Contemporary look at extracorporeal membrane oxygenation as a bridge to reoperative lung transplantation in the United States - a retrospective study.

The purpose of this study was to examine the influence of extracorporeal membrane oxygenation (ECMO) as a bridge to reoperative lung transplantation (LT) on outcomes and survival. A total of 1960 LT recipients transplanted a second time between 2005 and 2017 were analyzed using the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN). Of these recipients, 99 needed ECMO as a bridge to reoperative LT. Mean age was 50 ± 14 years, 47% were females, and the group with ECMO was younger [42 (30-59) vs. 55 (40-62) years]. In both univariate and multivariable analyses (adjusting for age and gender), the ECMO group had greater incidence of prolonged ventilation >48 h (83% vs. 40%, P < 0.001) and in-hospital dialysis (27% vs. 7%, P < 0.001). There were no differences in incidence of acute rejection (15% vs. 11%, P = 0.205), airway dehiscence (4% vs. 2%, P = 0.083), stroke (3% vs. 2%, P = 0.731), or reintubation (20% vs. 20%, P = 0.998). Kaplan-Meier survival analysis showed the ECMO group had reduced 1-year survival (66.6% vs. 83.0%, P < 0.001). After covariate adjustment, the ECMO group only had increased risk for 1-year mortality in the 2005-2011 era (HR = 2.57, 95% CI = 1.45-4.57, P = 0.001). For patients who require reoperative LT, bridging with ECMO was historically a significant predictor of poor outcome, but may be improving in recent years.

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV-associated posttransplant lymphoproliferative disorder and worse survival.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.

Aerosolization of Second-generation Triazoles: In Vitro Evaluation and Application in Therapy of Invasive Airway Aspergillosis.

BACKGROUND: A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered. METHODS: Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. RESULTS: Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (<5.4 µm) of 2.8 µm, 2.0, 86%; 3.4 µm, 2.4, 78%; and 3.0 µm, 2.3, 79% for voriconazole and 6, 12 mg/mL of posaconazole, respectively. Aspergillus fumigatus isolate from the patient was more susceptible to voriconazole, and hence aerosolized voriconazole was introduced around the third month posttransplant at 40 mg TID for 1 week, 40 mg BID for 1 week, followed by 40 mg daily thereafter, along with IV caspofungin (50 mg/d) and liposomal amphotericin B (300 mg/d). The aerosol regimen was well tolerated by the patient with undetectable trough plasma levels of voriconazole. Bronchoscopy at the fourth month revealed improvement in anastomotic plaques with reduction in bronchoalveolar lavage galactomannan values (7.48-2.15 ng/mL). This consolidated aerosolized and intravenous regimen was maintained until 2.97 years posttransplant. CONCLUSIONS: The intravenous solutions of both second-generation triazoles showed characteristics that were suitable for aerosol delivery. Our report further adds to the therapeutic experience with the use of aerosolized voriconazole for IA in a lung transplant patient.

Impaired Cytomegalovirus Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres.

RATIONALE: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high risk for CMV complications and effective immunity are incompletely understood. OBJECTIVES: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control. METHODS: We studied IPF-LTRs (n = 42) and age-matched non-IPF-LTRs (n = 42) and assessed CMV outcomes. We measured lymphocyte telomere length and DNA sequencing, and assessed CMV-specific T-cell immunity in LTRs at high risk for CMV events, using flow cytometry and fluorescence in situ hybridization. MEASUREMENTS AND MAIN RESULTS: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared with non-IPF-LTRs (69% vs. 31%; odds ratio, 4.98; 95% confidence interval, 1.95-12.50; P < 0.001). Within this subset, IPF-LTRs who had short telomeres had the highest risk of CMV complications (P < 0.01) including relapsing-viremia episodes, end-organ disease, and CMV resistance to therapy, as well as shorter time to viremia versus age-matched non-IPF control subjects (P < 0.001). The short telomere defect in IPF-LTRs was associated with significantly impaired CMV-specific proliferative responses, T-cell effector functions, and induction of the major type-1 transcription factor T-bet (T-box 21;TBX21). CONCLUSIONS: Because the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of LTRs has implications for risk assessment, management, and potential strategies for averting post-transplant CMV morbidities.

