Mitral valve repair in dogs using an ePTFE chordal implantation device: a pilot study.

OBJECTIVE: Mitral valve (MV) regurgitation due to degenerative MV disease is the leading cause of cardiac death in dogs. We carried out preliminary experiments to determine the feasibility and short-term effects of beating-heart MV repair using an expanded polytetrafluorethylene (ePTFE) chordal implantation device (Harpoon TSD-5) in dogs. ANIMALS: This study involved six healthy purpose-bred Beagles (weight range 8.9-11.4 kg). MATERIAL AND METHODS: Following a mini-thoracotomy performed under general anesthesia, the TSD-5 was used to place 1 or 2 artificial ePTFE cords on the anterior MV leaflet or the posterior MV leaflet via a left-ventricular transapical approach. The procedure was guided and monitored by transesophageal echocardiography. Postoperative antithrombotic treatment consisted of clopidogrel or a combination of clopidogrel and apixaban. Dogs were serially evaluated by transthoracic echocardiography at day 1, 7, 14, 21, and 30. The hearts were then examined for evaluation of tissues reactions and to detect signs of endothelialization. RESULTS: One or two chords were successfully implanted in five dogs. Four dogs completed the 30 days follow-up. One dog died intra-operatively because of aortic perforation. One dog died early post-operatively from a hemorrhagic pleural effusion attributed to overly aggressive antithrombotic treatment. One dog developed a thrombus surrounding both the knot and the synthetic cord. Postmortem exam confirmed secure placement of ePTFE knots in the mitral leaflets in all dogs and the presence of endothelialization of the knots and chords. CONCLUSIONS: These preliminary results demonstrate the feasibility of artificial chordal placement using an ePTFE cordal implantation device in dogs.

Traumatic rupture of an aberrant right subclavian artery.

We describe a patient who sustained a traumatic rupture of an aberrant right subclavian artery. An interposition graft was used to restore continuity of the artery to the descending thoracic aorta.

A partial conditioning approach to achieve mixed chimerism in the rat: depletion of host natural killer cells significantly reduces the amount of total body irradiation required for engraftment.

BACKGROUND: Mixed allogeneic bone marrow chimerism induces tolerance to solid organ grafts. Although we previously reported that partially ablative conditioning with 700 cGy of total body irradiation (TBI) is sufficient to allow for bone marrow engraftment in mice, we determined that a minimum of 1000 cGy was required in the rat. Because T cells and NK cells are critical in bone marrow graft rejection, our purpose was to examine whether targeting of radioresistant NK cells and/or T cells in the recipient hematopoietic microenvironment would reduce the TBI dose required for engraftment of allogeneic rat bone marrow. METHODS: Wistar Furth rats received either anti-NK3.2.3 monoclonal antibodies on days -3 and -2, anti-lymphocyte serum on day -5, a combination of both or no pretreatment. TBI was performed on day 0 and rats were reconstituted with 100x10(6) T cell-depleted bone marrow cells from ACI donors. RESULTS: Engraftment of T cell-depleted rat bone marrow was readily achieved in animals conditioned with 1000 cGy TBI alone (12/12) and the level of donor chimerism averaged 89%. At 900 cGy TBI alone only one of eight recipients engrafted. In striking contrast, 11 of 12 animals pretreated with anti-NK monoclonal antibodies and irradiated with 900 cGy showed donor chimerism at a mean level of 41%. No further enhancement of bone marrow engraftment could be achieved when recipients were pretreated with antilymphocyte serum alone or antilymphocyte serum plus anti-NK monoclonal antibodies. Mixed allogeneic chimeras exhibited stable multilineage chimerism and donor-specific tolerance to subsequent cardiac allografts. CONCLUSION: Specific targeting of radioresistant host NK cells allows for a significant reduction of the TBI dose required for allogeneic bone marrow engraftment.

T-cell depletion of allogeneic bone marrow using anti-alphabetaTCR monoclonal antibody: prevention of graft-versus-host disease without affecting engraftment potential in rats.

