Keith M. Wille

Standard versus High-Dose CVVHDF for ICU-Related Acute Renal Failure

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.

Impact of Hepatopulmonary Syndrome on Quality of Life and Survival in Liver Transplant Candidates

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.

Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

RATIONALE The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD. OBJECTIVES To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study. METHODS We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) within the first 72 hours after transplantation. MEASUREMENTS AND MAIN RESULTS Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearmans rho = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02). CONCLUSIONS Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

A Practical Citrate Anticoagulation Continuous Venovenous Hemodiafiltration Protocol for Metabolic Control and High Solute Clearance

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.

Obesity and Primary Graft Dysfunction after Lung Transplantation: The Lung Transplant Outcomes Group Obesity Study

RATIONALE Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation. OBJECTIVES To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation. METHODS We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios. MEASUREMENTS AND MAIN RESULTS Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass. CONCLUSIONS Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.

Anticoagulation for continuous renal replacement therapy.

Continuous renal replacement therapy (CRRT) has emerged as the preferred dialysis modality for critically ill patients with acute kidney injury, particularly those with hemodynamic instability. Anticoagulation is necessary for effective delivery of CRRT, but this requirement can also present challenges, as many critically ill patients with sepsis and inflammation already have a higher risk of bleeding as well as clotting. Without anticoagulation, CRRT filter and circuit survival are diminished, and therapy becomes less helpful. Heparins are presently the most commonly used anticoagulants worldwide for CRRT. They are widely available and can be easily monitored, but disadvantages include risks of hemorrhage, heparin resistance, and heparin‐induced thrombocytopenia (HIT). Because of the potential side effects of heparin, alternative methods of anticoagulation have been investigated, including regional heparin/protamine, low molecular weight heparins, heparinoids, thrombin antagonists (hirudin and argatroban), regional citrate, and platelet inhibiting agents (prostacyclin and nafamostat). Each of these techniques has unique advantages and disadvantages, and anticoagulation for CRRT should be adapted to the patient’s characteristics and institution’s experience. Of the alternative methods, citrate anticoagulation is gaining wider acceptance with the development of simplified and safer protocols.

Construct validity of the definition of primary graft dysfunction after lung transplantation

BACKGROUND This study tested the discriminant validity of International Society for Heart and Lung Transplantation (ISHLT) primary graft dysfunction (PGD) grades with lung injury biomarker profiles and survival. METHODS The study samples consisted of a multicenter prospective cohort study for the biomarker analysis and a cohort study of 450 patients for the mortality analyses. PGD was defined according to ISHLT consensus at 24, 48, and 72 hours after transplantation. We compared the changes in plasma markers of acute lung injury between PGD grades using longitudinal data models. To test predictive validity, we compared differences in the 30-day mortality and long-term survival according to PGD grade. RESULTS PGD Grade 3 demonstrated greater differences between plasma intercellular adhesion molecule 1 (ICAM-1), protein C, and plasminogen activator inhibitor type 1 (PAI-1) levels than did PGD Grades 0 to 2 at 24, 48, and 72 hours after lung transplantation (p < 0.05 for each). Grade 3 had the highest 30-day (test for trend p < 0.001) and overall mortality (log rank p < 0.001), with PGD Grades 1 and 2 demonstrating intermediate risks of mortality. The ability to discriminate both 30-day and overall mortality improved as the time of grading moved away from the time of transplantation (test for trend p < 0.001). CONCLUSIONS The ISHLT grading system has good discriminant validity, based on plasma markers of lung injury and mortality. Grade 3 PGD was associated with the most severely altered plasma biomarker profile and the worst outcomes, regardless of the time point of grading. PGD grade at 48 and 72 hours discriminated mortality better than PGD grade at 24 hours.

Plasma Cytokines and Chemokines in Primary Graft Dysfunction Post-Lung Transplantation

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case–control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein‐1 (MCP‐1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)‐inducible protein (IP‐10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL‐13) (p = 0.05) and higher levels of IL‐2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)‐α, and IFN‐γ decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

Elevated Pulmonary Artery Pressure Is a Risk Factor for Primary Graft Dysfunction Following Lung Transplantation for Idiopathic Pulmonary Fibrosis

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF. METHODS We performed a multicenter prospective cohort study of 126 lung transplant procedures performed for IPF between March 2002 and August 2007. The primary outcome was grade 3 PGD at 72 h after lung transplant. The mPAP was measured as the initial reading following insertion of the right-sided heart catheter during lung transplant. Multivariable logistic regression was used to adjust for confounding variables. RESULTS The mPAP for patients with PGD was 38.5 ± 16.3 mm Hg vs 29.6 ± 11.5 mm Hg for patients without PGD (mean difference, 8.9 mm Hg [95% CI, 3.6-14.2]; P = .001). The increase in odds of PGD associated with each 10-mm Hg increase in mPAP was 1.64 (95% CI, 1.18-2.26; P = .003). In multivariable models, this relationship was independent of confounding by other clinical variables, although the use of cardiopulmonary bypass partially attenuated the relationship. CONCLUSIONS Higher mPAP in patients with IPF is associated with the development of PGD.

CT Scan-Measured Pulmonary Artery to Aorta Ratio and Echocardiography for Detecting Pulmonary Hypertension in Severe COPD

BACKGROUND COPD is associated with significant morbidity primarily driven by acute exacerbations. Relative pulmonary artery (PA) enlargement, defined as a PA to ascending aorta (A) diameter ratio greater than one (PA:A>1) identifies patients at increased risk for exacerbations. However, little is known about the correlation between PA:A, echocardiography, and invasive hemodynamics in COPD. METHODS A retrospective observational study of patients with severe COPD being evaluated for lung transplantation at a single center between 2007 and 2011 was conducted. Clinical characteristics, CT scans, echocardiograms, and right-sided heart catheterizations were reviewed. The PA diameter at the bifurcation and A diameter from the same CT image were measured. Linear and logistic regression were used to examine the relationships between PA:A ratio by CT scan and PA systolic pressure (PASP) by echocardiogram with invasive hemodynamics. Receiver operating characteristic analysis assessed the usefulness of the PA:A ratio and PASP in predicting resting pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP]>25 mm Hg). RESULTS Sixty patients with a mean predicted FEV1 of 27%±12% were evaluated. CT scan-measured PA:A correlated linearly with mPAP after adjustment for multiple covariates (r=0.30, P=.03), a finding not observed with PASP. In a multivariate logistic model, mPAP was independently associated with PA:A>1 (OR, 1.44; 95% CI, 1.02-2.04; P=.04). PA:A>1 was 73% sensitive and 84% specific for identifying patients with resting PH (area under the curve, 0.83; 95% CI, 0.72-0.93; P<.001), whereas PASP was not useful. CONCLUSIONS A PA:A ratio>1 on CT scan outperforms echocardiography for diagnosing resting PH in patients with severe COPD.