Outcomes after lung transplantation for patients with occupational lung diseases.

Occupational lung diseases (OLD) including silicosis, asbestosis, and pneumoconiosis progress to end stage lung disease requiring lung transplantation (LT). Prognosis and treatment of OLDs are poorly understood and a paucity of data exists regarding LT outcomes. Additionally, transplant operative complexity for patients with OLD is high. A single center retrospective review of all single and bilateral LT recipients between May 2005 and Oct 2016 was performed. Patients were grouped by OLD, and nearest neighbor matching was performed at a ratio of 1:3 cases to controls. Thirty cases were matched to 88 controls. Seventeen patients (57%) with OLD required intraoperative support with either extra-corporeal membrane oxygenation (ECMO) or cardiopulmonary bypass (P = 0.02), and 5 (17%) required delayed chest closure (P = 0.05) which was more frequent than matched controls. In addition, operative time was significantly longer in patients with OLD (P = 0.03). Despite these factors, there were no significant differences in immediate post-operative outcomes including mechanical ventilator support, post-operative ECMO, and tracheostomy. Chronic lung allograft dysfunction and long-term survival were also similar between cases and controls. OLDs should not preclude LT. The operation should be performed at experienced centers.

Systematic review and meta-analysis of post-transplant lymphoproliferative disorder in lung transplant recipients.

A systematic review of papers in English on post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random-effects model, and heterogeneity among studies was quantitated using I2 values. Fourteen studies published from 2005 to 2015 were included in the meta-analysis. One hundred and sixty-four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67-fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98-29.70; P = .003). pOR of death for early onset PTLD (<1 year post-LT) vs late onset (>1 year post-LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20-1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI -0.48-0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08-2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31-3.52, P = .94). This meta-analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.

Comparative Effectiveness and Safety Analysis of Dual Antiplatelet Therapies Within an Integrated Delivery System.

BACKGROUND: Dual antiplatelet therapy is a mainstay of care for percutaneous coronary intervention (PCI) patients; however, uncertainty exists in real-world practice about comparative effectiveness and safety outcomes. OBJECTIVE: To evaluate outcomes of different oral P2Y12 inhibitors in PCI patients. METHODS: We retrospectively studied patients treated between July 1, 2010, and December 31, 2013. Patients received clopidogrel, prasugrel, ticagrelor, or more than 1 antiplatelet (switch) during PCI. Outcomes were evaluated for major adverse cardiovascular events (MACE) and bleeding at 1 year. Propensity score matching with Cox proportional hazards analysis was used to determine predictors of MACE and bleeding. RESULTS: A total of 8127 patients were included: clopidogrel (n = 6872), prasugrel (n = 605), ticagrelor (n = 181), and switch (n = 469). Treatment with prasugrel was associated with the lowest risk of MACE using multivariate regression (odds ratio [OR] = 0.57; 95% CI = 0.36-0.92; P = 0.02). In the propensity score-matched analysis, only the prasugrel group was associated with a lower risk of MACE compared with the clopidogrel group. Clopidogrel was associated with the lowest risk of major bleeding using multivariate regression (OR = 0.64; 95% CI = 0.42-0.98; P = 0.042). Both ticagrelor (hazard ratio [HR] = 2.00; 95% CI = 1.11-3.59) and the switch groups (HR = 1.65; 95% CI = 1.09-2.50) were associated with a greater risk of major bleeding compared with clopidogrel. However, no differences were found in the propensity score-matched analysis. CONCLUSIONS: Dual antiplatelet therapies differed in both MACE and bleeds in a real-world setting of PCI. Prasugrel was associated with fewer MACE, whereas clopidogrel had fewer major bleeding events.

Effect of aerosolized antipseudomonals on Pseudomonas positivity and bronchiolitis obliterans syndrome after lung transplantation.

