Effect of ischemic time on survival in clinical lung transplantation

Background. While there is convincing evidence that prolonged ischemic times correlate with reduced long-term survival in heart transplantation, the effect of ischemic time on outcome in clinical lung transplantation remains controversial. To assess the effect of ischemic time on outcomes in lung transplantation, we reviewed our experience.

Methods. The study was performed by retrospective chart review.

Results. First-time lung transplantation was performed on 392 patients between 1988 and 1998. All grafts were flushed with cold crystalloid preservation solution and stored on ice. Ischemic time data were available for 352 of 392 (90%) patients. Ischemic times were grouped as follows: 0 to 4 hours (n = 91), 4 to 6 hours (n = 201), more than 6 hours (n = 60). Ischemic time did not correlate with survival: 3-year actuarial survival = 56% (0 to 4 hours), 58% (4 to 6 hours), 68% (> 6 hours), p = 0.58. There was no significant difference in the incidence of biopsy-proven diffuse alveolar damage in the first 30 days after transplantation (31%, 32%, 38%), episodes of acute rejection in the first 100 days after transplantation (1.9, 1.8, 1.7), duration of intubation (median 3, 4, 3 days), or incidence of obliterative bronchiolitis (23%, 28%, 26%) between the three groups (0 to 4 hours, 4 to 6 hours, > 6 hours, respectively). A diagnosis of diffuse alveolar damage was associated with a significantly worse outcome (1-year survival = 82% versus 54%, p < 0.0001).

Conclusions. In contrast to heart transplantation, pulmonary allograft ischemic time up to 9 hours does not appear to have a significant impact on early graft function or survival. The presence of diffuse alveolar damage on biopsy early after transplantation does not correlate with prolonged ischemic time, but is associated with substantially reduced posttransplantation survival.     

Outcome of lung transplantation for patients requiring concomitant cardiac surgery

BACKGROUND: The clinical results of lung transplantation and concomitant cardiac surgery are unclear. The effect of cardiopulmonary bypass on the pulmonary allograft is controversial, and the effect of cardiac arrest and cardiac surgery in this setting is unknown. Our aim was to review the operative results and long-term survival in this group of patients. METHODS: A retrospective review of all lung transplantations between 1988 and 2003 was performed. Patients who had concomitant cardiac surgery during lung transplantation were compared with those who underwent lung transplantation alone. The variables analyzed included allograft ischemic times, use of cardiopulmonary bypass, early graft dysfunction, postoperative morbidity, survival, length of mechanical ventilation, length of stay in the intensive care unit, and overall hospital stay. RESULTS: During this period, 35 of 700 lung transplant recipients (15 single and 20 bilateral transplantations) underwent concomitant cardiac surgery. The cardiac procedures were for patent foramen ovale (n = 18), atrial septal defect (n = 9), ventricular septal defect (n = 2), coronary bypass (n = 4), and "other" (n = 2). Allograft ischemic time, use of extracorporeal membrane oxygenation, length of hospital stay, operative mortality, and survival were not significantly different between the 2 groups. Ventilator time and intensive care unit stay were longer in the cardiac surgery group. CONCLUSIONS: Cardiac surgery at the time of lung transplantation can be performed with acceptable morbidity and mortality. The immediate and long-term survival in these patients is similar to that of other lung transplant recipients. Lung transplantation should continue to be offered to patients with normal ventricular function who require concomitant limited cardiac surgery.     

Lung procurement by low-potassium dextran and the effect on preservation injury. Munich Lung Transplant Group.

BACKGROUND: This clinical study was performed to evaluate the effect of low-potassium dextran (LPD) solution on organ function in human lung transplantation. METHODS: A total of 80 patients were included in this study. Donor lungs were flushed with Euro-Collins (EC) solution in 48 cases or LPD (Perfadex) in 32 cases. Subsequently, single- (EC: n = 31; LPD: n = 15) or double-lung transplantations (EC: n = 17; LPD: n = 17) were performed. The evaluation parameters of transplant function were the reperfusion injury score (grade I to V); the alveolar/arterial oxygen ratio; the duration of respirator therapy; and the length of intensive care treatment and survival. RESULTS: Incidence and severity of reperfusion injury score were more severe in the EC group (31 of 48: grade I: n = 13; II: n = 8; III: n = 5; IV: n = 2; V: n = 3; LPD group: 17 of 32 patients; grade I: n = 12; II: n = 1; III: n = 3; IV: n = 0 grade V: n = 0), leading to death in three patients. In the LPD group, despite of the use of cardiopulmonary bypass, alveolar/arterial oxygen ratio values were significantly (P = 0.009) better during the early postoperative phase. Thirty-day mortality was 12% in the EC group and 6% in the LPD group. The one-year survival rate was 79% after the use of LPD (vs. EC: 62%). CONCLUSIONS: Graft preservation using LPD leads to better immediate and intermediate graft function after pulmonary transplantation and also results in better long-term survival.     