Bone marrow chimerism may solve two major limitations in the transplantation of solid organs and cellular grafts: (1) the requirement for life-long immunosuppressive therapy, and (2) acute and chronic rejection. When untreated bone marrow is transplanted into major histocompatibility complex (MHC)-disparate rats, lethal graft-vs-host disease (GVHD) occurs in the majority of recipients. T-cell depletion using anti-CD3 and anti-CD5 monoclonal antibody (mAb) to avoid GVHD led to an increased occurrence of failure of engraftment. We previously identified a cellular population in mouse bone marrow that facilitates engraftment of highly purified hematopoietic stem cells (HSC) across complete MHC barriers. In light of the fact that facilitating cells have a CD8+/CD3+/TCR- phenotype and mostly coexpress CD5, we evaluated in this study whether T-cell depletion of rat bone marrow using anti-alphabetaTCR mAb would retain engraftment potential yet avoid GVHD. T-cell depletion of bone marrow was performed using anti-alphabetaTCR mAb and immunomagnetic beads. Recipients were conditioned with 1100 or 1000 cGy of total body irradiation and reconstituted with 100 x 10(6) T-cell depleted (TCD) MHC- and minor antigen-disparate bone marrow cells. Animals were monitored clinically and histologically for GVHD. Chimerism was assessed by flow cytometry. Immunomagnetic bead depletion resulted in a reduction of T cells from 1.92%+/-0.21% to 0.10%+/-0.04% of total bone marrow. T-cell depletion did not remove facilitating cells (CD8+/alphabetaTCR-/gammadeltaTCR-/NK3.2.3-) from bone marrow. Further, the engraftment potential of TCD bone marrow was not affected, as 100% of animals engrafted and high levels of donor chimerism were detectable. Animals reconstituted with TCD bone marrow showed no clinical evidence of GVHD and histology revealed none to minimal changes, whereas recipients transplanted with untreated bone marrow succumbed to severe lethal GVHD. T-cell depletion using antialphabetaTCR mAb and immunomagnetic beads selectively removes T cells from the bone marrow graft while sparing facilitating cells that are required for engraftment of allogeneic bone marrow across MHC barriers. Moreover, the cells required for engraftment of HSC do not produce GVHD.

The pigtail catheter for pleural drainage: a less invasive alternative to tube thoracostomy.

BACKGROUND: Tube thoracostomy remains the standard of care for the treatment of pneumothoraces and simple effusions. This report describes a favorable experience with the 8.3 French pigtail catheter as a less invasive alternative to traditional chest tube insertion. METHODS: We retrospectively reviewed 109 consecutive pigtail catheter placements. Catheters were inserted under local anesthesia at the bedside without radiographic guidance. Pre- and post-insertion chest radiographs were reviewed to determine efficacy of drainage. RESULTS: Fifty-one of 109 patients (47%) were mechanically ventilated and 26 patients (24%) had a coagulopathy. There were no complications related to pigtail catheter insertion. Seventy-seven pigtail catheters were placed for pleural effusion and 32 for pneumothorax. Mean effusion volume decreased from 43 to 9 percent, and drainage averaged 2899 ml over 97 hours. Mean pneumothorax size diminished from 38 to 1 percent during an average 71-hour placement. Clinical success rates in the effusion and pneumothorax groups were 86 and 81 percent, respectively. CONCLUSION: The pigtail catheter offers reliable treatment of pneumothoraces and simple effusions and is a safe and less invasive alternative to tube thoracostomy.

Simultaneous donor bone marrow and cardiac transplantation: can tolerance be induced with the development of chimerism?

Mixed bone marrow chimerism (mixed chimerism) is defined by the coexistence of two genetically different bone marrow stem cells in an individual. The chimeric immune system recognizes donor antigen as self, yet is capable of mounting a normal response to third-party antigens. In animal models, mixed chimerism confers donor-specific tolerance for solid-organ and cellular grafts: tissue from the bone marrow donor is permanently accepted by mixed chimeras in the absence of conventional immunosuppressive agents. Clinical application of mixed chimerism to induce transplantation tolerance requires novel approaches to safely and reliably achieve engraftment of donor bone marrow in transplant recipients. Recent advances offer potential solutions to these obstacles and suggest that the application of mixed chimerism to induce tolerance to transplanted organs may soon be a clinical reality.

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.

Tacrolimus-based partial conditioning produces stable mixed lymphohematopoietic chimerism and tolerance for cardiac allografts.