PURPOSE: To describe the effects of aerosolized antipseudomonals (AAPs) on Pseudomonas (PS) culture positivity, bronchiolitis obliterans syndrome (BOS), and acute cellular rejection (ACR) in lung transplant recipients (LTRs). METHODS: Single-center, retrospective cohort study was performed of adult LTRs treated with either AAP for ≥28 days vs no AAP therapy or AAP therapy <28 days, indexed to a matched median date post lung transplantation (LT). Primary outcome was freedom from PS positivity by positive bronchoalveolar lavage or bronchial wash at 1 year. Secondary outcomes were freedom from BOS or BOS progression and ACR burden (defined by the novel composite rejection standardized score. Normality was assessed, and univariate and multivariate parametric and non-parametric statistical tests were used to assess baseline characteristics and outcomes, where appropriate. Freedom from events was compared using the Kaplan-Meier method with log-rank conversion and risk was assigned using multivariable Cox proportional hazards (PH) modeling. RESULTS: In total, 293 LTRs (105 with AAP, 188 with no AAP) were included. Median ages in AAP and control cohorts were 51 (30-63) and 62 (54-67) years (P<.01). Median AAP duration was 198 (interquartile range 94-395) days. Time to median positive PS culture was similar between AAP (median 1.02 [95% confidence interval {CI} 0.74-1.22] years) and control (median 0.96 [95% CI 0.72-1.21] years). Log-rank test for time-to-PS positivity was similar for both groups (log-rank P=.26). Incidence of PS culture positivity at 1 year was similar in APP vs controls (59.0% vs 54.8%, P=.48). In the non-cystic fibrosis (CF) subgroup, AAP use was protective against PS recurrence on univariate Cox PH model (hazard ratio [HR] 0.55, 95% CI 0.38-0.83) and on multivariate Cox PH adjusting for age and induction (HR 0.56, 95% CI 0.38-0.83). Incidence of new-onset BOS or BOS progression in APP vs control at 1 (17.1% vs 14.9%, P=.61) and 3 (38.1% vs 37.8%, P=.96) years was similar. CRSS was similar in APP vs control group at 1 year (0.42 vs 0.33, P=.41). CONCLUSION: AAP use was not associated with less PS positivity, BOS, or ACR in all LTRs. In the non-CF subgroup analysis, treatment with AAPS was associated with protection against recurrent PS. Limitations include retrospective design, heterogeneous AAP therapy among LTRs, and potential convenience sampling of LTRs receiving AAPs for >28 days at our center. Larger assessments and better controlled analyses are required to further define efficacy of AAPs after LT.

Janus kinase inhibition for immunosuppression in solid organ transplantation: Is there a role in complex immunologic challenges?

Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (γc). The γc is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family. Clinical outcomes have validated tofacitinib's pan-JAK activity in kidney transplantation after demonstrating an increased risk of infection and malignancy as compared to CNI-based regimens. After these trials, tofacitinib investigation for use in transplantation has effectively ceased. However, a post-hoc analysis has shed new light on the monitoring of tofacitinib exposure in order to predict infection and oncologic events. With new methods to monitor tofacitinib exposure, clinicians may be able to effectively reduce toxicities while providing a high level of immunosuppression. The purpose of this review to identify when, and for whom, JAK inhibitors may provide benefit in solid organ transplantation.

Rescue alemtuzumab for refractory acute cellular rejection and bronchiolitis obliterans syndrome after lung transplantation.

Refractory acute cellular rejection (rACR) is associated with death and bronchiolitis obliterans syndrome (BOS) post-lung transplantation. We report the largest cohort of lung transplant recipients (LTRs) treated with rescue alemtuzumab for rACR or BOS. RACR outcomes included burden of ACR 30 days before and 180 days after rescue assessed by a novel composite rejection standardized score (CRSS, range 0-6) and freedom from ≥A2 ACR. BOS outcomes included freedom from BOS progression and FEV1 decline >10%. Univariate parametric and nonparametric statistical approaches were used to assess treatment response. Kaplan-Meier method with log rank conversion was used to assess freedom from events. Fifty-seven alemtuzumab doses (ACR 40 and BOS 17) given to 51 patients were included. Median time to rescue was 722 (IQR 42-1403) days. CRSS declined significantly (3 vs 0.67, P<0.001) after rescue. Freedom from ≥A2 was 62.5% in rACR. Freedom from BOS progression was 52.9% at 180 days in the BOS cohort. Freedom from FEV1 decline >10% was 70% in BOS grade 1 and 14.3% in advanced BOS grades 2-3. Infections developed in 72.5% and 76.5% of rACR and BOS groups. Rescue alemtuzumab appears useful for rACR. Patients with BOS 1 may have transient benefit, and patients with advanced BOS seem not to respond to alemtuzumab.