Buttressing the staple line in lung volume reduction surgery: a randomized three-center study

Background. The intention of buttressing the staple line in lung volume reduction surgery is to reduce air leaks and to shorten the hospital stay. A randomized three-center study was carried out to test this hypothesis.

Methods. Sixty-five patients with a mean age of 59.2 ± 1.2 years underwent bilateral lung volume reduction surgery by video-assisted thoracoscopy using endoscopic staplers (ET 45B; Ethicon Endo-Surgery, Cincinnati, OH) either without or with bovine pericardium for buttressing (Peri-Strips Dry; Bio-Vascular, Inc, Saint Paul, MN). There were no differences between the control and treatment groups in lung function, degree of dyspnea, and arterial blood gases before and 3 months after LVRS.

Results. Seven patients (3 in the treatment group) needed a reoperation because of persistent air leak. The median duration of air leaks was shorter in the treatment group (0.0 day [range, 0 to 28 days versus 4 days [range, 0 to 27 days); p < 0.001), confirmed by a shorter median drainage time in this group (5 days [range, 1 to 35 days] versus 7.5 days [range, 2 to 29 days); p = 0.045). Hospital stay was comparable between the two groups (9.5 days [range, 6 to 44 days] versus 12.0 days [range, 5 to 46 days]; p = 0.14).

Conclusions. Buttressing the staple line significantly shortens the duration of air leaks and the drainage time. As hospital stay did not differ significantly between the two groups, cost-effectiveness may depend on the local situation.     

Intratracheal Surfactant Administration Preserves Airway Compliance During Lung Reperfusion

Background. Decreased airway compliance after lung transplantation has been observed with severe ischemia-reperfusion injury. Further, it has been shown that the surfactant system is impaired after lung preservation and reperfusion. We hypothesized that surfactant replacement after allograft storage could preserve airway compliance during reperfusion.

Methods. Rabbit lungs were harvested after flush with 50 mL/kg of cold saline solution. Immediate control lungs were studied with an isolated ventilation/perfusion apparatus using venous rabbit blood recirculated at 40 mL/min, room-air ventilation at 20 breaths/min, and constant airway pressure (n = 8). Twenty-four-hour control lungs were preserved at 4°C for 24 hours and then similarly studied (n = 7). Surfactant lungs underwent similar harvest and preservation for 24 hours, but received 1.5 mL/kg of intratracheal surfactant 5 minutes before reperfusion (n = 10). Airway pressure and flow were recorded continuously during 30 minutes of reperfusion. Tidal volume and airway compliance were calculated at 30 minutes.

Results. Tidal volume was 33.67 ± 0.57, 15.75 ± 5.72, and 29.83 ± 1.07 mL in the immediate control, 24-hour control, and surfactant groups, respectively (p = 0.004, surfactant versus 24-hour control). Airway compliance was 1.94 ± 0.27, 0.70 ± 0.09, and 1.46 ± 0.10 mL/mm Hg in the immediate control, 24-hour control, and surfactant groups, respectively (p = 0.002, surfactant versus 24-hour control).

Conclusions. We conclude that surfactant administration before reperfusion after 24 hours of cold storage preserves tidal volume and airway compliance in the isolated ventilated/perfused rabbit model of lung reperfusion injury.     

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°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 · kg⁻¹ · 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.     

Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation

Background. Reperfusion injury after pulmonary transplantation can contribute significantly to postoperative pulmonary dysfunction. We hypothesized that posttransplantation reperfusion injury would result in an increase in both in-hospital mortality and morbidity. We also hypothesized that the incidence of reperfusion injury would be dependent upon the cause of recipient lung disease and the interval of donor allograft ischemia.

