was that early ischemia-reperfusion injury after lung transplantation increases the risk of BOS. METHODS Data on 134 patients who had lung transplantation between January 1, 1990 and January 1, 2000, was used for univariate and multivariate logistic regression analysis. RESULTS After lung transplantation, 115 patients (115 of 134, 86%) survived more than 3 months. In that group, 41 patients developed BOS, of which 23 had progressive disease. Univariate analysis revealed that ischemia-reperfusion injury (p = 0.017) and two or more acute rejection episodes (p = 0.032) were predictors of BOS onset, whereas ischemia-reperfusion injury (p = 0.011) and cytomegalovirus infection (p = 0.009) predicted progressive BOS. Multivariate logistic regression analysis showed that ischemia-reperfusion injury was an independent predictor for both BOS development and BOS progression. Two or more acute rejection episodes were also an independent predictor of BOS development, whereas cytomegalovirus infection was an independent predictor of progressive BOS. CONCLUSIONS Ischemia-reperfusion injury increases the risk of BOS after lung transplantation.

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.

When to discontinue extracorporeal membrane oxygenation for postcardiotomy support

BACKGROUND Extracorporeal membrane oxygenation (ECMO) has demonstrated limited success in adult postcardiotomy shock. The goal of this study was to determine when to discontinue ECMO for postcardiotomy support. METHODS During a 7-year period ECMO was used in 51 postcardiotomy patients, of whom 16 (31%) weaned and 8 (16%) survived. RESULTS Patients in the heart transplant group were more likely to wean compared with patients in the non-heart transplant group (p = 0.03). Patients aged greater than 65 years (p = 0.04) or with ejection fractions of less than 30% after 48 hours of ECMO (p < 0.001) were less likely to wean. Time on ECMO was significantly longer for survivors in the heart transplant group (101.3 +/- 7.5 hours) compared with survivors in the non-heart transplant group (28.3 +/- 11.9 hours, p < 0.001). CONCLUSIONS After 48 to 72 hours, consideration should be given to discontinuing ECMO, either by moving to an implantable ventricular assist device or by withdrawal of support, except in those patients with heart transplants. In the latter, both severe postoperative pulmonary hypertension and reperfusion injury may take as long as 120 hours to reverse.

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.

Adenosine A2A agonist reduces paralysis after spinal cord ischemia: correlation with A2A receptor expression on motor neurons1

BACKGROUND The adenosine A2A agonist ATL-146e ameliorates reperfusion inflammation, reducing subsequent paralysis and neuronal apoptosis after spinal cord ischemia. We hypothesized that neuroprotection with ATL-146e involves inducible neuronal adenosine A2A receptors (A2A-R) that are upregulated after ischemia. METHODS Eighteen rabbits underwent laparotomy, and 14 sustained spinal cord ischemia from cross-clamping the infrarenal aorta for 45 minutes. One group (ischemia-reperfusion [I/R] + ATL) received ATL-146e intravenously for 3 hours during spinal cord reperfusion. A second group (I/R) received equivolume intravenous saline solution for 3 hours and served as an ischemic control, and a third group (Sham) underwent sham laparotomy. At 48 hours, all subjects were assessed for motor impairment using the Tarlov scoring system (0 to 5). Lumbar spinal cord sections were immunolabeled for A2A-R and graded in a blinded fashion using light microscopy. RESULTS There was a significant improvement in Tarlov scores in I/R + ATL animals compared with the I/R group. Sham-operated animals demonstrated no A2A-R immunoreactivity. There was a dramatic increase in A2A-R immunoreactivity in neurons of lumbar spinal cord sections from I/R compared with I/R + ATL and sham-operated animals. CONCLUSIONS Reduction in paralysis in animals receiving ATL-146e correlates with the new finding of A2A-R expression on lumbar spinal cord motor neurons after ischemia. Adenosine A2A agonists may exert neuroprotective effects by binding to inducible neuronal A2A-R that are upregulated during spinal cord reperfusion, and reduced in response to administration of an A2A-R-specific agonist.

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.

Elimination of fat microemboli during cardiopulmonary bypass

BACKGROUND Fat emboli have been implicated in cerebral dysfunction after cardiopulmonary bypass (CPB). We sought to identify the source of fat emboli during CPB and devise a technique for their elimination. METHODS Patients undergoing CPB were prospectively randomized to either cardiotomy suction (n = 7) or cell-saving suction device (n = 6). Blood was collected at various intervals during CPB, and the fat emboli were identified using oil red O stain. These emboli were grouped based on their diameter into 10- to 50-microm and more than 50-microm particles. The number of fat emboli per slide examined was graded according to the following scale: 1 (1 to 10), 2 (11 to 20), 3 (21 to 30), and 4 (> 30 emboli). In the second phase of the experiment, a 21-microm filter was attached in series, distal to the cardiotomy reservoir (n = 6), and fat emboli were quantified. RESULTS Blood from the pericardial well was saturated with fat emboli of both sizes. Patients randomized to the cardiotomy suction had a significantly higher number of fat emboli at the end of CPB when compared with those randomized to the cell-saving suction device and dual-filter group. Processed blood from both the cardiotomy reservoir and cell-saving device was noted to have an abundance of fat emboli when compared with blood processed through the dual filters. CONCLUSIONS Processed blood from both the cardiotomy reservoir and cell-saving device appear to have an abundance of fat emboli that are completely eliminated by using a 21-microm arterial filter in series with the cardiotomy reservoir. This intervention could potentially reduce neurocognitive dysfunction associated with CPB.

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.

Ventricular Reconstruction Results in Improved Left Ventricular Function and Amelioration of Mitral Insufficiency

IntroductionSurgical restoration of the left ventricular wall (Dor procedure) has been advocated as a therapy for left ventricular dysfunction due to ischemic cardiomyopathy. This procedure involves placement of an endoventricular patch through a ventriculotomy. MethodsWe reviewed our series of patients that underwent the Dor procedure within the past 4 years and examined their pre and postoperative ventricular function and mitral valve function. Pre and postoperative ejection fraction and degree of mitral regurgitation were analyzed using the paired Student t-test. We hypothesized that this procedure would result in improved ventricular function and that it would also help improve mitral valve function. ResultsThirty-four patients underwent this procedure, with one death. Of these, 30 patients underwent concomitant coronary artery bypass grafting and 8 patients had mitral intervention (seven had an Alfieri repair of the mitral valve, and one had mitral valve annuloplasty). The average preoperative ejection fraction among these patients was 26.8% (range 10–45%). The postoperative ejection fraction was significantly higher at 35.4% (range 25–52%) (P < .001). We noted an improvement in ejection fraction in 27 patients (82%). We also noted that 21 of 33 patients (64%) had improvement in the degree of mitral regurgitation based on echocardiography data (P < .001). ConclusionsWe conclude that the Dor procedure results in improvement in the left ventricular function. Furthermore, we also note that this procedure ameliorates mitral regurgitation in a majority of these patients even in the absence of associated mitral valve procedures, probably due to reduction in the size of the ventricle and improved orientation of the papillary muscles.

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.