Morphologically intact airways in lung fibrosis have an abnormal proteome.

Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

The circadian clock protein REVERBα inhibits pulmonary fibrosis development.

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinß1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.

Venoarterial extracorporeal membrane oxygenation for postcardiotomy cardiogenic shock-A six-year service evaluation.

Only a small number of English hospitals provide postcardiotomy venoarterial extracorporeal membrane oxygenation (VA-ECMO) and there are doubts about its efficacy and safety. The aim of this service evaluation was to determine local survival rates and report on patient demographics. This was a retrospective service evaluation of prospectively recorded routine clinical data from a tertiary cardiothoracic center in the United Kingdom offering services including cardiac and thoracic surgery, heart and lung transplantation, venovenous extracorporeal membrane oxygenation (VV-ECMO) for respiratory failure, and all types of mechanical circulatory support. In six years, 39 patients were supported with VA-ECMO for refractory postcardiotomy cardiogenic shock (PCCS). We analyzed survival data and looked for associations between survival rates and patient characteristics. The intervention was venoarterial-ECMO in patients with PCCS either following weaning from cardiopulmonary bypass or following a trial of inotropes and intra-aortic balloon counterpulsation on the intensive care unit. 30-day, hospital discharge, 1-year and 2-year survivals were 51.3%, 41%, 37.5%, and 38.5%, respectively. The median (IQR [range]) duration of support was 6 (4-9 [1-35]) days. Nonsurvival was associated with advanced age, shorter intensive care length of stay, and the requirement for postoperative hemofiltration. Reasonable survival rates can be achieved in selected patients who may have been expected to have a worse mortality without VA-ECMO. We suggest postoperative VA-ECMO should be available to all patients undergoing cardiac surgery be it in their own center or through an established pathway to a specialist center.

Study Comparing Vein Integrity and Clinical Outcomes in Open Vein Harvesting and 2 Types of Endoscopic Vein Harvesting for Coronary Artery Bypass Grafting: The VICO Randomized Clinical Trial (Vein Integrity and Clinical Outcomes).

BACKGROUND: Current consensus statements maintain that endoscopic vein harvesting (EVH) should be standard care in coronary artery bypass graft surgery, but vein quality and clinical outcomes have been questioned. The VICO trial (Vein Integrity and Clinical Outcomes) was designed to assess the impact of different vein harvesting methods on vessel damage and whether this contributes to clinical outcomes after coronary artery bypass grafting. METHODS: In this single-center, randomized clinical trial, patients undergoing coronary artery bypass grafting with an internal mammary artery and with 1 to 4 vein grafts were recruited. All veins were harvested by a single experienced practitioner. We randomly allocated 300 patients into closed tunnel CO2 EVH (n=100), open tunnel CO2 EVH (n=100), and traditional open vein harvesting (n=100) groups. The primary end point was endothelial integrity and muscular damage of the harvested vein. Secondary end points included clinical outcomes (major adverse cardiac events), use of healthcare resources, and impact on health status (quality-adjusted life-years). RESULTS: The open vein harvesting group demonstrated marginally better endothelial integrity in random samples (85% versus 88% versus 93% for closed tunnel EVH, open tunnel EVH, and open vein harvesting; P<0.001). Closed tunnel EVH displayed the lowest longitudinal hypertrophy (1% versus 13.5% versus 3%; P=0.001). However, no differences in endothelial stretching were observed between groups (37% versus 37% versus 31%; P=0.62). Secondary clinical outcomes demonstrated no significant differences in composite major adverse cardiac event scores at each time point up to 48 months. The quality-adjusted life-year gain per patient was 0.11 (P<0.001) for closed tunnel EVH and 0.07 (P=0.003) for open tunnel EVH compared with open vein harvesting. The likelihood of being cost-effective, at a predefined threshold of £20 000 per quality-adjusted life-year gained, was 75% for closed tunnel EVH, 19% for open tunnel EVH, and 6% for open vein harvesting. CONCLUSIONS: Our study demonstrates that harvesting techniques affect the integrity of different vein layers, albeit only slightly. Secondary outcomes suggest that histological findings do not directly contribute to major adverse cardiac event outcomes. Gains in health status were observed, and cost-effectiveness was better with closed tunnel EVH. High-level experience with endoscopic harvesting performed by a dedicated specialist practitioner gives optimal results comparable to those of open vein harvesting. CLINICAL TRIAL REGISTRATION: URL: https://www.isrctn.com. International Standard Randomised Controlled Trial Registry Number: 91485426.

