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Lung transplantation is a therapeutic modality frequently utilized in end-stage lung disease. Unfortunately, lung transplant recipients have poor clinical outcomes, often due to the development of chronic rejection in the transplanted allograft. This process is characterized by neutrophil influx and extracellular matrix remodeling leading to luminal obstruction and airway inflammation. The molecular mechanisms underlying chronic rejection are poorly understood and disease-specific biomarkers are lacking. We report that in addition to increased levels of interleukin-8 (IL-8), the level of neutrophil chemoattractant proline-glycine-proline (PGP) is elevated in chronic rejection patient bronchoalveolar lavage (BAL) fluid and correlates with loss of lung function. The enzymes responsible for generating PGP, matrix metalloproteases-8 and -9 (MMP-8, -9) and prolyl endopeptidase (PE), are also elevated in chronic rejection samples. Together, IL-8 and PGP account for most of the neutrophil chemoattractant capacity seen in chronic rejection BAL fluid. Using specific neutralizing antibodies to both IL-8 and PGP, we demonstrate that PGP is the major neutrophil chemoattractant found in BAL fluid from individuals at the time of chronic rejection. These findings highlight the influence of a matrix-derived neutrophil chemoattractant in post-transplantation organ rejection and provide opportunities for the development of unique diagnostics and therapeutics to potentially improve disease outcomes.

Various definitions of acute kidney injury (AKI) exist, making comparisons among studies difficult. Despite this, significant changes have occurred in the epidemiology of AKI during the last decade. Recent studies, including PICARD and BEST, have examined the epidemiology of ICU-related AKI in the USA and worldwide, respectively, and found that AKI remains a major cause of morbidity and mortality. The incidence of AKI has increased, most likely due to a trend toward older, more severely and chronically ill patients admitted to the hospital. Sepsis and multi-organ system failure continue to be strongly associated with AKI, as well as pre-morbid chronic kidney disease. The proportion of patients with AKI requiring dialysis is high. The mortality of ICU-related AKI, although still very elevated, may be decreasing. Understanding these changes, in the context of standardized definitions, will be essential for the design of successful interventional studies.

Background & Aims: Hepatopulmonary syndrome (HPS) affects 10%–30% of patients with cirrhosis and portal hypertension, but the impact on functional status, quality of life, and survival is poorly defined. We assessed the impact of HPS in patients evaluated for liver transplantation. Methods: We performed a prospective multicenter cohort study of patients being evaluated for liver transplantation in 7 academic centers in the United States. Patients with HPS (defined as an increased alveolar-arterial oxygen gradient with intrapulmonary vasodilation) were compared with those without HPS in terms of demographics and clinical variables. New York Heart Association functional class, quality of life, and survival were assessed. Results: Seventy-two patients with HPS and 146 patients without HPS were compared. There were no differences in age, sex, or etiology or severity of liver disease between the groups; however, patients with HPS were less likely to have a history of smoking ( P = .03). Patients with HPS had worse New York Heart Association functional class ( P = .005) and had significantly worse quality of life in certain domains compared with patients without HPS. In addition, patients with HPS also had a significantly increased risk of death compared with patients without HPS despite adjustment for age, sex, race/ethnicity, Model for End-Stage Liver Disease score, and liver transplantation (adjusted hazard ratio=2.41; 95% confidence interval, 1.31–4.41; P = .005). Conclusions: HPS was associated with a significant increase in risk of death as well as worse functional status and quality of life in patients evaluated for liver transplantation.

The effect of dosage of continuous venovenous hemodiafiltration (CVVHDF) on survival in patients with acute renal failure (ARF) is unknown. In this study, 200 critically ill patients with ARF were randomly assigned to receive CVVHDF with prefilter replacement fluid at an effluent rate of either 35 ml/kg per h (high dosage) or 20 ml/kg per h (standard dosage). The primary study outcome, survival to the earlier of either intensive care unit discharge or 30 d, was 49% in the high-dosage arm and 56% in the standard-dosage arm (odds ratio 0.75; 95% confidence interval 0.43 to 1.32; P = 0.32). Among hospital survivors, 69% of those in the high-dosage arm recovered renal function compared with 80% of those in the standard-dosage arm (P = 0.29); therefore, a difference in patient survival or renal recovery was not detected between patients receiving high-dosage or standard-dosage CVVHDF.

