Phil Botha

Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome.

Long-term survival after lung transplantation remains limited by the development of bronchiolitis obliterans syndrome (BOS). Allograft colonization with Pseudomonas aeruginosa is common particularly in recipients with BOS, but a possible etiological relationship remains unexplored. In 155 consecutive lung transplants, the development of allograft colonization with Pseudomonas was strongly associated with the development of BOS within 2 years of transplant (23.4% vs. 7.7% in those colonized and not colonized, respectively, P=0.006). Freedom from BOS was significantly shorter in those patients without any pretransplant bacterial reservoir developing de novo allograft pseudomonal colonization as compared with those remaining free of colonization (Kaplan-Meier log-rank P=0.014). The isolation of Pseudomonas preceded the diagnosis of BOS in 14 of 18 (78%) and by a median of 204 days (95% confidence interval 115–492) in patients developing both these complications. We conclude that de novo colonization of the lung allograft by Pseudomonas is strongly associated with the subsequent development of BOS.

Acute Hemodynamic Effects of Intravenous Sildenafil Citrate in Congestive Heart Failure: Comparison of Phosphodiesterase Type-3 and -5 Inhibition

BACKGROUND The reversibility of elevated pulmonary vascular resistance in heart failure bears an important relation to outcome after cardiac transplantation. The phosphodiesterase 3 (PDE3) and PDE5 inhibitors both increase levels of cyclic nucleotides in the vascular smooth muscle, causing vasodilatation. PDE3 inhibitors also have direct inotropic effects. We contrasted the acute hemodynamic responses to intravenous PDE3 and PDE5 inhibitors in patients with congestive cardiac failure to assess their relative suitability for reversibility testing in this setting. METHODS Thirty patients undergoing assessment for cardiac transplantation underwent right heart catheterization. Patients were randomized to receive an intravenous bolus of milrinone (0.05 mg/kg) or sildenafil citrate at a high (0.43 mg/kg) or low dose (0.05 mg/kg). RESULTS Differences between low- and high-dose sildenafil were not significant. Both agents caused similar reductions in systemic and pulmonary vascular resistance. Milrinone caused significantly greater reductions in pulmonary artery wedge and mean pulmonary artery pressure, and increases in heart rate. In all study groups, greater increases in cardiac index (>25%) were seen in patients with a higher pulmonary artery wedge pressure at baseline (29 +/- 1 vs 20 +/- 2 mm Hg; p < 0.001). CONCLUSIONS In end-stage congestive cardiac failure, intravenous milrinone and sildenafil both cause similar reductions in systemic and pulmonary vascular resistance; however, milrinone has more cardiac selective effects on left ventricular filling and heart rate. Both agents appear to have a suitable hemodynamic profile for testing of reversibility of secondary pulmonary hypertension in congestive cardiac failure. Larger studies are needed to confirm these results.

Current Strategies in Donor Selection and Management

Lung donor selection and management strategy continues to evolve, driven by the scarcity of donor lungs suitable for transplantation and the ever present risk of primary graft dysfunction. Selection, based both on data available at referral and that added by the retrieval team, was traditionally based on the transplant surgeons clinical experience. Closely analyzed clinical data on factors such as age, gas exchange, gram-stain, and even cytokine expression now allow increased objectivity of decision making. By contrast, the importance of variables such as length of ventilation and even ischemic time remain obscure. Optimal management, the key to promoting the marginal lung toward the ideal, is soundly based on the rapidly increasing appreciation of the pathophysiology of brain-stem death. Algorithms based on this knowledge can be proposed with some confidence, but proving their clinical worth is a challenge for the future.

Marginal lung donors: A diminishing margin of safety?

Lung donor shortages have resulted in the critical appraisal of cadaveric donor acceptability criteria and the gradual relaxation of once strict guidelines. Many centers have reported their results with these “extended criteria” donors and an increasing number of multicenter registry studies have also been published. The results have been contradictory and leave many questions unanswered. Important new data has however come to light since the last review of the subject by the International Society for Heart and Lung Transplantation Pulmonary Council. We review the current literature focusing on recent developments in the pursuit of an expanded lung donor pool with acceptable outcomes.