The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix.

Usual interstitial pneumonia (UIP) is a histological pattern characteristic of idiopathic pulmonary fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection-coupled mass spectrometry, we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 nonfibrotic alveolar specimens as controls. The data were subjected to qualitative and quantitative analysis and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared with the nonfibrotic control. Furthermore, FF were positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of FF was predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that FF are the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This essential information will inform future mechanistic studies on fibrosis progression.

A multicentre review comparing long term outcomes of endoscopic vein harvesting versus open vein harvesting for coronary artery bypass surgery.

Background: Utilisation of the Endoscopic Vein Harvesting (EVH) technique has been increasing for coronary artery bypass grafting (CABG) for the last two decades. Some surgeons remain concerned about the long-term patency of the long saphenous vein harvested endoscopically compared to traditional Open Vein Harvesting (OVH). The aim of this study was to perform a retrospective analysis of the outcomes between EVH and OVH from three UK centres with 10 years follow-up. Methods: 27,024 patients underwent CABG with long saphenous vein harvested by EVH (n=13,794) or OVH (n=13,230) in three UK centres between 2007 and 2019. Propensity modelling was used to calculate the Inverse Probability of Treatment Weights (IPTW). The primary endpoint was mortality from all causes and secondary endpoints were length of hospital stay, postoperative complications, and incidence of repeat coronary re-vascularisation for symptomatic patients. IPTW was used to balance the two intervention groups for baseline and preoperative co-morbidities. Results: Median follow-up time was 4.54 years for EVH and 6.00 years for OVH. Death from any cause occurred in 13.8% of the EVH group versus 20.8% in the OVH group over the follow-up period. The hazard ratio of death (EVH to OVH) was 0.823 (95% CI: 0.767, 0.884). Length of hospital stay was similar between the groups (p=0.86). Post-operative pulmonary complications were more common in EVH vs OVH (14.7% vs. 12.8%, p<0.001), but repeat coronary re-vascularisation was similar between the groups. Conclusions: This large retrospective multicentre analysis indicates that EVH has a lower risk of mortality compared with OVH during the follow-up period of the study. The observed benefits of EVH may outweigh the risks but should be considered on a case-by-case basis. We hope this review gives confidence to other cardiac centres that offering an EVH approach to conduit harvesting does not affect long term patient outcomes.

Use of keyhole vein removal technique has been increasing for coronary artery bypass surgery for last two decades. However, some surgeons remain worried about the quality and long-term effect of the vein tube removed using keyhole method compared to traditional Open Vein Harvesting (OVH). The aim of this study was to perform a retrospective analysis of the outcomes between keyhole and OVH from three UK centres with 10 years follow-up. In total, 27,024 patients underwent coronary artery bypass surgery with long saphenous vein harvested by either keyhole (n=13,794) or OVH (n=13,230) over a period of 2007­2019. The median follow-up time was 4.54 years for keyhole method and 6.00 years for OVH. Death from any cause occurred in 13.8% of the keyhole group versus 20.8% in the OVH group over the follow-up period. In conclusion, the keyhole surgery survival is not as bad as we hypothesised.

The haemodynamic effects of adjunctive hormone therapy in potential heart donors: a prospective randomized double-blind factorially designed controlled trial.

