C. Bermudez

Initial Experience With Single Cannulation for Venovenous Extracorporeal Oxygenation in Adults

PURPOSE Historically, venovenous extracorporeal membrane oxygenation has required dual cannulation. A single-venous cannulation strategy may facilitate implantation and patient mobilization. Here we present our early experience with a single cannulation technique. DESCRIPTION Review of venovenous extracorporeal membrane oxygenation support using internal jugular vein insertion of the Avalon elite bicaval dual lumen catheter (Avalon Laboratories, Rancho Dominguez, CA) in 11 consecutive patients with severe respiratory failure. EVALUATION Adequate oxygenation was obtained in all patients: 115 mm Hg PaO(2) (median), 53 to 401 mm Hg (range). Median time of support was 78 hours (range, 3 to 267 hours). No mortality was directly related to the cannulation strategy. There were three nonfatal cannulation-related events. Two patients had proximal cannula displacement requiring repositioning. One patient suffered an acute thrombosis of the cannula. CONCLUSIONS Our series supports single-venous cannulation in venovenous extracorporeal membrane oxygenation as a promising technique. It may be an excellent alternative to current cannulation strategies in patients requiring prolonged support and specifically for those considered for a bridge-to-lung transplantation.

Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients

BACKGROUND Sensitized heart transplant candidates are evaluated for donor-specific anti-HLA IgG antibody (DSA) by Luminex single-antigen bead (SAB) testing (SAB-IgG) to determine donor suitability and help predict a positive complement-dependent cytotoxicity crossmatch (CDC-XM) by virtual crossmatching (VXM). However, SAB testing used for VXM does not correlate perfectly with CDC-XM results and individual transplant programs have center-specific permissible thresholds to predict crossmatch positivity. A novel Luminex SAB-based assay detecting C1q-binding HLA antibodies (SAB-C1q) contributes functional information to SAB testing, but the relationship between SAB strength and complement-binding ability is unclear. METHODS In this retrospective study, we identified 15 pediatric and adult heart allograft candidates with calculated panel-reactive antibody (cPRA) >50% by SAB-IgG and compared conventional SAB-IgG results with SAB-C1q testing. RESULTS Pre- and post-transplant DSA by SAB-C1q correlated with DSA by SAB-IgG and also with CDC-XM results and early post-transplant endomyocardial biopsy findings. Individual HLA antibodies by SAB-IgG in undiluted sera correlated poorly with SAB-C1q; however, when sera were diluted 1:16, SAB-IgG results were well correlated with SAB-C1q. In some sera, HLA antibodies with low mean fluorescent intensity (MFI) by SAB-IgG exhibited high SAB-C1q MFIs for the same HLA antigens. Diluting or heat-treating these sera increased SAB-IgG MFI, consistent with SAB-C1q results. In 13 recipients, SAB-C1q-positive DSA was associated with positive CDC-XM and with early clinical post-transplant antibody-mediated rejection (cAMR). CONCLUSIONS Risk assessment for positive CDC-XM and early cAMR in sensitized heart allograft recipients are correlated with SAB-C1q reactivity.

Efficacy of extracorporeal membrane oxygenation as a bridge to lung transplantation

BACKGROUND Preoperative extracorporeal membrane oxygenation (ECMO) is a risk factor for poor outcome and currently considered a contraindication to lung transplantation. The lung allocation score system was introduced in May 2005 and prioritizes lung allocation to those with the greatest respiratory impairment. The purpose of this study is to determine whether ECMO as a bridge to lung transplantation is an acceptable option to support those in respiratory failure until donor lungs become available in the lung allocation score era. METHOD A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011 was conducted using a prospectively collected institutional registry database. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pretransplant ECMO; 7 patients who received ECMO patients did not survive or were deemed unfit for transplantation. These patients were compared with a control group of 691 patients who did not receive pretransplant ECMO. RESULTS The duration of pretransplant ECMO was 171 ± 242 hours (median, 91 hours). Venovenous ECMO was used for respiratory failure in 15 patients, whereas venoarterial ECMO was used for circulatory collapse due to pulmonary hypertension in 9 patients. Patients in the retransplant ECMO group were younger (46 ± 15 years vs 57 ± 14 years, P < .01) compared with the control group, with no difference in recipient gender (male/female: 10/14 vs 380/311), donor age (33 ± 14 years vs 36 ± 15 years), or donor gender (male/female: 10/14 vs 352/339). Emphysema was less common (1, 4% vs 260, 38%, P < .01), and cystic fibrosis (5, 21% vs 72, 10%, P = .09), redo lung transplant (3, 13% vs 28, 4%, P = .08), and bronchiectasis (2, 8% vs 6, 1%, P = .03) were more common in the pretransplant ECMO group. Patients in the pretransplant ECMO group had a significantly higher lung allocation score (87 ± 9 vs 44 ± 15, P < .01). All patients in the pretransplant ECMO group underwent double lung transplants on pump (cardiopulmonary bypass/ECMO), and single lung transplants were performed in 171 patients (25%) and pump was used in 243 patients (35%) in the control group. The cardiopulmonary bypass time was longer in the pretransplant ECMO group (277 ± 69 minutes vs 225 ± 89 minutes, P = .02), with no difference in ischemic time (343 ± 93 minutes vs 330 ± 98 minutes, P = .54). Cadaveric lobar lung transplants were performed because of the urgency to overcome size mismatch with an oversized donor more frequently in 25% (n = 6, no mortality with the longest follow-up at 6 years) of patients in the pretransplant ECMO group versus 0.3% (n = 2) of patients in the control group (P < .01). Post-transplant ECMO was used for primary graft dysfunction in 13 patients (54%) in the pretransplant ECMO group and 41 patients (6%) in the control group (P < .01). The median hospital stay was 46 days in the pretransplant ECMO group versus 27 days in the control group (P = .16). The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pretransplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group (P = .787). CONCLUSIONS Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pretransplant ECMO, the graft survival is good (2-year survival, 74%). ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes.