De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation.

BACKGROUND: The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. METHODS: We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). RESULTS: We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001). CONCLUSIONS: Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.

Characterization, prophylaxis, and treatment of infectious complications in craniomaxillofacial and upper extremity allotransplantation: a multicenter perspective.

BACKGROUND: Vascularized composite allotransplants consist of heterogeneous tissues from different germ layers, which include skin, muscle, bone, fat, nerves, and lymph nodes. The antigenic diversity of these tissues, particularly of the highly immunogenic skin component, necessitates potent immunosuppressive regimens similar to that of some solid organ transplants. Indeed, the lifelong, high-dose, multidrug immunosuppressive protocols expose vascularized composite allotransplant recipients to considerable risk of infectious, metabolic, and neoplastic sequelae. In this article, the authors review the infectious risk to patients after vascularized composite allotransplantation, with special attention to the somewhat limited experience with the prophylaxis and treatment of infections after this innovative reconstructive surgery. METHODS: A review of the literature was undertaken to elucidate the characterization, prophylaxis, and treatment of all documented infectious complications. RESULTS: Infections in face and hand vascularized composite allotransplants follow a course similar to that of solid organ transplants. Several differences exist, including the unique flora of craniomaxillofacial transplants, the increased risk of donor-derived infections, and the alteration of the risk-to-benefit ratio for cytomegalovirus infections. CONCLUSIONS: The patient with a face or limb transplant has many of the same infectious risks as a lung transplant recipient, which include bacterial, viral, and fungal infections. Because of the anatomy, mucosal exposure, and differing donor flora, however, the face or limb transplant is susceptible to invasive diseases from a variety of microbes.

Colloids in the intensive care unit.

PURPOSE: The most recent published evidence on the use of colloids versus crystalloids in critical care is reviewed, with a focus on population-dependent differences in safety and efficacy. SUMMARY: Colloids offer a number of theoretical advantages over crystalloids for fluid resuscitation, but some colloids (e.g., hydroxyethyl starch solutions, dextrans) can have serious adverse effects, and albumin products entail higher costs. The results of the influential Saline Versus Albumin Fluid Evaluation (SAFE) trial and a subsequent SAFE subgroup analysis indicated that colloid therapy should not be used in patients with traumatic brain injury and other forms of trauma due to an increased mortality risk relative to crystalloid therapy. With regard to patients with severe sepsis, two meta-analyses published in 2011, which collectively evaluated 82 trials involving nearly 10,000 patients, indicated comparable outcomes with the use of either crystalloids or albumins. For patients requiring extracorporeal cardiopulmonary bypass (CPB) during heart surgery, the available evidence supports the use of a colloid, particularly albumin, for CPB circuit priming and postoperative volume expansion. In select patients with burn injury, the published evidence supports the use of supplemental colloids if adequate urine output cannot be maintained with a crystalloid-only rescue strategy. CONCLUSION: The results of the SAFE trial and a subgroup analysis of SAFE data suggest that colloids should be avoided in patients with trauma and traumatic brain injury. There are minimal differences in outcome between crystalloids and hypo-oncotic or iso-oncotic albumin for fluid resuscitation in severe sepsis; in select populations, such as patients undergoing cardiac surgery, the use of iso-oncotic albumin may confer a survival advantage and should be considered a first-line alternative.

Prophylaxis and treatment of respiratory syncytial virus in adult immunocompromised patients.