AIMS: The aim of this study was to assess the haemodynamic effects of tri-iodothyronine (T3) and methylprednisolone in potential heart donors. METHODS AND RESULTS: In a prospective randomized double-blind trial, 80 potential cardiac donors were allocated to receive T3 (0.8 microg kg(-1) bolus; 0.113 microg kg(-1) h(-1) infusion) (n = 20), methylprednisolone (1000 mg bolus) (n = 19), both drugs (n = 20), or placebo (n = 21) following initial haemodynamic assessment. After hormone or placebo administration, cardiac output-guided optimization was initiated, using vasopressin as a pressor and weaning norepinephrine and inotropes. Treatment was administered for 5.9 +/- 1.3 h until retrieval or end-assessment. Cardiac index increased significantly (P < 0.001) but administration of T3 and methylprednisolone alone or in combination did not affect this change or the heart retrieval rate. Thirty-five per cent (14/40) of initially marginal or dysfunctional hearts were suitable for transplant at end-assessment. At end-assessment, 50% of donor hearts fulfilled criteria for transplant suitability. CONCLUSION: Cardiac output-directed donor optimization improves donor circulatory status and has potential to increase the retrieval rate of donor hearts. Tri-iodothyronine and methylprednisolone therapy do not appear to acutely affect cardiovascular function or yield.

Outcome of CentriMag™ extracorporeal mechanical circulatory support use in critical cardiogenic shock (INTERMACS 1) patients.

Purpose: Prognosis of patients presenting with INTERMACS 1 critical cardiogenic shock is generally poor. The aim of our study was to investigate the results of CentriMag™ extracorporeal short-term mechanical circulatory support as a bridge to decision in patients presenting with critical cardiogenic shock in our unit. Methods: We retrospectively analysed 63 consecutive patients from January 2005 to June 2017, who were treated with a CentriMag™ device at our institution as a bridge to decision. Patients requiring extracorporeal support for post-cardiotomy shock and for primary graft dysfunction after heart transplantation were excluded. Results: Patients' median age was 44 years (IQR 31-52, range 15.4-62.0) and 42 (67%) were male. Primary diagnosis at presentation was ischaemic cardiomyopathy (n = 24; 38.1%), viral myocarditis (n = 19; 30.2%), idiopathic dilated cardiomyopathy (n = 8; 12.7%), and others (n = 12; 19%). The median duration of support was 25 (IQR 9.5-56) days. A total of 7 (11%) patients were supported with peripheral veno-arterial (VA) extra corporeal membrane oxygenation (ECMO), 6 (9%) with central VA ECMO, 8 (13%) with left ventricular assist device (LVAD), 17 (27%) with biventricular assist device (BiVAD), and 25 (40%) with ECMO and then converted to BiVAD. Overall, 22 (34.9%) patients died while on CentriMag™ mechanical circulatory support. Complications included bleeding requiring reoperation/intervention in 24 (38%), renal failure requiring dialysis in 29 (46%), bacterial infections in 23 (37%), fungal infections in 15 (24%), critical limb ischaemia in 6 (10%), and stroke in 8 (13%). The overall survival to successful explant from CentriMag™ was 65.1% (n = 41) and survival to hospital discharge was 58.7% (n = 37). Of these, 10 (16%) had cardiac recovery and were successfully explanted, 20 (32%) were bridged to heart transplantation, 11 (17%) were bridged to long-term left ventricular assist device, 3 (4.7%) were later on transplanted, and 1 (1.6%) recovered to decommissioning. The 1-, 5-, and 10-year survival rates were 55%, 46%, and 23% respectively. Conclusion: Our results demonstrate an excellent outcome with the use of the CentriMag™ device in this seriously ill population. Despite requiring multiple procedures, over 58% of patients were discharged from hospital with 5-year survival of 46%.

Establishing a heart transplant programme using donation after circulatory-determined death donors: a United Kingdom based single-centre experience.

OBJECTIVES: Demand for heart transplant donors worldwide continues to outstrip supply. Transplanting hearts following donation after circulatory-determined death (DCD) is increasingly recognized as a safe and effective alternative. As the fourth centre worldwide to have established such a programme, our goal was to present our initial experience. METHODS: This was a single-centre retrospective observational study. All DCD hearts were retrieved using direct procurement and perfusion. Continuous normothermic perfusion of the procured heart was then established on the TransMedics® Organ Care System. The primary outcome of this study was the 30-day survival rate. RESULTS: Between May 2017 and December 2018, 8 DCD hearts were procured and 7 were subsequently implanted, including in 2 patients who had left ventricular assist devices explanted. During the same time period, 30 patients received donation after brainstem death heart transplants. Therefore, the DCD heart transplant programme led to a 23% increase in transplant activity. The median donation warm ischaemic time was 34 min [interquartile range (IQR) 31-39 min]. The median functional warm ischaemic time was 28 min (IQR 25-30 min). The median time spent by the organ on the Organ Care System was 263 min (IQR 242-296 min). The overall 30-day survival rate was 100% and the 90-day survival rate was 86%. Postoperative extracorporeal membrane oxygenation was required in 3/7 (43%). CONCLUSIONS: DCD heart transplants can lead to a 23% increase in heart transplant activity and should be adopted by more institutions across the world. Already established transplant programmes with good early outcomes can start such a programme safely.