BACKGROUND: Thoracic organ transplantation remains limited by the reciprocal problems of rejection and the toxicities of nonspecific immunosuppression. Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance without immunosuppressive drugs. We have previously described a nonmyeloablative conditioning regimen based on recipient treatment with antilymphocyte serum, tacrolimus, and low-dose total-body irradiation that yields long-term multilineage allogeneic bone marrow chimerism in the rat. We have now investigated whether mixed bone marrow chimerism that arises from this partial conditioning strategy produces permanent acceptance of donor-specific cardiac allografts. METHODS AND RESULTS: Mixed allogeneic chimeras (ACI-->WF) were prepared by treating Wistar Furth recipients with a single dose of antilymphocyte serum 5 days before bone marrow transplantation and tacrolimus 1 mg/kg/d from days -1 to 10. Five hundred cGy total-body irradiation was administered immediately before infusion of 1 x 10(8) donor (ACI) T-cell depleted marrow cells. All recipients were chimeric, with a mean level of donor chimerism = 26.3 +/- 3.5%. Chimeras underwent heterotopic cardiac transplantation 4 weeks after bone marrow transplantation. All donor-specific (ACI) grafts were permanently accepted (follow-up, 230 to 360 days). Third-party grafts were rapidly rejected. Histology of long-surviving donor-specific grafts was without evidence of acute or chronic rejection. Second-set donor-specific skin grafts transplanted to chimeras 135 days after heart transplantation showed long-term survival (> 130 days), whereas third-party skin grafts were rapidly rejected. Mixed lymphocyte reaction demonstrated in vitro donor-specific hyporeactivity. CONCLUSIONS: A tacrolimus-based nonmyeloablative recipient conditioning regimen produces mixed bone marrow chimerism and donor-specific tolerance to cardiac allografts in the rat.

Traumatic aortic rupture: diagnosis and management.

BACKGROUND: Traumatic aortic rupture is a relatively uncommon lesion that presents the cardiothoracic surgeon with unique challenges in diagnosis and management. To address controversial aspects of this disease, we reviewed our experience. METHODS: The study was performed by retrospective chart review. RESULTS: Forty-two patients with traumatic thoracic aortic ruptures were managed between January 1988 and June 1997. Nine arrived without vital signs and died in the emergency department. Admission chest radiographs were normal in 3 patients (12%) and caused significant delays in diagnosis. Four of 30 patients admitted with vital signs had rupture before thoracotomy and died. Twenty-six underwent aortic repair. In 1 patient repair was performed with simple aortic cross-clamping, whereas a second was managed with a Gott shunt. The remaining 24 patients had repair with partial left heart bypass. In 1 patient hypothermic circulatory arrest was required. Two patients (7.7%) died. There were no cases of new postoperative paraplegia in the bypass group. There was no morbidity directly attributable to the administration of heparin for cardiopulmonary bypass. CONCLUSIONS: In a discrete group of patients with traumatic rupture of the aorta, the rupture will become complete during the first few hours of hospital admission; aggressive medical treatment with beta-blockade and vasodilators in the interval before the operation is an essential aspect of management. Active distal circulatory support with partial left-heart bypass provides the optimal means of preventing spinal cord ischemia during repair of acute traumatic aortic rupture.

Mixed allogeneic chimerism prevents obstructive airway disease in a rat heterotopic tracheal transplant model.

BACKGROUND: Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance for a variety of solid organ and cellular grafts. We used a rat heterotopic tracheal transplant model for chronic rejection to investigate whether mixed chimerism could successfully prevent obstructive airway disease. METHODS: Mixed allogeneic chimeras were prepared by reconstituting lethally irradiated Wistar-Furth (WF) recipients with a mixture of 5 x 10(6) T-cell-depleted syngeneic (WF) and 100 x 10(6) T-cell-depleted allogeneic (ACI) bone marrow cells (ACI + WF --> WF). Mixed chimerism was present in all animals 28 days after bone marrow transplantation. Donor-specific, syngeneic, or major histocompatibility complex (MHC)-disparate allogeneic tracheas were implanted in recipient's omentum and removed for histologic analysis 30 to 150 days after transplantation. RESULTS: At 30 days after implantation, median luminal obstruction grades (0=none, 4=complete) of syngeneic and allogeneic tracheas were 0 and 4, respectively. Donor-specific (ACI) tracheas implanted in chimeric (ACI + WF --> WF) recipients were remarkably free of obstruction (median luminal obstruction grade=0 at 150 days) and had excellent preservation of respiratory epithelium. Third-party F344 tracheas implanted in chimeric recipients developed progressive luminal obstruction (grade 2 at 30 days, grade 3 at 90 days). CONCLUSIONS: Mixed allogeneic chimerism induces donor-specific tolerance and prevents development of the characteristic fibroproliferative obstructive lesion of bronchiolitis obliterans in a rat heterotopic tracheal transplant model. Excellent preservation of tracheal structure and morphology was achieved across major and minor histocompatibility barriers.

A partial conditioning strategy for achieving mixed chimerism in the rat: tacrolimus and anti-lymphocyte serum substantially reduce the minimum radiation dose for engraftment.