Methods. We performed a retrospective study of all lung transplant recipients at our institution from June 1990 until June 1998. One hundred patients received 120 organs during this time period. We compared two groups of patients in this study: those experiencing a significant reperfusion injury (22%) and those who did not (78%).

Results. In-hospital mortality was significantly greater in patients experiencing reperfusion injury (40.9% versus 11.7%, p < 0.02). Posttransplantation reperfusion injury also resulted in prolonged ventilation (393.5 versus 56.8 hours, p < 0.001) and an increased length of stay in both the intensive care unit (22.2 versus 10.5 days, p < 0.01) and in the hospital (48.8 versus 25.6 days, p < 0.03). The incidence of reperfusion injury could not be attributed to length of donor organ ischemia (221.5 versus 252.9 minutes, p < 0.20). The clinical impact of reperfusion injury was significantly greater in patients undergoing transplantation for preexisting pulmonary hypertension (6/14) than those with chronic obstructive pulmonary disease or emphysema alone (6/54) (42.9% versus 11.1%, p < 0.012).

Conclusions. Clinically significant pulmonary reperfusion injury increased in-hospital mortality and morbidity resulting in prolonged ventilation, length of stay in the intensive care unit, and cost of hospitalization. The incidence of reperfusion injury was not dependent upon the duration of donor organ ischemia but increased with the presence of preoperative pulmonary hypertension. These findings suggest that recipient pathophysiology and donor allograft quality may play important roles in determining the incidence of reperfusion injury.     

Reliable eighteen-hour lung preservation at 4 degrees and 10 degrees C by pulmonary artery flush after high-dose prostaglandin E1 administration.

Pulmonary preservation is improved by hypothermia, but the optimal preservation temperature is not known. The effects of two different preservation temperatures, 4 degrees and 10 degrees C, on lung function were studied in a canine left lung allograft survival model allowing selective perfusion of either lung. After donor treatment with high-dose prostaglandin E1, (25 micrograms/kg), lungs were flushed with modified Euro-Collins solution (50 ml/kg) and stored in Euro-Collins solution for 18 hours at 4 degrees C in group I (n = 8) and 10 degrees C in group II (n = 6). Pulmonary gas exchange and hemodynamics were compared on the day of transplantation (day 0) and 3 days later (day 3). Rapid, high-flow, low-pressure flush was achieved uniformly in both groups (flush time: group I, 35.1 +/- 2.4 second; group II, 35.3 +/- 3.0 seconds; p = 0.96; flush pressure: group I, 9.8 +/- 0.7 mm Hg; group II, 10.1 +/- 1.1 mm Hg; p = 0.8). Transplanted lungs provided similar excellent oxygenation in both groups on day 0 (arterial oxygen tension, group I, 451 +/- 82 mm Hg; group II, 497 +/- 37 mm Hg; p = 0.61; inspired oxygen fraction = 1.0) and day 3 (arterial oxygen tension, group I, 551 +/- 57 mm Hg; group II, 587 +/- 19 mm Hg; p = 0.55), with a statistically significant improvement from day 0 to day 3 in both groups (group I, p = 0.034; group II, p = 0.038). There was no difference in arterial carbon dioxide tension, base excess, cardiac output, blood pressure or pulmonary artery pressure between the two groups. We conclude that a large bolus of prostaglandin E1 into the pulmonary artery produces a high-flow, low-pressure flush with modified Euro-Collins solution; with this technique, equivalent, reliable 18-hour lung preservation can be achieved at 4 degrees and 10 degrees C flush and storage temperatures.     

Gene transfer of tumor necrosis factor inhibitor improves the function of lung allografts