Randomized Study Comparing the Effect of Carbon Dioxide Insufflation on Veins Using 2 Types of Endoscopic and Open Vein Harvesting.

OBJECTIVE: The aim of the study was to assess whether the use of carbon dioxide insufflation has any impact on integrity of long saphenous vein comparing 2 types of endoscopic vein harvesting and traditional open vein harvesting. METHODS: A total of 301 patients were prospectively randomized into 3 groups. Group 1 control arm of open vein harvesting (n = 101), group 2 closed tunnel (carbon dioxide) endoscopic vein harvesting (n = 100) and Group 3 open tunnel (carbon dioxide) endoscopic vein harvesting (open tunnel endoscopic vein harvesting) (n = 100). Each group was assessed to determine the systemic level of partial arterial carbon dioxide, end-tidal carbon dioxide, and pH. Three blood samples were obtained at baseline, 10 minutes after start of endoscopic vein harvesting, and 10 minutes after the vein was retrieved. Vein samples were taken immediately after vein harvesting without further surgical handling to measure the histological level of endothelial damage. A modified validated endothelial scoring system was used to compare the extent of endothelial stretching and detachment. RESULTS: The level of end-tidal carbon dioxide was maintained in the open tunnel endoscopic vein harvesting and open vein harvesting groups but increased significantly in the closed tunnel endoscopic vein harvesting group (P = 0.451, P = 0.385, and P < 0.001). Interestingly, partial arterial carbon dioxide also did not differ over time in the open tunnel endoscopic vein harvesting group (P = 0.241), whereas partial arterial carbon dioxide reduced significantly over time in the open vein harvesting group (P = 0.001). A profound increase in partial arterial carbon dioxide was observed in the closed tunnel endoscopic vein harvesting group (P < 0.001). Consistent with these patterns, only the closed tunnel endoscopic vein harvesting group demonstrated a sudden drop in pH over time (P < 0.001), whereas pH remained stable for both open tunnel endoscopic vein harvesting and open vein harvesting groups (P = 0.105 and P = 0.869, respectively). Endothelial integrity was better preserved in the open vein harvesting group compared with open tunnel endoscopic vein harvesting or closed tunnel endoscopic vein harvesting groups (P = 0.012) and was not affected by changes in carbon dioxide or low pH. Significantly greater stretching of the endothelium was observed in the open tunnel endoscopic open tunnel endoscopic vein harvesting group compared with the other groups (P = 0.003). CONCLUSIONS: This study demonstrated that the different vein harvesting techniques impact on endothelial integrity; however, this does not seem to be related to the increase in systemic absorption of carbon dioxide or to the pressurized endoscopic tunnel. The open tunnel endoscopic harvesting technique vein had more endothelial stretching compared with the closed tunnel endoscopic technique; this may be due to manual dissection of the vein. Further research is required to evaluate the long-term clinical outcome of these vein grafts.

A comprehensive review on learning curve associated problems in endoscopic vein harvesting and the requirement for a standardised training programme.

Endoscopic vein harvesting is becoming one of the most favourable vein harvesting techniques in multiple bypass coronary surgery, due to its short term post-operative benefits with high patient satisfaction. However, long-term graft patency has been both supported and questioned in the literature. Graft failure can be affected by harvesting methods and operator's experience. Endoscopic vein harvesting is associated with a learning curve period, during which the incidence of vein trauma is high due to unfamiliarity with the surgical technique. There is a paucity of structured learning tools for novice practitioners, meaning that training differs significantly between hospital centres. Inconsistent training methods can lead to poor surgical technique, which can have a significant impact on vein quality and stress level of the practitioner. In turn, this can lead to increased postoperative complications and longer surgical duration. The main aim of this literature review is to understand the impact of the learning curve on the vein conduit and whether there is a requirement for a standardised training programme for the novice practitioners.