Development of partial conditioning strategies to achieve reliable engraftment of allogeneic bone marrow with minimum recipient morbidity could extend the therapeutic application of bone marrow transplantation (BMT) to enzyme deficiency states, hemoglobinopathies, autoimmune diseases, and the induction of tolerance for solid organ and cellular allografts. In this study we describe a nonmyeloablative rat BMT model and examine the effect of clinically available immunosuppressants on the minimum amount of total body irradiation (TBI) required for allogeneic engraftment. Donor ACI marrow was depleted of T cells using immunomagnetic beads and transplanted to major histocompatibility complex- and minor antigen-mismatched Wistar Furth (WF) rats (ACI --> WF) conditioned with varying doses of TBI. Recipients conditioned with TBI alone required myeloablation with 1000 cGy for reliable allogeneic marrow engraftment. Administration to WF recipients of a single dose of anti-lymphocyte serum (ALS) 5 days prior to BMT together with a limited course of tacrolimus (1 mg/kg/day) resulted in engraftment of ACI bone marrow at only 500 cGy TBI. ACI --> WF recipients were stable mixed chimeras (mean donor chimerism 49% at 330 days post-BMT). Chimerism was multilineage. All recipient animals were free of graft-versus-host disease. These results suggest that a nonmyeloablative conditioning strategy based on low-dose TBI and a limited course of tacrolimus plus ALS can produce long-term mixed multilineage chimerism.

Cardiopulmonary bypass is associated with early allograft dysfunction but not death after double-lung transplantation.

OBJECTIVES: To assess the effect of cardiopulmonary bypass on allograft function and recipient survival in double-lung transplantation. METHODS: Retrospective review of 94 double-lung transplantations. RESULTS: Cardiopulmonary bypass was used in 37 patients (CPB); 57 transplantations were accomplished without bypass (no-CPB). Bypass was routinely used for patients with pulmonary hypertension (n = 27) and for two recipients undergoing en bloc transplantation. Cardiopulmonary bypass was required in eight (12.3%) of the remaining 65 patients. Mean ischemic time was longer in the CPB group (346 vs 315 minutes, p = 0.04). The CPB group required more perioperative blood (11.4 vs 6.0 units, p = 0.01). Allograft function, assessed by the arterial/alveolar oxygen tension ratio, was better in the no-CPB group at 12 and 24 hours after operation (0.54 vs 0.39 at 12 hours, p = 0.002; and 0.63 vs 0.38 at 24 hours, p = 0.001). The CPB group had more severe pulmonary infiltrates at both 1 and 24 hours (p = 0.005). Diffuse alveolar damage was more common in the CPB group (69% vs 35%, p = 0.002). Median duration of intubation was longer in the CPB group (10 days) than in the no-CPB group (2 days, p = 0.002). The 30-day mortality rate (13.5% vs 7.0% in the CPB and no-CPB groups) and 1-year survival (65% vs 67%, CPB and no-CPB) were not significantly different. CONCLUSIONS: In the absence of pulmonary hypertension, cardiopulmonary bypass is only occasionally necessary in double-lung transplantation. Bypass is associated with substantial early allograft dysfunction after transplantation.

Abciximab and excessive bleeding in patients undergoing emergency cardiac operations.

BACKGROUND: Abciximab (ReoPro; Eli Lilly and Co, Indianapolis, IN) is a monoclonal antibody that binds to the platelet glycoprotein IIb/IIIa receptor and produces powerful inhibition of platelet function. Clinical trials of abciximab in patients undergoing coronary angioplasty have demonstrated a reduction in thrombotic complications and have encouraged the widespread use of this agent. We have observed a substantial incidence of excessive bleeding among patients who receive abciximab and subsequently require emergency cardiac operations. METHODS: The records of 11 consecutive patients who required emergency cardiac operations after administration of abciximab and failed angioplasty or stent placement were reviewed. RESULTS: The interval from the cessation of abciximab administration to operation was critical in determining the degree of coagulopathy after cardiopulmonary bypass. The median values for postoperative chest drainage (1,300 versus 400 mL; p < 0.01), packed red blood cells transfused (6 versus 0 U; p = 0.02), platelets transfused (20 versus 0 packs; p = 0.02), and maximum activated clotting time (800 versus 528 seconds; p = 0.01) all were significantly greater in the early group (cardiac operation < 12 hours after abciximab administration; n = 6) compared with the late (cardiac operation >12 hours after abciximab administration; n = 5) group. CONCLUSIONS: This report suggests that the antiplatelet agent abciximab is associated with substantial bleeding when it is administered within 12 hours of operation.