The impact of mechanical circulatory support on outcomes in paediatric heart transplantation

OBJECTIVES Internationally, the number of donors for cardiac transplantation has remained static, while the number of patients requiring transplantation for congenital heart disease (CHD) has increased. Although the availability of mechanical circulatory support (MCS) may increase the number of transplants performed by reducing deaths while waiting, it may also lead to increased morbidity post-transplantation. We sought to assess the impact of mechanical support on post-transplant outcomes in a single centre. METHODS We assessed the outcomes of paediatric (age ≤16 years) heart transplantation in a single unit in the era of mechanical support (1998-2012) by retrospective cohort study. Outcomes before (1998-2005) and after (2005-2012) the routine use of the Berlin Heart EXCOR device were contrasted. RESULTS A total of 167 patients underwent heart transplantation during this period. The diagnosis was dilated cardiomyopathy in 61.7%, two-ventricle CHD in 11.4%, single ventricle CHD in 16.8% and miscellaneous in 10.1%. Sixty-nine (41%) were bridged to transplant by mechanical support; with extracorporeal membrane oxygenation in 19 (28%), ventricular assist device in 40 (58%) and a combination in 10 (14.0%). Post-transplant mortality at 30 days was significantly greater in those supported by MCS than without (7 vs 1%, P < 0.05), and a greater proportion of patients had neurological (23 vs 8%, P < 0.01) and major respiratory sequelae (20 vs 4%, P < 0.001). There was no significant increase in the need for post-transplant mechanical support (10 vs 6%, P = 0.3) in those supported prior to transplant. The number of transplants performed increased from 67 in 1998-2005 to 100 in the most recent era (2005-2012), and an increased proportion of these patients have been supported mechanically prior to transplantation (51 vs 27%, P < 0.01). CONCLUSION Along with strategies to increase donor utilization, MCS has allowed an increase in cardiac transplant activity at the expense of a higher early mortality and morbidity.

Is CFTR-delF508 really absent from the apical membrane of the airway epithelium?

Background Understanding where mutant CFTR is localised in airway epithelia is essential in guiding the best therapeutic approach to correct the dysfunction of the CFTR protein. The widely held paradigm is that CF patients harbouring the commonest mutation, CFTR-delF508, trap CFTR within the endoplasmic reticulum and target it for degradation. However there are conflicting reports concerning expression and localisation of CFTR-delF508 in lung tissue. To attempt to resolve this fundamental issue we developed a novel approach to measure CFTR-delF508 in the lower airways of patients who have undergone lung transplantation for advanced CF. By sampling CF and non-CF epithelium simultaneously from the same individual, confounding factors of different airway microenvironments which may have influenced previous observations can be overcome. Methods Epithelia sampled by bronchial brushing above (CF) and below (non-CF) the bronchial anastomosis were stained for CFTR and the localisation and level of expression assessed (n = 12). Results There was no significant difference in the proportion of tall columnar cells showing CFTR immunostaining as a discrete band at the apical membrane in cells harbouring the CFTR-delF508 mutation compared to non-CF cells (p = 0.21, n = 12). However, the amount of CFTR expressed at the apical surface was reduced by ∼50% in CF cells compared to non-CF cells (p = 0.04, n = 5). Conclusions Our novel observation challenges the prevailing paradigm that CFTR is essentially absent from the apical membrane of respiratory cells harbouring the CFTR-delF508 mutation. Moreover, it raises the possibility that the new generation of CFTR potentiators may offer a realistic therapeutic option for CF patients.

Sildenafil citrate augments myocardial protection in heart transplantation.