A randomized study comparing traditional monofilament knotted sutures with barbed knotless sutures for donor leg wound closure in coronary artery bypass surgery.

OBJECTIVES: Surgical knots on the suture line provide an anchoring function, but also represent a potential source of infection and irritation on the donor leg after coronary artery bypass surgery. Knotless barbed sutures were designed to prevent knot-related complications. This study compared knot-related wound complication rates between patients receiving traditional monofilament sutures and those receiving barbed knotless sutures for closure of the donor leg. METHODS: One hundred and forty-two patients were randomized into two groups. Group 1 (n = 70) received traditional monofilament sutures and Group 2 (n = 72) received barbed knotless sutures. All wounds were assessed on postoperative days 3 and 5 and weeks 2, 4 and 6 using a validated wound scoring system. Antibiotics usage and general practitioner and district nurse visits were recorded. RESULTS: No demographic differences were observed between groups. Leg wound skin closure times were significantly shorter in Group 2 compared with Group 1 (P < 0.001). Group 1 demonstrated a greater incidence of excessive scarring (P < 0.001), itching (P < 0.001), irritation (P < 0.001) and adverse skin tissue reactions (P < 0.001) than Group 2. Fewer general practitioner visits were recorded in Group 1 compared with Group 2 (P = 0.051). CONCLUSION: Knotless barbed suture usage significantly reduces the incidence of knot-related leg wound complications compared with traditional monofilament knotted sutures. This may be related to differences in the rate of absorption of the suture material or an associated decrease in the incidence of adverse skin tissue reactions that may delay postoperative wound healing.

Early donor management increases the retrieval rate of hearts for transplantation in marginal donors.

OBJECTIVES: Organ donations continue to fall, failing to meet the clinical requirements for heart transplantation. Furthermore, the pathophysiology of brain stem death including hormonal and inflammatory changes may lead to significant donor heart injury. Early donor management may potentially alleviate these changes and therefore increase the number of available hearts for transplantation. We aimed to investigate whether early management of borderline donors can increase the heart retrieval rate. METHODS: Between September 2011 and February 2013, we performed early donor management of 26 potential heart donors in the intensive care units of the respective donor hospitals. At the time of referral donors were considered as borderline based on high-dose inotrope requirements, history of hypertension and cardiopulmonary resuscitation. Our management protocol included insertion of a pulmonary artery catheter and performance of cardiac output studies, weaning noradrenaline and commencing arginine vasopressin, and administration of tri-iodothyronine, methylprednisolone and insulin. Our primary end-point was donor heart acceptance, depending collectively on the results of cardiac output studies, cardiac contractility and coronary artery patency at the time of retrieval operation. RESULTS: We retrieved 14 (56%) borderline hearts after donor management (Group A) with a 30-day survival rate of 86%. Twelve (44%) organs were declined due to poor heart function (n=8; 66.7%; P<0.001) and/or palpable coronary artery disease (n=4; 33.3%; P=0.018) (Group B). The mean age of Groups A and B was 42.77 and 47.78 years, respectively (P=0.19). Most of the female donors, i.e. 10 (83%), were declined, and only 4 (27%) were accepted (P=0.005). Majority of patients in both groups (Group A: 71.4%; n=10; and Group B: 66.7%; n=8) were on high-dose noradrenaline (>0.08 µg kg(-1) min(-2)) at the time of donor offer. Group A had a mean cardiac output of 6.29 and 3.09 l/min for Group B (P=0.01). A positive smoking history was present in 28.6% (n=4) and 33.5% (n=4) in Groups A and B, respectively (P=0.793). Cardiopulmonary resuscitation was performed on 3 (21.4%) patients in Group A and 2 (16.7%) in Group B (P=0.759). A history of hypertension was present in 7.1% (n=1) of the Group A and 33.3% (n=4) of the Group B donors. CONCLUSIONS: In our study, we were able to retrieve more than half of the potential heart donors as a result of early active donor management without impacting on the post-transplant recipient outcome. Early active donor management may assist in increasing the number of heart transplantations, thus warranting further investigation.