Single- versus double-lung transplantation for pulmonary hypertension.

OBJECTIVES: Uncertainty persists as to the best lung transplant operation for patients with pulmonary hypertension. To quantify short- and long-term outcomes after single- and double-lung transplantation for pulmonary hypertension, we reviewed our clinical experience. METHODS: A retrospective review of 58 lung transplants at a single institution between 1989 and 1996 was performed. Recipients had primary (n = 19) or secondary (n = 39) pulmonary hypertension. RESULTS: Thirty-seven double- and 21 single-lung transplants were performed. The groups were well matched with regard to preoperative characteristics. Cardiopulmonary bypass time was longer (151 vs 250 minutes) in the double-lung group. Excluding 10 patients surviving less than 30 days (6 double- and 4 single-lung transplants), median duration of intubation (7.5 vs 10 days), length of stay in the intensive care unit (10 vs 16 days), and hospital stay (32 vs 52 days) were not significantly different for the single- and double-lung groups, respectively. Actuarial survival was nearly identical, with 81% and 84% 1-month survivals for the single- and double-lung groups, and identical 1-year (67%) and 4-year (57%) survivals for both groups. Late functional status was similar for recipients of single- and double-lung grafts. During the period of this study, 58 patients with pulmonary hypertension died on our center's waiting list before coming to transplantation. CONCLUSIONS: These data suggest that lung transplant recipients with pulmonary hypertension have similar outcomes after single- or double-lung transplantation. These results support cautious preferential application of single-lung transplantation for pulmonary hypertension.

Influence of panel-reactive antibody on survival and rejection after lung transplantation.

BACKGROUND: Panel-reactive antibody (PRA) is commonly used before thoracic organ transplantation to estimate a potential recipient's degree of humoral sensitization. METHODS: To assess the influence of an elevated PRA on survival and the incidence of rejection in pulmonary transplantation, the records of 247 patients that underwent single or double lung transplantation were reviewed. RESULTS: Twenty-one of 247 patients (8.5%) had PRA values greater than 10%. Survival of this population was not significantly different from that of patients with low PRA levels: 74% (low PRA) vs 65% (elevated PRA) at 1 year and 58% in both groups at 3 years. The acute rejection rates (episodes/first 100 days) for the elevated and low PRA groups were 2.1 and 1.9, respectively (p = NS). Obliterative bronchiolitis developed in 38.9% of the high and 31.2% of the low PRA groups (p = NS). Six of 247 patients had a retrospective positive lymphocytotoxic cross-match result; three had PRA values greater than 10%. Patients with a positive cross-match result experienced similar survival and incidence of rejection as the remainder of the population. Among 957 patients evaluated for lung transplantation, 16 (1.7%) had a PRA (with dithiothreitol) greater than 15%. All had a history of pregnancy, blood transfusion, connective tissue disease, or previous transplantation. CONCLUSIONS: Humoral sensitization is uncommon in the lung transplantation population. A modestly elevated PRA does not predict survival or the development of acute rejection or bronchiolitis obliterans. PRA testing before lung transplantation should be reserved for those patients with specific risk factors for humoral sensitization.

Chimerism and thoracic organ transplantation.

Current nonspecific immunosuppression for thoracic organ transplantation is limited by infection, end-organ toxicity, malignancy, and failure to completely control rejection. Donor-specific transplantation tolerance after bone marrow transplantation and the creation of mixed chimerism is a promising means for achieving drug-free allograft acceptance. This review explores bone marrow transplantation as a method for tolerance induction, the superior clinical characteristics of mixed chimerism, and recent developments that enhance marrow engraftment, minimize graft-versus host disease, and avoid lethal conditioning of the recipient. The importance of microchimerism in clinical transplantation and clinical trials aimed at augmentation of this phenomenon are reviewed.

Acute aortic dissection after blunt chest trauma.

Medial dissection of the aorta after blunt trauma is a rare occurrence. We report the case of a 79-year-old woman injured in a motor vehicle crash who suffered an acute DeBakey type I aortic dissection.

Dermoid sinus removal in a rhodesian ridgeback dog.

A three year old Rhodesian Ridgeback dog with a history of a small draining tract in the dorsal cervical area, was found to have a dermoid sinus on surgical exploration. The affected tissue was removed and histopathology done. The sinus is an inherited condition in this breed of dog, with surgical correction and neutering of affected individuals the treatments of choice to reduce the incidence of the dermoid sinus condition in the next generation.