Primary graft dysfunction (PGD), a form of acute lung injury occurring within 72 h following lung transplantation, is characterized by pulmonary edema and diffuse alveolar damage. We hypothesized that higher concentrations of intercellular adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF) would be associated with the occurrence of PGD. A total of 128 lung transplant recipients among 7 lung transplant centers were enrolled in a multicenter, prospective, cohort study. Blood specimens were collected preoperatively and at 6, 24, 48 and 72 h following lung transplantation. The primary outcome was Grade 3 PGD at 72 h after transplant. Logistic regression and generalized estimating equations (GEE) were used to analyze plasma ICAM-1 and vWF. At each postoperative timepoint, mean plasma ICAM-1 concentrations were higher for patients with PGD versus no PGD. The GEE contrast estimate for the association of plasma ICAM-1 with PGD was 107.5 ng/mL (95% CI 38.7, 176.3), p = 0.002. In the multivariate analyses, this finding was independent of all clinical variables except pulmonary artery pressures prior to transplant. There was no association between plasma vWF levels and PGD. We conclude that higher levels of plasma ICAM-1 are associated with PGD following lung transplantation.

Obstacles to the widespread use of continuous renal replacement therapy (CRRT) include the need for anticoagulation, customized solutions, and complex protocols that carry an attendant risk for error, raise cost, and increase pharmacy and nursing workload. However, high solute clearance using CRRT with an effluent rate of 35 ml/kg per h has also recently been associated with improved survival in critically ill patients with acute renal failure. No published CRRT protocols using dilute regional citrate anticoagulation have achieved adequate metabolic control, effective anticoagulation, and high solute clearance in a practical, user-friendly, and economical manner. The safety and the efficacy of continuous venovenous hemodiafiltration at effluent rates of 35 ml/kg per h in critically ill acute renal failure patients were evaluated prospectively using a standardized bicarbonate-based dialysate; a systemic calcium infusion; and two separate trisodium citrate replacement solutions, a 0.67% solution and a 0.5% solution. All patients achieved adequate metabolic control, the desired effluent rate of 35 ml/kg per h, and high solute clearance. Use of the 0.67% citrate replacement solution resulted in mild alkalosis, whereas the 0.5% solution maintained appropriate acid-base balance. There was no difference in dialyzer survival between the 0.67 and 0.5% citrate groups (80 versus 82%; P = 0.60, Kaplan-Meier analysis). Dilute regional citrate as part of a CRRT protocol with a standard 25-mmol/L bicarbonate dialysate provides adequate metabolic control, high diffusive and convective clearance, and excellent dialyzer patency in a practical and cost-effective manner.

Sustained low-efficiency dialysis (SLED) is an increasingly popular form of renal replacement therapy for patients with renal failure in the intensive care unit. Advantages of SLED are efficient clearance of small solutes, good hemodynamic tolerability, flexible treatment schedules, and reduced costs. Studies comparing outcomes of SLED with those of other dialysis modalities are being performed.

Sustained low-efficiency dialysis (SLED) is an increasingly popular form of renal replacement therapy for patients with renal failure in the intensive care unit. Advantages of SLED are efficient clearance of small solutes, good hemodynamic tolerability, flexible treatment schedules, and reduced costs. Studies comparing outcomes of SLED with those of other dialysis modalities are being performed.

Objective The prevalence and prognostic significance of nontraumatic hypotension measured in the emergency department (ED) have not been studied. We hypothesized that ED hypotension confers risk of in-hospital mortality. Design Prospective cohort study. Setting Large urban ED with 115,000 visits per year. Participants Nontrauma ED patients aged > 17 years admitted to the hospital were prospectively identified on a random sample of 24-h blocks during 2004 to 2005. "Exposures" had any systolic BP (SBP) Outcome measures Mortality rates were compared with confidence intervals (CIs), Kaplan-Meier survival curves, and multivariate logistic regression. Results A total of 4,790 patients were enrolled during the study period, with 887 patients (19%) in the exposure group. Exposures were more likely to die in the hospital compared with nonexposures (8% vs 3%; 95% CI for difference of 5%, 4 to 8%). Exposures were more likely to have sudden and unexpected death compared with nonexposures (2% vs 0.2%, 95% CI for difference of 1.8%, 1 to 3%). Kaplan-Meier estimates showed increased mortality in the exposure group at all time points (log-rank test, p Conclusion Nontraumatic hypotension was documented in 19% of a random sample of ED patients admitted to the hospital. Patients exposed to hypotension had a significantly increased risk of death during hospitalization.