Histological and immunohistochemical evaluation of human saphenous vein harvested by endoscopic and open conventional methods.

OBJECTIVES: The introduction of endoscopic saphenous vein harvesting (ESVH) has been reported to decrease saphenectomy-associated wound pain and infection, compared with the traditional open conventional saphenous vein harvesting (OCSVH) technique. Despite all these benefits, the rate of adoption among surgeons has been variable. Criticism of this technique centres on the risk of injury at the time of vein harvest with its potential detrimental effect on structural viability and long-term patency. The aim of our study is to investigate the endothelial preservation of saphenous vein grafts harvested by various extraction methods. METHODS: A prospective, observational study of 30 human saphenous vein grafts was performed to evaluate endothelial preservation by haematoxylin-eosin and CD 31 staining methods. The saphenous vein was harvested endoscopically either by an open tunnel (OT-ESVH), closed tunnel (CT-ESVH) or an OCSVH harvesting technique. Research samples were collected without distension to avoid intraluminal dilatation and endothelial disruption. Both haematoxylin-eosin and immunohistochemistry slides were imaged by a high-resolution slide-scanning system. RESULTS: Haematoxylin-eosin staining of the CT-ESVH group showed mostly preserved endothelium (P = 0.398) with some endothelial stretching (P = 1.0) and no endothelial detachment (P = 0.197). The OT-ESVH group showed marked endothelial stretching (P = 0.053). However, the OCSVH group showed significantly more endothelial detachment than the endoscopic groups (P = 0.01). The mean grading score of immunohistochemistry using the CD 31 antibody was much lower in the OT-ESVH group (1.6 ± 0.84, P = 0.009), showing more poorly preserved endothelial cells than the CT-ESVH and OCSVH groups. CONCLUSIONS: We observed more endothelial stretching in the OT-ESVH group, which in our opinion, was due to lack of subcutaneous tissue separation, poor visualization and traction stresses across the wall of the saphenous vein. However, the OCSVH method revealed poor endothelial protection with areas of endothelial detachment, not observed with both endoscopic techniques. Interestingly, most preserved endothelium was found in the CT-ESVH group, which was previously known to be associated with worse graft patency.

Measurement of extravascular lung water following human brain death: implications for lung donor assessment and transplantation.

OBJECTIVES: The measurement of extravascular lung water could aid the assessment and guide the management of potential lung donors following brain death. We therefore sought to validate a single indicator thermodilution extravascular lung water index (EVLWI-T) measurement using gravimetry and to assess the impact and clinical correlates of elevated EVLWI-T in potential lung donors and transplant recipients. METHODS: In a prospective study, we measured serial EVLWI-T and haemodynamic and oxygenation data in 60 potential lung donors. To validate the EVLWI-T measurement, we measured in vivo thermodilution EVLWI (EVLWI-T) and gravimetric ex vivo EVLWI (EVLWI-G) in donor lungs rejected for transplant using the Holcroft and Trunkey modification of Pearce's method. We assessed the clinical correlates of elevated lung water and measured interleukin-8 and hepatocyte growth factor in bronchoalveolar lavage (BAL) fluid. RESULTS: The mean EVLWI-T (n = 60) was 9.7 (4.5) ml kg(-1), being >7-10 ml kg(-1) in 23/60 and >10 ml kg(-1) in 16/60 potential donors. Donor lungs with EVLWI >10 ml kg(-1) were more likely to be receiving norepinephrine (P = 0.04), have higher pulmonary capillary wedge pressures (P = 0.008), be unsuitable for transplantation (P = 0.007) and, if transplanted, have worse survival (P = 0.04). Lungs submitted to gravimetric analysis [n = 20 in 11 donors (9 double and 2 single)] had EVWLI-T of 10.8 (2.7) and EVLWI-G was 10.1 (2.5). There was a strong correlation between EVLW-T and EVLW-G (r = 0.7; P = 0.014), but EVLWI-T over-predicted the EVLWI-G by ≈ 1 ml kg(-1) (EVLW-T = 1.05 × EVLW-G). Cytokine levels in BAL fluid were elevated. CONCLUSIONS: Elevated lung water is found in >50% of potential lung donors, predicts lung suitability for transplant and may adversely affect recipient outcome. Although EVLWI-T intrinsically overestimates gravimetric lung water, its measurement may aid the assessment of organ suitability. Lung water accumulation and the proinflammatory response may both be targets for modifying therapy.