Background. Sildenafil citrate has been shown to induce myocardial protective effects in a variety of experimental settings. Whether these effects could be used to enhance myocardial protection afforded by crystalloid cardioplegia, volatile anesthesia and hypothermia during cardiac transplantation remains to be established. Methods. We investigated the use of sildenafil-mediated cardioprotection in a rat model of heterotopic cardiac transplantation. Sildenafil citrate (0.7 mg/kg) was administered intravenously to the donor 30 min before onset of ischemia or 5 min before reperfusion in the recipient. In situ cardioplegic arrest was followed by an ischemic time of 3 or 6 hr, transplantation, and blood reperfusion. Myocardial functional recovery was studied in vivo by using a left ventricular balloon and cellular injury quantified by assay of troponin I release and apoptosis. Results. Sildenafil preconditioning but not postconditioning significantly improved initial myocardial systolic and diastolic function after 3 hr of hypothermic cardioplegic arrest (114±4 mm Hg vs. 83±4 mm Hg generated pressure, [P<0.01]). The protective effect of sildenafil declined over a 3-hr period of reperfusion along with overall myocardial function, no longer reaching statistical significance at 3 hr. The protective effects of sildenafil were abolished by the putative blocker of the mitochondrial ATP sensitive potassium channel, 5-hydroxydecanoate, before sildenafil administration. Protein kinase C delta showed significant translocation after sildenafil administration in the donor. Conclusions. We conclude that sildenafil citrate pretreatment augments myocardial functional recovery after an ischemic time relevant to clinical cardiac transplantation. This effect is associated with protein kinase C activation/translocation and inhibited by 5-hydroxydecanoate.

Standardization of transplant procurement procedures

STANDARDIZATION OF TRANSPLANT PROCUREMENT PROCEDURES To the Editor: We read with interest the article by Pasque and applaud the author’s efforts to standardize thoracic organ retrieval. Organ procurement has been conducted by surgical teams from the geographically nearest transplant center on the Zonal Retrieval Scheme in the United Kingdom since 1995. This has significantly improved cost-effectiveness and enhanced the safety of surgical teams. We recommend a number of important additions to the organ retrieval procedure that we believe to be vital in facilitating organ preservation and improving recipient outcomes. Cardiac output monitoring (usually by using a Swan–Ganz catheter) is extremely useful, if not indispensable, in the assessment and optimization of donor hemodynamic parameters, and we strongly recommend it as a routine. We have also found individual pulmonary vein gas sampling to be useful in recognizing unilateral dysfunction, allowing a greater number of single lungs to be identified as suitable for transplantation. Extension of cardiac ischemic time even beyond 1 hour progressively increases early mortality, and therefore minimization is vital. To this end, we routinely pack and dispatch the donor heart before completion of the donor pneumonectomy. The author suggests extubation of the donor followed by tracheal sta-

An Unusual Combination of Double Inlet Left Ventricle With Discordant Ventriculoarterial Connections and Bilateral Arterial Ducts

The presence of bilaterally persistent arterial ducts is an uncommon abnormality. Here, we describe the anatomy and successful management of an unusual patient with bilateral ducts in the setting of double inlet left ventricle, discordant ventriculoarterial connections, aortic atresia, and a severely hypoplastic and serpentine aortic arch.

Modified Technique for the Implantation of Berlin Heart Excor Ventricular Assist Device in Children

The Berlin Heart Excor (BHE) assist device has become our standard mechanical support device for long-term support in children with heart failure. We report two useful surgical modifications for the implantation of the BHE in the pediatric population, improving ease of implantation as well as subsequent surgical procedures at the time of explantation or transplantation. The first modification entails the use of a polytetrafluoroethylene graft for cannulation via the innominate artery for arterial perfusion during cardiopulmonary bypass. This graft is preserved and reused for institution of bypass at the time of transplantation or explantation of the device after recovery. The second modification consists of an extension of the BHE arterial cannula using a length of knitted polyester graft. This allows for improved positioning of the arterial cannula in the ascending aorta or main pulmonary artery, facilitates vascular anastomosis, and improves hemostasis.