Purpose Free hemoglobin (freeHgb) is a potent oxidant released from red cells in conditions such as sepsis, hemolysis, hemodialysis and cardiopulmonary bypass. We determined whether plasma freeHgb is elevated in lung transplant recipients and whether levels are associated with primary graft dysfunction (PGD). We also tested whether the potential oxidative injury associated with freeHgb is potentiated by high FiO2 at reperfusion. Methods and Materials Patients were lung recipients in the Lung Transplant Outcomes Group cohort and included 40 cases with Grade 3 PGD at 72h after transplant and 80 controls with no PGD, frequency matched for diagnosis (COPD, IPF) and procedure (single, bilateral). Plasma freeHgb was measured pre-op, and at 6 and 24h after reperfusion. PGD status was determined by ISHLT criteria. Results FreeHgb was detectable in 91% of pre-op, 97% of 6h and 85% of 24h samples. Pre-op [median 30 mg/dL (IQR 20-50 )] and 6h [30 (10-80)] levels were similar, but fell at 24h [20 (10-40), p=0.002]. Post-op freeHgb levels were similar between cases and controls although levels were higher in those who underwent cardiopulmonary bypass [80 (40–150) vs 20 (10–40), p Figure ). Conclusions High pre-op levels of plasma freeHgb associate with PGD, particularly when FiO2 is high at reperfusion. FreeHgb may be a mediator of oxidative injury during ischemia reperfusion and high levels of inspired O2 may potentiate this oxidative injury.

Objective. The purpose of this study was to validate a 3-stage asthma case-detection procedure for elementary school-aged children.Methods. The study was performed in 10 elementary schools in 4 inner-city school systems, with a total enrollment of 3539 children. Results of the case-detection procedure were compared with the diagnosis of an asthma specialist study physician, to determine the sensitivity and specificity of the case-detection procedure.Results. Ninety-eight percent of children returned the asthma symptoms questionnaires, and 79% of those children consented to additional testing. Results indicated that the 3-stage procedure had good validity, with sensitivity, specificity, and predictive value of 82%, 93%, and 93%, respectively. A 2-stage procedure using questionnaires and spirometry had similar validity, with sensitivity, specificity, and predictive value of 78%, 93%, and 93%, respectively. However, given the time and expense associated with the 2- or 3-stage procedure and the difficulty of obtaining physician follow-up evaluation of the case-detection diagnosis, schools may prefer to use a 2-item questionnaire that has a lower sensitivity (66%) but higher specificity (96%) and predictive value (95%).Conclusions. Case-detection programs are generally well received by school personnel and can identify children with unrecognized or undiagnosed disease, as well as those with a current diagnosis but poorly controlled disease. This study yields substantial information regarding the validity, yield, and specific types of children who might be identified with the use of such procedures. For the choice of the method of case detection used in a school, the strengths and weaknesses of each procedure, as well as the resources available for case detection, physician referral, and follow-up procedures, must be considered.

The traditional incision for bilateral sequential lung transplantation is the bilateral anterolateral transsternal thoracotomy with approximation of the sternal fragments with interrupted stainless steel wire loops; this technique may be associated with an unacceptable incidence of postoperative sternal disruption causing chronic pain and deformity. Approximation of the sternal ends was achieved with peristernal cables that passed behind the sternum two intercostal spaces above and below the sternal division, which were then passed through metal sleeves in front of the sternum, the cables tensioned, and the sleeves then crimped. Forty-seven patients underwent sternal closure with this method, and satisfactory bone union occurred in all patients. Six patients underwent removal of the peristernal cables: 1 for infection (with satisfactory bone union after the removal of the cables), 3 for cosmetic reasons, 1 during the performance of a median sternotomy for an aortic valve replacement, and 1 in a patient who requested removal before commencing participation in football. This technique of peristernal cable approximation of sternal ends has successfully eliminated the problem of sternal disruption associated with this incision and is a useful alternative for preventing this complication after bilateral lung transplantation.