Echocardiography in the potential heart donor.

BACKGROUND: The relationship between echocardiographic left ventricular(LV) systolic function (E-function) and pulmonary artery catheter(PAC) assessment of hemodynamic function (H-function) in potential heart donors is ill defined. We investigated this and determined (a) whether optimization could improve abnormal E-function, (b) feasibility and usefulness of repeat transthoracic echocardiography (TTE), and (c) whether thyroid status and therapy affected E-function. MATERIALS AND METHODS: Transthoracic E-function imaging was performed at baseline and 4 hr in potential donors (enrolled in a randomized controlled trial of tri-iodothyronine+/-methylprednisolone [MP] therapy) undergoing PAC-guided algorithmic optimization. Images were analyzed post hoc for LV wall thickness, ejection fraction, and Tei index. RESULTS: The study comprised 66 donors. Both LV ejection fraction (LVEF) and LV-Tei correlated with cardiac index (CI; P<0.001), and LV Tei was most frequently measurable and repeatable(P=0.01). Normal LVEF independently predicted end-assessment H-functional suitability (odds ratio 1.05, 95% confidence interval 1.007-1.088 [P=0.021]) but had poor specificity. Initial subnormal E-function was identified in 29 of 66 of hearts, of which 58% (17/29) achieved H-function suitability criteria. In 52 hearts, repeat E-function assessment was possible. Nineteen of 52 had initially subnormal E-function, which improved in over half (53%). H-function could be manipulated to meet functional suitability criteria for transplant even without E-function change. Neither initial thyroid status nor hormonal therapy affected LV function. CONCLUSIONS: Echocardiography is possible in most potential heart donors. Normal E-function predicts hemodynamic suitability for transplantation but lacks specificity. More than 50% of hearts with subnormal E-function can attain hemodynamic transplantation criteria after donor management. Repeat echocardiography is feasible but has a limited role. Both initial echocardiography and PAC-guided management should be used routinely.

Donor cardiac troponin-I: a biochemical surrogate of heart function.

OBJECTIVE: Cardiac troponin-I (cTnI) levels in the potential heart transplant donor may be a marker of heart dysfunction and predictive of recipient outcome. We studied the prevalence of cTnI elevation, its association with heart function and usability and its relationship with the time duration from coning. METHODS: In a prospective study, cTnI measurement, Swan-Ganz catheterisation and transthoracic echocardiography were performed at initial assessment in 79 potential heart donors (mean age 43 +/- 13.1 years). All donors were then managed according to a strict algorithm to optimise cardiac function, some receiving hormonal therapy as part of a randomised trial. Donor heart suitability for transplantation was assessed after 7 h of management. The association of cTnI with initial functional indices was assessed and outcome compared for donors categorised according to cTnI level < or = 1 microg l(-1) or >1 microg l(-1). RESULTS: Serum cTnI levels negatively correlated with initial cardiac index (CI) (p = 0.003), right (p < 0.001) and left ventricular ejection fraction (p = 0.001) and positively with LV Tei index (p = 0.003). Serum cTnI was >1 microg l(-1) in 29/79 donors. Higher CVP (10 +/- 5.1 vs 7.9 +/- 2.9; p = 0.026) and PAWP (12 +/- 5.4 vs 8.1 +/- 3.1; p = 0.002), lower cardiac index (2.7 +/- 1.1 vs 3.6 +/- 0.9; p = 0.001) and fractional shortening (p < 0.01) and worse wall motion score index (p < 0.01) were observed in the cTnI >1 microg l(-1) group. CTnI and functional markers correlated with the time duration from coning. CONCLUSION: The donor cTnI level represents a biochemical surrogate of functional donor heart assessment. High cTnI is associated with worse donor heart function and may act as a prompt for detailed assessment and optimisation.