OBJECTIVE: To review the literature regarding current strategies and strategies under active development for the prevention and treatment of respiratory syncytial virus (RSV) infections in immunocompromised adults. DATA SOURCES: The MEDLINE/PubMed, EMBASE, and Cochrane databases were queried from January 1980 to December 2011 for articles in English using these associated search terms: respiratory syncytial virus, ribavirin, intravenous immunoglobulin, IVIG, palivizumab, motavizumab, lung, pneumonia, transplantation, bone marrow, cancer, malignancy, and vaccine. STUDY SELECTION AND DATA EXTRACTION: All relevant original studies, meta-analyses, systematic reviews, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search. DATA SYNTHESIS: RSV in the immunocompromised adult can lead to significant morbidity and mortality. Treatment of RSV-infected adults is limited to antiviral therapy with ribavirin (aerosolized, oral, intravenous) and immunomodulation with intravenous immunoglobulins, corticosteroids, and palivizumab. Existing literature is predominantly case reports, small trials, and retrospective reviews of patients infected with RSV who have undergone lung or hematopoietic stem cell transplantation (HSCT). Palivizumab may be a viable option for prophylaxis against RSV in high-risk adults. Ribavirin is the most studied treatment option and should remain the backbone of multidrug regimens. Of the routes of administration, aerosolized ribavirin carries the preponderance of evidence and, though challenging, is preferred to limit systemic toxicities in the infected patient. Addition of an immunomodulator to ribavirin may provide a survival benefit over ribavirin alone; however, this has only been studied in a subset of HSCT patients with lower respiratory tract RSV infection. CONCLUSIONS: Research most strongly supports the use of aerosolized ribavirin as the treatment strategy for immunocompromised adults with RSV. Addition of an immunomodulator may provide a survival benefit over ribavirin alone. Strategies and supportive data for the prevention of RSV infection in the high-risk adult are critically needed.

Intravenous neostigmine for postoperative acute colonic pseudo-obstruction.

OBJECTIVE: To review the literature on the safety and effectiveness of neostigmine for the treatment of postoperative acute colonic pseudo-obstruction. DATA SOURCES: The MEDLINE/PubMed, EMBASE, and Cochrane databases from November 1969 to November 2011 were queried for articles published in English, using the search terms neostigmine, acute colonic pseudo-obstruction, postoperative, surgery, and Ogilvie syndrome. STUDY SELECTION AND DATA EXTRACTION: All relevant original studies, meta-analyses, systematic reviews, guidelines, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search. DATA SYNTHESIS: Neostigmine may provide an effective treatment option for postoperative acute colonic pseudo-obstruction (ACPO) after conservative treatment measures have failed. One randomized controlled trial, 8 prospective and 3 retrospective observational studies, and 9 case reports evaluated neostigmine for ACPO. Included studies were limited by small sample sizes and heterogeneous populations not focused on postoperative patients, use of adjuvant agents, and lack of a consistent neostigmine regimen. CONCLUSIONS: Neostigmine may be a safe and effective treatment option for postoperative ACPO; however, current data do not support its use as a first-line intervention. Prospective and retrospective studies have demonstrated improvement in clinical symptoms, reduction in time to resolution, and reduction of recurrence for patients who failed conservative management. Prospective clinical trial data that evaluate early neostigmine versus conservative management are critically needed to determine neostigmine's role as a first-line therapy for ACPO.

Impact of Early Postoperative Hydrocortisone Administration in Cardiac Surgical Patients After Cardiopulmonary Bypass.