Purpose Primary graft dysfunction (PGD) is a complex phenotype secondary to multiple factors, including effects from many genes. We hypothesized plasma levels of plasminogen activator inhibitor-1 (PAI-1) could facilitate the discovery of SNPs important in PGD pathogenesis. Methods and Materials We performed a nested case-control study within the multi-center Lung Transplant Outcomes Group cohort. Plasma PAI-1 levels were measured 24 hours post reperfusion. A SNP/protein association was tested in a linear model adjusted for recipient age, cardiopulmonary bypass, diagnosis, and population admixture using the 50K Illumina HumanCVD BeadChip v2. Significance cutoffs were set at p -4 for SNP/protein association and p Results Of 1028 enrollees, 374 were evaluated for SNP/protein association and 654 used for validation. 42 SNPs met significance cutoffs for association; however, of those only rs3168046 and rs3793965 had minor allele frequencies greater than 5% and met our pre-specified significance. Both SNP’s encode Toll interacting protein (TOLLIP) and were in tight LD (R 2 =0.97). After adjusting for PAI-1 protein levels with PGD as response, PAI-1 plasma levels were demonstrated to mediate the candidate SNP PGD association. Conclusions Using PAI-1 as a quantitative trait for PGD can identify genetic variations which are important in PGD susceptibility. PAI-1 levels are associated with certain TOLLIP genotypes and may improve individual risk assessment based on innate immune function in lung transplant patients. Further studies examining these relationships are indicated.

TAC BD then oral TAC, n 90,Aug 08-Jul 10; C) oral TAC BD, n 18 D) IV TAC BD 4hr bolus then oral TAC, n 62 (both Jul 10-Jul 11). SL TAC was specifically prepared by pharmacy to optimize buccal absorption. CSA/TAC trough levels at days 1-7, 14 and 28, acute rejection (AR ISHLT grade 2, day 90) and neurotoxicity/ nephrotoxicity events were analyzed. Target trough CSA/TAC levels were 250ng/ml & 8mcg/ml (HPLC) respectively. Results: Along with CSA/TAC all patients received immunosuppression as per institution protocol. Induction with ATG or Simulect was also similar per group (p-ns). There were no differences in recipient/donor demographics, ICU & total LOS between groups. Neurotoxicity nor significant nephrotoxicity were not apparent in any group. Despite extensive education, administration of SL TAC proved impractical with unacceptable trough level variability & poor efficacy.

or disease was assessed with multivariate regression. Results: 27 pts received BAS induction and 36 received no induction(NI). No significant difference was seen in baseline demographics between groups. AR occurred 11 times in 9 pts (33%) in the BAS group compared to 9 times in 8 pts (22%) in the NI group. Use of BAS was associated with a non-significant trend toward increased risk of AR development, HR 2.0 (95% CI .77-5.4, p 0.15). No significant difference in 1 year survival (BAS 96% vs NI 89%) was seen (p .97). In addition, no significant association was seen between the use of BAS and the development of CMV (p .53) or Aspergillus infection/ colonization/disease (p .58). Conclusions: Our single-center experience finds no evidence that BAS is effective in reducing the rate of acute rejection in the first year after lung transplantation.

donor lung before LTx and to determine if it predicts recipient outcome after LTx. Methods: From 05/1998 to 10/2001, we prospectively collected clinical data and lung biopsies (at the end of cold ischemia) from 89 donors. Expression levels of IL-8, IL-6, IL-10, TNF, IFN, IL-1 were measured by real-time quantitative RT-PCR (qRT-PCR). Results: In total, 12 patients (13.5%) died within 30 days after LTx, 5 (5.6%) from primary graft failure (PGF). No donor factor was significantly associated with 30-day mortality. Patients who died within 30 days had significantly higher IL-6 levels (p 0.0061). IL-8 and IL-1 demonstrated a similar tendency (p 0.19 and 0.20 respectively). Patients with poor outcomes also tended to have lower levels of IL-10 and IFN(p 0.19 and 0.051 respectively). Using ratios of high cytokines (IL-8, IL-6, TNF, IL-1 ) to low cytokines (IL-10, IFN) increased the correlation. A stepwise logistic regression model using ratios of IL-8/IL-10 and IL-6/IFNwas highly predictive for death from PGF (p 0.0001). Using this model, we defined high, intermediate and low risk groups. These groups had striking differences in both early and late survival (Wilcoxon test: p 0.0001, log-rank test: p 0.0001). Mortality at 90 days was 78 14, 21 8 and 4 3 % in the high, intermediate and low risk groups, respectively. Conclusions: qRT-PCR analysis of multiple cytokines shows significant promise to biologically evaluate the donor lung before LTx. Further refinements in this approach will lead to improved precision in donor lung assessment, improved donor utilization and improved outcomes after LTx.