The proinflammatory environment in potential heart and lung donors: prevalence and impact of donor management and hormonal therapy.

BACKGROUND: Brain stem death can elicit a potentially manipulable cardiotoxic proinflammatory cytokine response. We investigated the prevalence of this response, the impact of donor management with tri-iodothyronine (T3) and methylprednisolone (MP) administration, and the relationship of biomarkers to organ function and transplant suitability. METHODS: In a prospective randomized double-blinded factorially designed study of T3 and MP therapy, we measured serum levels of interleukin-1 and -6 (IL-1 and IL-6), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein, and procalcitonin (PCT) levels in 79 potential heart or lung donors. Measurements were performed before and after 4 hr of algorithm-based donor management to optimize cardiorespiratory function and +/-hormone treatment. Donors were assigned to receive T3, MP, both drugs, or placebo. RESULTS: Initial IL-1 was elevated in 16% donors, IL-6 in 100%, TNF-alpha in 28%, CRP in 98%, and PCT in 87%. Overall biomarker concentrations did not change between initial and later measurements and neither T3 nor MP effected any change. Both PCT (P =0.02) and TNF-alpha (P =0.044) levels were higher in donor hearts with marginal hemodynamics at initial assessment. Higher PCT levels were related to worse cardiac index and right and left ventricular ejection fractions and a PCT level more than 2 ng x mL(-1) may attenuate any improvement in cardiac index gained by donor management. No differences were observed between initially marginal and nonmarginal donor lungs. A PCT level less than or equal to 2 ng x mL(-1) but not other biomarkers predicted transplant suitability following management. CONCLUSIONS: There is high prevalence of a proinflammatory environment in the organ donor that is not affected by tri-iodothyronine or MP therapy. High PCT and TNF-alpha levels are associated with donor heart dysfunction.

Early donor management increases the retrieval rate of lungs for transplantation.

BACKGROUND: Lung transplantation activity is frustrated by donor lung availability. We sought to examine the effect of active donor management and hormone administration on pulmonary function and yield in cadaveric heart-beating potential lung donors. METHODS: We studied 182 potential lung donors (arterial oxygen tension [PaO2]/fractional inspired oxygen [FIO2] ratio > or = 230). From this group, 60 patients (120 lungs) were allocated, within a randomized trial, to receive methylprednisolone (1 g), triiodothyronine (0.8 microg/kg bolus and 0.113 microg/kg/h infusion), both methylprednisolone and triiodothyronine, or placebo as soon as feasible after consent and initial assessment. Trial donors underwent protocol-guided optimization of ventilation and hemodynamics, lung water assessment, and bronchoscopy. Function was assessed by PaO2/FIO2 ratio, extravascular lung water index (EVLWI), and pulmonary vascular resistance (PVR). A nontrial group of 122 donors (244 lungs) received similar management without bronchoscopy, pulmonary artery flotation catheter monitoring, or lung water assessment. RESULTS: Within the trial, management commenced within a median of 2 hours (interquartile range, 0.5 to 3.5 hours) of consent and continued for an average of 6.9 +/- 1.2 hours. The PaO2/FIO2 ratio deteriorated (p = 0.028) from 397 +/- 78 (95% CL, 376 to 417) to 359 +/- 126 (95% CL, 328 to 390) and EVLWI from 9.7 +/- 4.5 mL/kg (95% CL, 8.6 to 10.9 mL/kg) to 10.8 +/- 5.2 mL/kg (95% CL, 9.4 to 12.2 mL/kg; p = 0.009). PVR remained unchanged (p = 0.28). At end management, 48 of 120 trial lungs (40%) were transplanted versus 66 of 244 nontrial lungs (27%; p = 0.016). Neither methylprednisolone and triiodothyronine nor T3 increased lung yield or affected PaO2/FIO2 or EVLWI; however, methylprednisolone attenuated the increase in EVLWI (p = 0.009). CONCLUSIONS: Early active management of lung donors increases yield. Steroid administration reduces progressive lung water accumulation.