BACKGROUND: Tumor necrosis factor is an important mediator of lung transplant acute rejection. Soluble type I tumor necrosis factor receptor binds to tumor necrosis factor-alpha and -beta and inhibits their function. The objectives of this study were to demonstrate efficient in vivo gene transfer of a soluble type I tumor necrosis factor receptor fusion protein (sTNF-RI-Ig) and determine its effects on lung allograft acute rejection. METHODS: Three groups of Fischer rats (n = 6 per group) underwent recipient intramuscular transfection 24 hours before transplantation with saline, 1 x 10(10) plaque-forming units of control adenovirus encoding beta-galactosidase, or 1 x 10(10) plaque-forming units of adenovirus encoding human sTNF-RI-Ig (Ad.sTNF-RI-Ig). One group (n = 6) received recipient intramuscular transfection with 1 x 10(10) Ad.sTNF-RI-Ig at the time of transplantation. Brown Norway donor lung grafts were stored for 5 hours before orthotopic lung transplantation. Graft function and rejection scores were assessed 5 days after transplantation. Time-dependent transgene expression in muscle, serum, and lung grafts were evaluated by using enzyme-linked immunosorbent assay of human soluble type I tumor necrosis factor receptor. RESULTS: Recipient intramuscular transfection with 1 x 10(10) plaque-forming units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered 24 hours before transplantation compared with saline, beta-galactosidase, and Ad.sTNF-RI-Ig transfection at the time of transplantation (435.8 +/- 106.6 mm Hg vs 142.3 +/- 146.3 mm Hg, 177.4 +/- 153.7 mm Hg, and 237.3 +/- 185.2 mm Hg; P =.002,.005, and.046, respectively). Transgene expression was time dependent, and there was a trend toward lower vascular rejection scores (P =.066) in the Ad.sTNF-RI-Ig group transfected 24 hours before transplantation. CONCLUSIONS: Recipient intramuscular Ad.sTNF-RI-Ig gene transfer improves allograft function in a well-established model of acute rejection. Maximum benefit was observed when transfection occurred 24 hours before transplantation.     

Combined treatment with endothelin- and PAF-antagonists reduces posttransplant lung ischemia/reperfusion injury.

BACKGROUND: Pathophysiologic changes of posttransplant lung ischemia/reperfusion injury are mediated by redundant cellular and humoral mechanisms. We investigated the protective effect of combined administration of platelet activating factor (PAF) and endothelin (ET) antagonists after prolonged ischemia in a small animal lung transplantation model. METHODS: Orthotopic left lung transplantation was performed after 20 hours cold ischemia in male Fischer (F344) rats weighing 200-250 g. Group I served as control. In Group II, donors received 1 mg/kg body weight of the endothelin antagonist TAK-044, and recipients 2 mg/kg. Group III was treated with the PAF antagonist TCV-309 (donor: 50 microg/kg; recipient: 100 microg/kg) (Takeda Chemicals Ltd.). Group IV received a combined treatment with both substances at the same dosage. Twenty-four hours after reperfusion, the native contralateral lung was occluded to assess gas exchange of the graft only, and 5 minutes later the thoracic aorta was punctured for arterial blood gas analysis (n = 5). In other animals (n = 5), lung tissue was frozen 24 hours after reperfusion and assessed for myeloperoxidase activity (MPO) and thiobarbituric acid reactive substances. RESULTS: Combined inhibition of PAF and ET-1 at the receptor level resulted in significantly improved graft function as compared to controls (Group I), and to groups treated with either TAK-044 or TCV-309. This was determined by a higher arterial oxygen content (112 +/- 9 mmHg, p = .00061 vs control, 48 +/- 5 mmHg), reduced MPO activity (0.35 +/- 0.02 deltaOD/mg/min, p = .000002 vs control, 1.1 +/- 0.1 deltaOD/mg/min) and reduced lipid peroxidation (59.5 +/- 2.5 pmol/g, p = .011 vs control, 78.5 +/- 4.1 pmol/g). The improvement of arterial oxygen (Group II 77 +/- 10 mmHg, p = .027 vs control; Group III 84 +/- 8 mmHg, p = .0081 vs control) and reduction of MPO activity (Group II 0.85 +/- 0.061 deltaOD/mg/min, p = .017; Group III 0.92 +/- 0.079 deltaOD/mg/min, p = .058) in groups treated with either a PAF antagonist or an ET antagonist was significantly less than in Group IV. CONCLUSIONS: Combined donor and recipient treatment with an ET antagonist and a PAF antagonist results in superior posttransplant graft function 24 hours after reperfusion, suggesting a synergistic role of ET-1 and PAF in the mediation of reperfusion injury in this model. Single treatment with either of the antagonists revealed only a slight improvement compared to untreated controls.     