BACKGROUND: The usefulness of glucocorticoids after cardiac surgery with cardiopulmonary bypass has been a matter of debate for many years. Exposure to cardiopulmonary bypass evokes the systemic inflammatory response syndrome in patients undergoing cardiac surgery. Intravenous glucocorticoids have been used to reduce proinflammatory cytokine release, slow leukocyte migration, and decrease capillary leak associated with cardiopulmonary bypass. OBJECTIVE: To assess the impact of early postoperative hydrocortisone administration on duration of vasoactive medication administration and the incidence of postoperative atrial fibrillation in cardiac surgical patients after cardiopulmonary bypass. METHODS: A retrospective cohort study (between July 1, 2004, and June 30, 2008) was conducted at a large, university-affiliated, tertiary-care medical center. One-hundred forty-seven patients who underwent cardiac surgery with cardiopulmonary bypass, 72 of whom received at least 1 dose of hydrocortisone (treatment), and 75 similar patients who did not receive hydrocortisone (control), were randomly selected. RESULTS: Cardiopulmonary bypass and aortic cross-clamp times were similar between treatment and control groups (128 vs 124 minutes, p = 0.56; 103 vs 98 minutes, p = 0.39). Patients who received hydrocortisone had a significantly shorter time to discontinuation of all vasoactive medications (79.6 vs 21.1 hours, p < 0.001), and less postoperative atrial fibrillation (OR 0.28, 95% CI 0.14 to 0.56, p < 0.001). Patients in the treatment group experienced significantly more hyperglycemia (89 vs 71%, p = 0.006); however, major and minor bleeding or infection rates did not differ significantly between groups. CONCLUSIONS: Patients treated with hydrocortisone after cardiac surgery with cardiopulmonary bypass experienced a significantly shorter time to discontinuation of all vasoactive medications and less postoperative atrial fibrillation than patients not treated with hydrocortisone. These benefits came at the expense of significantly more hyperglycemia.

Tonapofylline: a selective adenosine-1 receptor antagonist for the treatment of heart failure.

IMPORTANCE OF THE FIELD: The heart failure and cardiorenal syndromes are major public health hazards, affecting one in five persons during their lifetime. Alternatives to traditional loop-diuretics, including vasopressin and adenosine A(1) receptor antagonists are now in development. AREAS COVERED IN THIS REVIEW: The pathophysiologic rationale for the use of tonapofylline, an intravenous and oral adenosine A(1) receptor antagonist, in patients with heart failure and/or the cardiorenal syndrome are reviewed. A comprehensive review of published literature describing its medicinal chemistry, pharmacokinetics, efficacy, safety and tolerability are provided. We searched the Medline/PubMed and Embase databases for the terms 'BG9928', 'tonapofylline', 'Adentri', 'adenosine', 'heart failure', 'renal failure' and 'cardiorenal syndrome' from 1 January 1992 to the present. References from pertinent manuscripts were also reviewed for additional relevant content. WHAT THE READER WILL GAIN: The reader will better appreciate the potential role of tonapofylline in patients with heart failure and/or the cardiorenal syndrome. Additionally, the reader will gain an understanding of the current state of drug development and the rationale for the need for continued research. TAKE HOME MESSAGE: Tonapofylline promotes natriuresis and diuresis, and may preserve glomerular filtration rate in patients with heart failure. Additionally, pilot data indicate that tonapofylline may be renoprotective in the setting of concomitant treatment with a loop-diuretic. Adverse effects were generally mild.

Induction immunosuppression for orthotopic heart transplantation: a review.

OBJECTIVES: To describe the appropriateness and safety of induction immunosuppression for patients at risk for fatal rejection, and to describe the safety and effectiveness profiles of the induction regimens available in the United States. DATA SOURCES: MEDLINE/PubMed database, EMBASE database, Google Scholar; references from pertinent articles were also reviewed to identify additional data. STUDY SELECTION: A systematic literature review from January 1, 1980, through June 30, 2008, was performed. Included articles ranged from case series to prospective randomized controlled double-blind placebo-controlled trials that detailed the following topics with respect to induction immunosuppression: risk of fatal rejection, renal sparing, malignancy, OKT3, rabbit or equine antithymocyte globulin, daclizumab, basiliximab, and alemtuzumab. RESULTS: Patients at highest risk for fatal rejection experienced a survival benefit from induction immunosuppression, whereas all other patients experienced no benefit or harm. Most of the early data detail positive experiences with polyclonal antibody regimens. Several newer trials compare the use of polyclonal strategies with the use of anti-CD25 targeted monoclonal antibodies. Few researchers have assessed the usefulness of an anti-CD52 approach. Overall, induction therapy remains a poorly studied and widely variable practice among the major US heart transplant centers. CONCLUSION: At present, the unrestricted use of induction for all patients does not seem prudent. Induction should be individualized for each patient on the basis of a well-designed protocol, careful analysis of the transplant center's demographics, and the effectiveness and safety profiles of the regimens used.