Incidence and Patterns of Adverse Event Onset During the First 60 Days After Ventricular Assist Device Implantation

BACKGROUND Although ventricular assist devices (VADs) provide effective treatment for end-stage heart failure, VAD support remains associated with significant risk for adverse events (AEs). To date there has been no detailed assessment of the incidence of a full range of AEs using standardized event definitions. We sought to characterize the frequency and timing of AE onset during the first 60 days of VAD support, a period during which clinical observation suggests the risk of incident AEs is high. METHODS A retrospective analysis was performed utilizing prospectively collected data from a single-site clinical database including 195 patients aged 18 or greater receiving VADs between 1996 and 2006. Adverse events were coded using standardized criteria. Cumulative incidence rates were determined, controlling for competing risks (death, transplantation, recovery-wean). RESULTS During the first 60 days after implantation, the most common AEs were bleeding, infection, and arrhythmias (cumulative incidence rates, 36% to 48%), followed by tamponade, respiratory events, reoperations, and neurologic events (24% to 31%). Other events (eg, hemolysis, renal, hepatic events) were less common (rates <15%). Some events (eg, bleeding, arrhythmias) showed steep onset rates early after implantation. Others (eg, infections, neurologic events) had gradual onsets during the 60-day period. Incidence of most events did not vary by implant era (1996 to 2000 vs 2001 to 2006) or by left ventricular versus biventricular support. CONCLUSIONS Understanding differential temporal patterns of AE onset will allow preventive strategies to be targeted to the time periods when specific AE risks are greatest. The AE incidence rates provide benchmarks against which future studies of VAD-related risks may be compared.

Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplant: Midterm Outcomes

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is used occasionally as a bridge to lung transplantation. The impact on mid-term survival is unknown. We analyzed outcomes after lung transplant over a 19-year period in patients who received ECMO support. METHODS From March 1991 to October 2010, 1,305 lung transplants were performed at our institution. Seventeen patients (1.3%) were supported with ECMO before lung transplant. Diagnoses included retransplantation (n = 6), pulmonary fibrosis (n = 6), cystic fibrosis (n = 4), and chronic obstructive pulmonary disease (n = 1). Fifteen patients underwent double lung transplant, one patient had single left lung transplant and one patient had a heart-lung transplant. Venovenous and venoarterial ECMO were implanted in eight and nine cases, respectively. Median duration of support was 3.2 days (range, 1 to 49 days). Mean patient follow-up was 2.3 years. RESULTS Thirty-day, 1-year, and 3-year survivals were 81%, 74%, and 65%, respectively, for the supported patients and 93%, 78%, and 62% in the control group (p = 0.56). Two-year survival was not affected by ECMO type, with survival of five out of nine patients supported by venoarterial ECMO vs seven out of eight patients supported by venovenous ECMO (p = 0.17). At 1- year follow-up, allograft function for the ECMO-supported patients did not differ from the control group (forced expiratory volume in one second, 2.35 L vs 2.09 L, p = 0.39) (forced vital capacity, 3.06 L vs 2.71 L, p = 0.34). CONCLUSIONS Extracorporeal membrane oxygenation as a bridge to lung transplantation is associated with higher perioperative mortality but acceptable mid-term survival in carefully selected patients. Late allograft function did not differ in patients who received ECMO support before lung transplant from those who did not receive ECMO.

Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients

BACKGROUND Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. METHODS We performed a retrospective, case-control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. RESULTS SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p = 0.02), residence in locations with high levels of sun exposure (p = 0.0001), single-lung transplant (p = 0.02) and duration (p = 0.03) and cumulative dose (p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. CONCLUSIONS Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.

Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation: Long-Term Survival

BACKGROUND Primary graft dysfunction (PGD) after lung transplantation is a major cause of morbidity and mortality. Venovenous or venoarterial extracorporeal membrane oxygenation (ECMO) allows lung recovery; however, the optimal approach and impact on long-term survival are unknown. We analyzed outcomes after ECMO use for PGD after lung transplantation at a single center over a 15-year period and assessed long-term survival. METHODS From March 1991 to March 2006, 763 lung or heart-lung transplants were performed at our center. Fifty-eight patients (7.6%) required early (0 to 7 days after transplant) ECMO support for PGD. Venovenous or venoarterial ECMO was implemented (32 and 26 cases) depending on the patients hemodynamic stability, surgeons preference, and the era of transplantation. Mean duration of support was 5.5 days (range, 1 to 20). Mean follow-up was 4.5 years. RESULTS Thirty-day and 1- and 5-year survivals were 56%, 40%, and 25%, respectively, for the entire group. Thirty-nine patients were weaned from ECMO, 21 venovenous and 18 venoarterial (53.8% and 46.2%), with 1- and 5-year survivals of 59% and 33%, inferior to recipients not requiring ECMO (p = 0.05). Survival at 30 days and at 1 and 5 years was similar for the patients supported with venoarterial or venovenous ECMO (58% versus 55%, p = 0.7; 42% versus 39%, p = 0.8; 29% versus 22%, p = 0.6). CONCLUSIONS Extracorporeal membrane oxygenation can provide acceptable support for PGD irrespective of the method used. Long-term survival of patients with primary graft dysfunction requiring ECMO (overall and weaned) was inferior to that of patients who did not require ECMO.

Antireflux Surgery Preserves Lung Function in Patients With Gastroesophageal Reflux Disease and End-stage Lung Disease Before and After Lung Transplantation

BACKGROUND Gastroesophageal reflux disease (GERD) is common in patients with end-stage lung disease (ESLD). GERD may cause obliterative bronchiolitis after lung transplantation (LTx), represented by a decline in forced expiratory volume in 1 second (FEV(1)). OBJECTIVES To identify the patterns of reflux in patients with ESLD and to determine whether antireflux surgery (ARS) positively impacts lung function. DESIGN Retrospective review of prospectively collected data. SETTING Tertiary care university hospital. PATIENTS Forty-three patients with ESLD and documented GERD (pre-LTx, 19; post-LTx, 24). INTERVENTIONS Antireflux surgery. MAIN OUTCOME MEASURES Reflux patterns including laryngopharyngeal reflux as measured by esophageal impedance, and FEV(1), and episodes of pneumonia and acute rejection before and after ARS. RESULTS Before ARS, 19 of 43 patients (44%) were minimally symptomatic or asymptomatic. Laryngopharyngeal reflux events, which occurred primarily in the upright position, were common in post-LTx (56%) and pre-LTx (31%) patients. At 1 year after ARS, FEV(1) significantly improved in 91% of the post-LTx patients (P < .01) and 85% of the pre-LTx patients (P = .02). Of patients with pre-ARS declining FEV(1), 92% of post-LTx and 88% of pre-LTx patients had a reversal of this trend. Episodes of pneumonia and acute rejection were significantly reduced in post-LTx patients (P = .03) or stablilized in pre-LTx patients (P = .09). CONCLUSIONS There should be a low threshold for performing objective esophageal testing including esophageal impedance because GERD may be occult and ARS may improve or prolong allograft and native lung function.

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

ABSTRACT Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n = 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n = 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (P = 0.005). Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (P = 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml (P = 0.01) and among patients with no trough of >1.5 μg/ml (P = 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P = 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml.

Pulsatile left ventricular assist device support as a bridge to decision in patients with end-stage heart failure complicated by pulmonary hypertension

BACKGROUND Severe pulmonary hypertension (PH) in heart failure (HF) is a risk factor for adverse outcomes after heart transplantation (HTx). Left ventricular assist devices (LVADs) improve pulmonary hemodynamics, but our understanding of the degree of improvement and the effect on outcomes is still evolving. METHODS We reviewed invasive pulmonary hemodynamics from 58 consecutive patients receiving LVAD support as a bridge to HTx from 1996 to 2003. The primary outcome was change in baseline transpulmonary gradient (TPG) during LVAD support and after HTx/recovery. The secondary outcome was post-HTx survival. RESULTS All patients (age, 49 +/- 14 years, 79% male, 40% ischemic) received a pulsatile LVAD (median support, 97 days; interquartile range [IQR], 31-222). Hemodynamic measurements were obtained at baseline (median, 1 day; IQR, 1-3), during early (median, 1 day; IQR, 0-4) and late (median, 75 days; IQR, 24-186) LVAD support, and after HTx/recovery (median, 28 days; IQR, 17-40). Improvement in TPG occurred throughout LVAD support and was sustained after HTx/recovery. Levels of TPG reductions in patients with a baseline TPG in the highest quartile (14.1-26.0 mm Hg) were 8.6 +/- 3.5 vs 6.5 +/- 3.1 mm Hg in the lowest quartile (2.0-7.7 mm Hg) during LVAD support (p = 0.102), with 90% vs 100% 30-day post-HTx survival (P = 0.113). CONCLUSION Pulmonary hemodynamics and post-HTx survival were similar after pulsatile LVAD support in patients with and without pre-implant PH. LVAD support may be a useful strategy to reverse PH in carefully selected patients, thus improving candidacy for HTx.