Contralateral Lung Injury Associated With Single-Lung Ischemia-Reperfusion Injury

Background. There have been very few studies on the effect of single-lung ischemia-reperfusion on the function of the contralateral lung. This study was designed to clarify the effect.

Methods. Fifteen mongrel dogs were divided into two groups. In group 1 (n = 7), the left lung was subjected to ischemia without ventilation for 90 minutes, and then reperfused. In group II (n = 8), the lung was not subjected to ischemia, and was ventilated during the 90-minute ischemia of group I. Arterial blood gas, hemodynamics, extravascular lung water, and airway pressure were measured. Pulmonary biopsy was performed to evaluate adenine nucleotide levels. The protein concentration and phosphorous concentration of phospholipids in bronchoalveolar lavage fluid were measured.

Results. Group I, with perfusion and ventilation of the right lung alone, was significantly inferior to group II with respect to arterial blood gas, right pulmonary compliance, extravascular lung water of the right lung, and the protein concentration in the bronchoalveolar lavage fluid of the right lung after the 90-minute period.

Conclusions. These results indicate that 90 minutes of warm ischemia and reperfusion of the left lung caused deterioration of not only the left but also contralateral right pulmonary function.     

Optimizing timing of early extubation in coronary artery bypass surgery patients

Background. This study was designed to assess the safety and efficacy of extubation performed within 4 hours of the patient’s arrival in the surgical intensive care unit after coronary artery bypass graft surgery.

Methods. A matched retrospective cohort study was performed including 412 consecutive patients undergoing isolated coronary artery bypass graft surgery between January 1996 and December 1997, constituting the experience of a single surgeon (J.H.L.). Early extubation (defined as extubation within 8 hours of arrival at the surgical intensive care unit) was achieved in 308 of 412 patients (75%). Patients extubated in fewer than 4 hours after arrival (n = 200) were compared with patients extubated within 4 to 8 hours (n = 108).

Results. Four deaths occurred in 412 patients, for an overall operative mortality rate of 1.0%. Patients extubated in fewer than 4 hours were younger than those extubated 4 or more hours after admission (62 versus 67 years old, respectively; p = 0.001), more likely to be male (74% versus 63%, p < 0.05), and had shorter aortic cross-clamp times (49.4 ± 15.0 versus 53.5 ± 14.0 minutes, p < 0.05) and cardiopulmonary bypass (CPB) times (65.2 ± 18.6 versus 72.1 ± 19.1 minutes, p < 0.05) compared to patients extubated later. Moreover, patients extubated in fewer than 4 hours had a shorter surgical intensive care unit length of stay (33.8 ± 25.7 versus 43.1 ± 43.0 hours, p < 0.05) and shorter postoperative length of stay (5.4 ± 2.4 versus 6.2 ± 2.6 days, p = 0.01) than those extubated later.

Conclusions. Extubation in fewer than 4 hours may offer a substantial advantage in terms of accelerated recovery compared with extubation within 4 to 8 hours. Very few differences in clinical parameters were noted between the two groups we studied, suggesting that efforts to reduce extubation times further might be worthwhile.     

Reperfusion injury in the lung preserved for 24 hours

The left lower lobes of 28 canine lungs were isolated, preserved, and then reperfused for 150 minutes. Five groups of lobes were studied: group 1, control (n = 5); group 2, one hour of warm ischemia (n = 5); group 3, one hour of warm ischemia + oxygen free radical scavengers (n = 5); group 4, 24 hours of cold ischemia (n = 8); and group 5, 24 hours of cold ischemia + oxygen free radical scavengers (n = 5). Oxygen free radical scavengers consisted of superoxide dismutase and catalase (100 micrograms/mL) given at the moment of reflow. Extravascular lung water (grams per gram of blood-free dry lobe weight) after reperfusion was 2.75 +/- 0.19, 5.46 +/- 0.60, 4.08 +/- 0.37, 9.43 +/- 0.98, and 6.91 +/- 0.95 for groups 1 through 5, respectively (p less than 0.05, groups 2 through 5 versus group 1; p less than 0.05, group 2 versus group 3 and group 4 versus group 5). Lung tissue lipid peroxidation, measured as thiobarbituric acid reactive material, was 117 +/- 14, 314 +/- 19, and 163 +/- 25 nmol/g dry lobe weight for groups 1, 4, and 5, respectively (p less than 0.05, group 4 versus group 1 and group 4 versus group 5). The data suggest that oxygen free radical scavengers attenuate reperfusion injury after long-term hypothermic lung preservation.     

