Susan K. Pingleton

Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients.

ObjectivePhase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DesignMulticenter, double-blind, phase III, placebo-controlled, randomized study. SettingA total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PatientsA total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. InterventionAfter randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. Measurements and Main Results The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17–96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor &agr; concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. ConclusionLenercept had no significant effect on mortality in the study population.

Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome

Objective To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Design A prospective, randomized, double-blind, placebo-controlled, multicenter study. Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network. Patients A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group). Interventions Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing. Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure–free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo. Conclusions In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

Enteral alimentation and gastrointestinal bleeding in mechanically ventilated patients.

The incidence of upper gastrointestinal (GI) bleeding in mechanically ventilated ICU patients receiving enteral alimentation was reviewed and compared to bleeding occurring in ventilated patients receiving prophylactic antacids or cimetidine. Of 250 patients admitted to our ICU during a 1-yr time period, 43 ventilated patients were studied. Patients in each group were comparable with respect to age, respiratory diagnosis, number of GI hemorrhage risk factors, and number of ventilator, ICU, and hospital days. Twenty-one patients had evidence of GI bleeding. Fourteen of 20 patients receiving antacids and 7 of 9 patients receiving cimetidine had evidence of GI bleeding. No bleeding occurred in 14 patients receiving enteral alimentation. Complications of enteral alimentation were few and none required discontinuation of enteral alimentation. Our preliminary data suggest the role of enteral alimentation in critically ill patients may include not only protection against malnutrition but also protection against GI bleeding.

Aligning compensation with education: design and implementation of the Educational Value Unit (EVU) system in an academic internal medicine department.

The authors report the development of a new metric for distributing university funds to support faculty efforts in education in the department of internal medicine at the University of Kansas School of Medicine. In 2003, a committee defined the educational value unit (EVU), which describes and measures the specific types of educational work done by faculty members, such as core education, clinical teaching, and administration of educational programs. The specific work profile of each faculty member was delineated. A dollar value was calculated for each 0.1 EVU. The metric was prospectively applied and a faculty survey was performed to evaluate the faculty’s perception of the metric. Application of the metric resulted in a decrease in university support for 34 faculty and an increase in funding for 23 faculty. Total realignment of funding was US

Helium-oxygen mixtures during bronchoscopy.

1.6 million, or an absolute value of US

Nonhemorrhagic gastrointestinal complications in acute respiratory failure.

29,072 ± 38,320.00 in average shift of university salary support per faculty member. Survey results showed that understanding of the purpose of university funding was enhanced, and that faculty members perceived a more equitable alignment of teaching effort with funding. The EVU metric resulted in a dramatic realignment of university funding for educational efforts in the department of internal medicine. The metric was easily understood, quickly implemented, and perceived to be fair by the faculty. By aligning specific salary support with faculty’s educational responsibilities, a foundation was created for applying mission-based incentive programs.

Aligning Clinical Compensation With Clinical Productivity: Design and Implementation of the Financial Value Unit (FVU) System in an Academic Department of Internal Medicine

Fiberoptic bronchoscopy in mechanically ventilated patients has been limited to endotracheal tubes of 8.0--8.5 mm diameter. When performed through smaller tubes, pressures exceeding ventilator limits may occur, alveolar ventilation may become impaired, or progressive hyperinflation from airway obstruction during expiration may result. In this study, the efficacy of a 70% helium-30% oxygen ventilating gas mixture was compared to 30% oxygen in air in a laboratory mechanical lung analog and during 15 bronchoscopies in 7 intubated patients. One patient with a 7.5 mm tube was studied. With the helium-oxygen mixture, ventilator pressures were not exceeded, alveolar ventilation was uncompromised, and hyperinflation did not occur. Bronchoscopy may be safely performed through endotracheal tubes smaller than 8.0 mm using a helium-oxygen mixture.

Aspiration of enteral feeding in mechanically ventilated patients: how do we monitor?

While GI hemorrhage is a recognized complication of critical illness, nonhemorrhagic GI complications are less well described. We studied prospectively the incidence and predisposing factors of nonhemorrhagic GI complications in 124 acute respiratory failure (ARF) patients over a 13-month period. Diarrhea occurred in 51% (63/124), decreased bowel sounds in 50% (62/124), and abdominal distention in 46% (57/124). Patients with pneumonia as the etiology of respirator failure had the highest number of different complications (five per ICU stay). Ileus was found more frequently in patients with a past history of liver disease (p less than .03). Antacid administration was associated with a significant increase in diarrhea (p less than .01), as were the combined treatments of antacids and cimetidine (p less than .02). Patients with ARF have a high incidence of nonhemorrhagic GI complications. Diarrhea is the most common complication and occurs more frequently in patients who receive antacids.

Reduction of venous thromboembolism (VTE) in hospitalized patients: aligning continuing education with interprofessional team-based quality improvement in an academic medical center.

A new metric was developed and implemented at the University of Kansas School of Medicine Department of Internal Medicine, the financial value unit (FVU). This metric analyzes faculty clinical compensation compared with clinical work productivity as a transparent means to decrease the physician compensation variability and compensate faculty equitably for clinical work. The FVU is the ratio of individual faculty clinical compensation compared with their total work relative value units (wRVUs) generated divided by Medical Group Management Association (MGMA) salary to wRVUs of a similar MGMA physician. The closer the FVU ratio is to 1.0, the closer clinical compensation is to that of an MGMA physician with similar clinical productivity. Using FVU metrics to calculate a faculty salary gap compared with MGMA median salary and wRVU productivity, a divisional production payment was established annually. From FY 2006 to FY 2011, both total faculty numbers and overall clinical activity increased. With the implementation of the FVU, both clinical productivity and compensation increased while, at the same time, physician retention rates remained high. Variability in physician compensation decreased. Dramatic clinical growth was associated with the alignment of clinical work and clinical compensation in a transparent and equable process.