Aditya K. Kaza

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.

Analysis of the US Food and Drug Administration Manufacturer and User Facility Device Experience Database for Adverse Events involving Amplatzer Septal Occluder Devices and Comparison with the Society of Thoracic Surgery Congenital Cardiac Surgery Database

OBJECTIVE Amplatzer (AGA Medical Corporation, Plymouth, Minn) septal and vascular occluder devices have significantly altered the care of patients with congenital heart disease. The relative frequency and consequence of complications resulting from the attempted placement of such devices, however, have not been well assessed. The purpose of this study is to use large databases to assess the frequency and severity of such complications and compare them with those of surgical atrial septal defect closure. METHODS The US Food and Drug Administration Manufacturer and User Facility Device Experience database was quarried for all adverse events for Amplatzer septal occluder devices, which were categorized and analyzed with particular emphasis on management and outcome. The Society of Thoracic Surgery database was likewise quarried for the same data regarding atrial septal defect closures over a contemporaneous time period. By using a literature-derived denominator for total Amplatzer implant numbers, the results of the 2 therapies were compared. RESULTS Since July 1, 2002, 223 adverse events in patients undergoing Amplatzer atrial septal defect closure were submitted to the Food and Drug Administration, resulting in 17 deaths (7.6%) and 152 surgical rescue operations (68.2%). Society of Thoracic Surgery data demonstrated 1537 primary operations with 2 deaths (0.13%) and 6 reoperations (0.39%). By extrapolating on published estimates of Amplatzer implantation to provide an implant denominator (n = 18,333), there was no difference between overall mortality for surgical (0.13%) and device closure (0.093%, P = .649). Rescue operation for device adverse events (0.83%) was 2.1 times more likely than reoperation for surgical closure (0.39%, P = .063). Mortality per adverse event was higher for device closure (7.6%) than for surgical closure (1.2%, P = .004), and the need for surgery per adverse event was higher for device closure (68.2%) than for surgical closure (3.6%, P < .001). The mortality for surgical management of a device adverse event (2.6%) was 20-fold higher than for primary elective atrial septal defect closure (0.13%, P < .0001). CONCLUSION Overall crude mortality for device and surgical closure atrial septal defect closure is equivalent, and the need for subsequent operation (surgical rescue) is more common in patients undergoing device closure than reoperation is in patients undergoing surgical closure. Complications from device closure tend to be serious and most often require urgent or emergency operative management, whereas the mortality for surgical management of a device complication appears higher than that of elective atrial septal defect closure. Further information is required in the form of postmarketing surveillance, such as a mandatory user registry with periodic end-user notification.

Evaluating Failing Fontans for Heart Transplantation: Predictors of Death

BACKGROUND Late complications of the Fontan operation represent a significant management challenge. Failing Fontan patients have two modes of presentation: impaired ventricular function (IVF) and those with preserved ventricular function (PVF) but with failing Fontan physiology (protein-losing enteropathy [PLE] and plastic bronchitis [PB]). This study evaluated whether failing Fontan patients referred for heart transplantation had a different outcome based on the mode of presentation. METHODS The medical records of all Fontan patients evaluated for heart transplantation at a single institution from 1994 to 2008 were retrospectively reviewed. Demographic, hemodynamic, and laboratory data were collected. Patients were stratified into an IVF or PVF group by echocardiographic criteria. Descriptive statistics and Kaplan-Meier analysis were used for hypothesis testing. RESULTS Thirty-four Fontan patients were evaluated for heart transplantation. According to echo description of systolic function, 18 were categorized as IVF and 16 as PVF. The IVF group had a significantly lower cardiac index and venous oxygen saturation, and significantly higher systemic vascular resistance vs the PVF group (p < 0.05). PLE or PB was present in 13 PVF patients and none in the IVF group. Twenty patients underwent transplantation, with similar rates amongst the IVF and PVF groups. Within 1 year from evaluation, 2 IVG patients and 7 PVF patients had died (p = 0.052). CONCLUSIONS Failing Fontan patients with PVF have decreased overall survival independent of whether they underwent transplantation. This trend indicates a need to improve the management and timing for transplantation amongst this population.

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.

Variation in Perioperative Care across Centers for Infants Undergoing the Norwood Procedure

OBJECTIVES In the Single Ventricle Reconstruction trial, infants undergoing the Norwood procedure were randomly allocated to undergo a right ventricle-to-pulmonary artery shunt or a modified Blalock-Taussig shunt. Apart from shunt type, subjects received the local standard of care. We evaluated variation in perioperative care during the Norwood hospitalization across 14 trial sites. METHODS Data on preoperative, operative, and postoperative variables for 546 enrolled subjects who underwent the Norwood procedure were collected prospectively on standardized case report forms, and variation across the centers was described. RESULTS Gestational age, birth weight, and proportion with hypoplastic left heart syndrome were similar across sites. In contrast, all recorded variables related to preoperative care varied across centers, including fetal diagnosis (range, 55%-85%), preoperative intubation (range, 29%-91%), and enteral feeding. Perioperative and operative factors were also variable across sites, including median total support time (range, 74-189 minutes) and other perfusion variables, arch reconstruction technique, intraoperative medication use, and use of modified ultrafiltration (range, 48%-100%). Additional variation across centers was seen in variables related to postoperative care, including proportion with an open sternum (range, 35%-100%), median intensive care unit stay (range, 9-44 days), type of feeding at discharge, and enrollment in a home monitoring program (range, 1%-100%; 5 sites did not have a program). Overall, in-hospital death or transplant occurred in 18% (range across sites, 7%-39%). CONCLUSIONS Perioperative care during the Norwood hospitalization varies across centers. Further analysis evaluating the underlying causes and relationship of this variation to outcome is needed to inform future studies and quality improvement efforts.

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.

Would access to device therapies improve transplant outcomes for adults with congenital heart disease? Analysis of the United Network for Organ Sharing (UNOS)

BACKGROUND Patients with congenital heart disease (CHD) now survive into adulthood and often present with end-stage heart failure (HF). HF management and approach to orthotopic heart transplant (OHT) may differ from adults without CHD. We sought to compare OHT waitlist characteristics and outcomes for these 2 groups. METHODS The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database was used to identify adults (≥18 years) listed for OHT from 2005 to 2009. The cohort was divided into those with or without CHD. RESULTS Of 9,722 adults included, 314 (3%) had CHD. Adults with CHD were younger (35 ± 13 vs 52 ± 12 years, p < 0.01) and more often had undergone prior cardiac surgery (85% vs. 34%, p < 0.01). Patients with CHD were less likely to have a defibrillator (44% vs 75%, p < 0.01) or ventricular assist device (5% vs 14%, p < 0.01) and were more likely to be listed at the lowest urgency status than patients without CHD (64% vs 44%, p < 0.01). Fewer CHD patients achieved OHT (53% vs 65%, p < 0.001). Although overall waitlist mortality did not differ between groups (10% vs 8%, p = 0.15), patients with CHD were more likely to experience cardiovascular death (60% vs 40%, p = 0.03), including sudden in 44% and due to HF in 16%. CONCLUSIONS Despite lower urgency status, patients with CHD have greater cardiovascular mortality awaiting OHT than those without. Increased defibrillator use could improve survival to OHT, because sudden death is common. VAD support may benefit select patients, but experience in CHD is limited. Referral to specialized adult congenital heart centers can enhance utilization of device therapies and potentially improve waitlist outcomes.