The influence of warm and cold ischemic time on the outcome of cadaveric renal transplantation

The influence of warm and cold ischemic time (WIT and CIT) on renal allograft function and allograft survival rates was analyzed from the Eurotransplant data. From 1977 through 1980 renal allograft recipients were divided into three groups, according to the length of the WIT of their graft: group I, 0-10 min (n = 2,636); group II, 11-20 min (n = 108); group III, 21-35 min (n = 17). Differences in graft function or graft survival have not been observed between these groups. It is concluded that donor kidneys with a WIT up to 20 min are acceptable for transplantation. The transplantation results in group III suggest that 35 min is a safe limit for acceptance, but the small number of transplantations in this group does not justify a firm conclusion. A combined analysis of warm and cold ischemia shows that simple cold storage up to 50 h is safe and acceptable, provided that warm ischemia is kept minimal (less than 10 min). It seems advisable to keep hypothermic preservation within the limit of 30 h, when WIT exceeds 10 min.     

8-Br-cyclic GMP given during reperfusion improves post-transplant lung edema and free radical injury.

Substitution of the NO-pathway reduces ischemia/reperfusion injury following lung transplantation. 8-Br-cGMP is a membrane permeable analogue of cGMP, the second messenger of NO. In this study the effect of continuous administration of 8-Br-cGMP on early graft function was evaluated. METHODS: Unilateral left lung transplantation was performed in 10 weight-matched pigs (23-30 kg). Donor lungs were flushed with 1.51 cold (1 degree C) LPD solution and preserved for 20 hours. In Group I (n = 5), 8-Br-cGMP (0.2 mg/kg/h) was given continuously over the entire observation time starting 15 min before reperfusion. Group II served as control, no 8-Br-cGMP was administered. In both groups, 250 microg PGE1 was injected into the pulmonary artery (PA) before flush. One hour after reperfusion the recipients contralateral right PA and bronchus were ligated to assess isolated graft function only. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, mean systemic arterial pressure and gas exchange were assessed during a 5-hour observation period. Lipid peroxidation as indicator for free radical mediated injury and neutrophil migration to the allograft were measured at the end of the assessment. RESULTS: EVLWI was significantly reduced in animals treated with 8-Br-cGMP (overall difference P = 0.024) with a peak 2 hours after reperfusion (Group I, 8.2+/-0.3 mg/ml vs Group II, 10.1+/-0.6 mg/ml; P = 0.039). Also in Group I the free radical mediated tissue injury was significantly lower when compared to Group II (Group I, 61.8+/-12.3 pmol/g vs Group II, 120.7+/-7.2 pmol/g; P = 0.006). A tendency towards a reduced neutrophil migration after 8-Br-cGMP infusion was shown; however, the changes in comparison to the control animals were not statistically significant (Group I, 1.0+/-0.2 deltaOD/mg/min vs Group II, 1.7+/-0.3 deltaOD/mg/min; P = 0.13). Pulmonary- and systemic hemodynamics, and allograft gas exchange did not differ between groups. CONCLUSIONS: The results indicate that substitution of the NO pathway by administration of the second messenger cGMP at the time of reperfusion improves post-transplant lung allograft function.     

Successful extended hypothermic cardiopulmonary preservation for heart-lung transplantation

The inability to obtain sufficiently extended hypothermic organ preservation is a major restriction on clinical heart-lung transplantation. We used core cooling, nonrecirculating retrograde heart perfusion, and lung immersion with liposomal recombinant human superoxide dismutase in an attempt to provide effective 12-hour cardiopulmonary preservation. Donor dogs supported by cardiopulmonary bypass were rapidly cooled to 15 degrees C with cardioplegic arrest, and heterotopic heart and unilateral left lung transplantations were performed. In control dogs (n = 7), hearts and lungs, harvested after core cooling and cardioplegic arrest, were transplanted with a total mean ischemic time of 88 +/- 5 minutes. In group II (n = 7), heart-lung blocks were similarly excised but preserved at 4 degrees C for 12 hours (756 +/- 30 minutes) and then transplanted. During preservation, the lungs were immersed in hyperosmolar extracellular solution. For the heart, retrograde coronary sinus perfusion was performed with intracellular solution containing perfluorochemicals at a temperature of 4 degrees C and a rate of 30 ml/hr for 12 hours. In group III (n = 7), donor organs were similarly excised and preserved for 12 hours (726 +/- 39 minutes), except that liposomal recombinant human superoxide dismutase was administered during harvest, preservation, and reperfusion. Myocardial function, assessed by the ratio of end-systolic pressure to end-systolic dimension, after the 12-hour preservation period in both experimental groups was similar to that of the control group 4 and 6 hours after transplantation. The mean arterial oxygen capacity of the transplanted left lung during ventilation with an inspired oxygen concentration of 40% was also similar in each group. In contrast, the 12-hour preservation of pulmonary function assessed by pulmonary vascular resistance, the accumulation of extravascular lung water, and histologic evidence of alveolar wall injury, interstitial edema, and perivascular hemorrhage were significantly impaired in the absence of liposal recombinant human superoxide dismutase. These findings suggest that successful extended cardiopulmonary preservation for heart-lung transplantation is possible with core cooling, nonrecirculating retrograde heart perfusion, and hypothermic lung immersion incorporating liposomal recombinant human superoxide dismutase.     

Bilateral sequential single lung transplantation for pulmonary hypertension and Eisenmenger's syndrome

BACKGROUND: Lung transplantation, with and without intracardiac repair for pulmonary hypertension (PH) and Eisenmenger's syndrome (EIS), has become an alternative transplant strategy to combined heart and lung transplantation (HLT). METHODS: Thirty-five patients with PH or EIS underwent either bilateral sequential single lung transplantation (BSSLT, group I, n = 13) or HLT (group II, n = 22). Another 74 patients, who underwent BSSLT for other indications, served as controls (group III). Immediate allograft function, early and medium-term outcomes, lung function, and 2-year survival were compared between the groups. RESULTS: Comparisons between groups I and II showed no significant difference in any variables except percent predicted forced vital capacity. Immediate allograft function was significantly inferior (p < 0.05) and the blood loss was greater (p < 0.01) in group I when compared with those in group III. However, this resulted in no significant difference in early and medium-term outcomes, and 2-year survival between the 2 groups. CONCLUSIONS: BSSLT for PH and EIS can be performed as an alternative procedure to HLT without an increase in early and medium-term morbidity and mortality. Results are comparable with BSSLT performed for other indications.     

Cardiotomy Suction: A Major Source of Brain Lipid Emboli During Cardiopulmonary Bypass

Background. Brain injury remains a significant problem in patients undergoing cardiac surgery assisted by cardiopulmonary bypass (CPB). Autopsy brain specimens of patients after cardiac operations with CPB reveal numerous acellular lipid deposits (10 to 70 μm) in the microvasculature. We hypothesize that these small capillary and arterial dilatations result from a diffuse inflammatory response to CPB or from emboli delivered by the bypass circuit. This study was undertaken to determine which aspect of CPB is most clearly associated with these dilatations.

Methods. Thirteen dogs were studied in four groups: group I (n = 3), right-heart CPB; group II (n = 2), lower-extremity CPB; group III (n = 3), hypothermic CPB; and group IV (n = 5), hypothermic CPB with cardiotomy suction. All dogs in all groups were maintained on CPB for 60 minutes and then euthanized. Brain specimens were harvested, fixed in ethanol, embedded in celloidin, and stained with the alkaline phosphate histochemical technique so that dilatations could be counted.

Results. All dogs completed the protocol. The mean density of dilatations per square centimeter for each group was as follows: group I, 1.77 ± 0.77; group II, 4.17 ± 1.65; group III, 4.54 ± 1.69; and group IV, 46.5 ± 14.5. In group IV (cardiotomy suction), dilatation density was significantly higher than in group III (hypothermic cardiopulmonary bypass) (p = 0.04) and all other groups (p = 0.04).

Conclusions. Blood aspirated from the surgical field and subsequently reinfused into dogs undergoing CPB produces a greater density of small capillary and arterial dilatations than CPB without cardiotomy suction, presumably because of lipid microembolization.     

Preconditioning: myocardial function and energetics during coronary hypoperfusion and reperfusion

Background. Ischemic preconditioning (IP) is gaining more acceptance as a protective method in beating heart surgery. Yet it remains controversial whether preconditioning can attenuate myocardial dysfunction during reperfusion after severe coronary hypoperfusion. We examined this issue and also the issue of whether this protection is mediated by adenosine A₁ receptors.

Methods. In isolated, blood-perfused rabbit hearts, the effects of IP (3 minutes of no flow ischemia and 8 minutes of reperfusion) during 30 minutes of coronary hypoperfusion and 60 minutes of reperfusion were investigated. In two groups (n = 8 each) with and without (control group) preconditioning, ventricular function was assessed by load-insensitive measures: slope of the end-systolic pressure–volume relation (E_max), slope of the stroke work/end-diastolic volume relation (M_w), and end-diastolic pressure–volume relation. External efficiency was calculated, and contractile efficiency was assessed using the reciprocal of the myocardial oxygen consumption–pressure–volume area relationship. To investigate the possible role of adenosine, the adenosine A₁ receptor antagonist DPCPX (2.5 μmol/L) was administered before preconditioning in a third group (n = 7).

Results. The effects of hypoperfusion on systolic function, diastolic function (dP/dt_min, end-diastolic pressure–volume relation), external efficiency, and contractile efficiency were similar in both the IP and control groups. Lactate efflux was significantly reduced after preconditioning (p = 0.02). During reperfusion, recovery of systolic function and coronary flow were significantly improved in the IP group compared with controls: aortic flow, 85% versus 63% (p = 0.01); dP/dt_max, 91% versus 67% (p = 0.001); pressure–volume area, 97% versus 68% (p = 0.01); E_max, 74% versus 62% (p = 0.03); and M_w, 94% versus 84% (p = 0.04). Release of creatine kinase was reduced in the IP group, 9.6 ± 1.3 U · 5 min⁻¹ · 100 g⁻¹ wet weight, versus controls, 12.7 ± 2.7 U · 5 min⁻¹ · 100 g⁻¹ wet weight (p = 0.04). During reperfusion, contractile efficiency (p = 0.03) and external efficiency (p = 0.02) recovered better in preconditioned than in untreated hearts. Recovery was less pronounced in the DPCPX group compared with the IP group (p, not significant).

Conclusions. The results, derived from load-insensitive measures, confirm that IP provides protection after episodes of severe hypoperfusion by attenuating systolic dysfunction without improving diastolic dysfunction and reduces the severity of anaerobic metabolism as well as ischemic injury. Contractile efficiency and external efficiency both indicate improved energetics after IP (oxygen utilization by the contractile apparatus). The protective effect, at least in part, is mediated by adenosine A₁ receptors.     

Activity and transport of antithrombin during acute limb ischemia

Antithrombin (AT III), a major circulating anticoagulant, may be influenced by ischemia-induced changes in microvascular integrity and contribute to localized hypercoagulability. In a nonheparinized intact canine hindlimb model we determined AT III activity by chromogenic substrate assay (S-2238); coagulation changes with fibrinogen, activated partial thromboplastin time (aPTT), and prothrombin time (PT); and transvascular exchange by lymph-to-plasma total protein concentration ratio. Femoral venous plasma and lymph samples were assayed during 1 hour of steady state (C), 6 or 8 hours of aortoiliac occlusion (I), and 1 or 3 hours of reperfusion (R). Four groups were studied: GI, sham operated (n = 5); GII, moderate ischemia (n = 7), arterial pressure 30% to 45% C, GIII, 6 hours of severe ischemia (n = 7), arterial pressure 5% to 20% C; and GIV, 8 hours of severe ischemia (n = 5), arterial pressure 5% to 20% C. All parameters varied near baseline in the control group and the group with moderate ischemia. Fibrinogen decreased after 3 hours of ischemia in GIII from 218 +/- 38 to 175 +/- 46 mg/dl (mean +/- SEM) and in GIV from 254 +/- 39 to 201 +/- 44 mg/dl (p less than 0.005) as aPTT and PT increased. All parameters returned to baseline on R in GIII only. Plasma AT III decreased in GIV from 89% +/- 4.6% to 53.6% +/- 16.2% (p less than 0.005) after 3 hours and remained low during late I and R.(ABSTRACT TRUNCATED AT 250 WORDS)