Recurrent portopulmonary hypertension after liver transplantation: management with epoprostenol and resolution after retransplantation.

We report a case of portopulmonary hypertension in which the pulmonary hypertension resolved after initial orthotopic liver transplantation. Portopulmonary hypertension recurred when the transplanted liver failed and again resolved after a second liver transplantation. Intravenous epoprostenol was administered perioperatively to control the pulmonary hypertension in both instances.

Filgrastim in patients with pneumonia and severe sepsis or septic shock.

STUDY OBJECTIVES: Evaluate the safety of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) administration, combined with standard therapy, in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: ICU, multicenter. PATIENTS: Eighteen patients with pneumonia and hypotension, or in the absence of shock, two or more end-organ dysfunctions, were enrolled and treated. Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim (n = 12) and placebo (n = 6) groups were 25.0 and 49.5 years and 31.5 and 56.5 years, respectively. INTERVENTION: Filgrastim (300 microg) or placebo was administered IV daily for up to 5 days. MEASUREMENTS AND RESULTS: Study end points included safety; biological response, including endogenous cytokine levels, endotoxin levels, and neutrophil counts; and mortality. Cytokine and endotoxin levels were highly variable in both groups. By day 29, 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died. There were no differences in types and occurrences of adverse events, including ARDS, or in outcome between the two groups. Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients. CONCLUSION: Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock. Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted.

Changing pattern of organ dysfunction in early human sepsis is related to mortality.

OBJECTIVE: We examined the pattern of organ system dysfunction, the evolution of this pattern over time, and the relationship of these features to mortality in patients who had sepsis syndrome. DESIGN: Prospective, multicenter, observational study. SETTING: Intensive care units in tertiary referral teaching hospitals. PATIENTS: A total of 287 patients who had sepsis syndrome were prospectively identified in intensive care units. MATERIALS AND MEASUREMENTS: Cardiovascular, pulmonary, neurologic, coagulation, renal, and hepatic dysfunction were assessed at onset and on day 3 of sepsis syndrome. Organ dysfunction was classified as normal, mild, moderate, severe, and extreme dysfunction. We calculated the occurrence rate and associated 30-day mortality rate of organ dysfunction at the onset of sepsis syndrome. We then measured the change in organ dysfunction from onset to day 3 of sepsis syndrome and determined, for individual organ systems, the associated 30-day mortality rate. RESULTS: At the onset of sepsis syndrome, clinically significant pulmonary dysfunction was the most common organ failure, but was not related to 30-day mortality. Clinically significant cardiovascular, neurologic, coagulation, renal, and hepatic dysfunction were less common at the onset of sepsis syndrome but were significantly associated with the 30-day mortality rate. Worsening neurologic, coagulation, and renal dysfunction from onset to day 3 of sepsis syndrome were associated with significantly higher 30-day mortality than with improvement or no change in organ dysfunction. CONCLUSIONS: Increased mortality rate in sepsis syndrome is associated with a pattern characterized by failure of nonpulmonary organ systems and, in particular, worsening neurologic, coagulation, and renal dysfunction over the first 3 days. Although initial pulmonary dysfunction is common in patients with sepsis syndrome, it is not associated with an increased mortality rate.

Prior healthcare utilization as a predictor of survival for medical intensive care unit patients.

OBJECTIVE: To determine whether measures of inpatient care utilization from the year preceding admission to a medical intensive care unit (MICU) improve physiology-based predictions of hospital and 1-yr survival. DESIGN: Inception cohort study with a validation cohort. SETTING: The MICU in university-affiliated Department of Veterans Affairs Medical Center. PATIENTS: A total of 1,200 consecutive patients admitted to the MICU. MEASUREMENTS AND MAIN RESULTS: Increased use of inpatient health care before MICU admission was associated with increased mortality. However, inpatient utilization data failed to improve physiology-based logistic models for hospital and 1-yr survival (p > .15 for improvement in the area under the receiver operating characteristic curve for both end points in the validation cohort), whereas physiologic data improved models derived from measures of inpatient care (p < .001 for both end points). Empirically derived inpatient care models used only information from the few days preceding MICU admission, despite the availability of a full year of data. CONCLUSIONS: Chronic illness, as gauged by a need for frequent inpatient care in the year before MICU admission, is not independently predictive of poor short- or long-term survival. Clinicians should not attempt to predict survival of prospective MICU patients by the extent of previous inpatient care.

Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group.

OBJECTIVES: The objective was to compare the clinical and physiologic characteristics of febrile septic patients with hypothermic septic patients; and to examine plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha and interleukin 6 (IL-6) and the lipid mediators thromboxane B2 (TxB2) and prostacyclin in hypothermic septic patients in comparison with febrile patients. Most importantly, we wanted to report the effect of ibuprofen treatment on vital signs, organ failure, and mortality in hypothermic sepsis. SETTING: The study was performed in the intensive care units (ICUs) of seven clinical centers in the United States and Canada. PATIENTS: Four hundred fifty-five patients admitted to the ICU who met defined criteria for severe sepsis and were suspected of having a serious infection. INTERVENTION: Ibuprofen at a dose of 10 mg/kg (maximum 800 mg) was administered intravenously over 30 to 60 mins every 6 hrs for eight doses vs. placebo (glycine buffer vehicle). MEASUREMENTS AND MAIN RESULTS: Forty-four (10%) septic patients met criteria for hypothermia and 409 were febrile. The mortality rate was significantly higher in hypothermic patients, 70% vs. 35% for febrile patients. At study entry, urinary metabolites of TxB2, prostacyclin, and serum levels of TNF-alpha and IL-6 were significantly elevated in hypothermic patients compared with febrile patients. In hypothermic patients treated with ibuprofen, there was a trend toward an increased number of days free of major organ system failures and a significant reduction in the 30-day mortality rate from 90% (18/20 placebo-treated patients) to 54% (13/24 ibuprofen-treated patients). CONCLUSIONS: Hypothermic sepsis has an incidence of approximately 10% and an untreated mortality twice that of severe sepsis presenting with fever. When compared with febrile patients, the hypothermic group has an amplified response with respect to cytokines TNF-alpha and IL-6 and lipid mediators TxB2 and prostacyclin. Treatment with ibuprofen may decrease mortality in this select group of septic patients.

Psychological and cognitive outcomes of a randomized trial of exercise among patients with chronic obstructive pulmonary disease.

Exercise rehabilitation is recommended increasingly for patients with chronic obstructive pulmonary disease (COPD). This study examined the effect of exercise and education on 79 older adults (M age = 66.6 +/- 6.5 years; 53% female) with COPD, randomly assigned to 10 weeks of (a) exercise, education, and stress management (EXESM; n = 29); (b) education and stress management (ESM; n = 25); or (c) waiting list (WL; n = 25). EXESM included 37 sessions of exercise, 16 educational lectures, and 10 weekly stress management classes. ESM included only the 16 lectures and 10 stress management classes. Before and after the intervention, assessments were conducted of physiological functioning (pulmonary function, exercise endurance), psychological well-being (depression, anxiety, quality of life), and cognitive functioning (attention, motor speed, mental efficiency, verbal processing). Repeated measures multivariate analysis of variance indicated that EXESM participants experienced changes not observed among ESM and WL participants, including improved endurance, reduced anxiety, and improved cognitive performance (verbal fluency).

The Center for Epidemiological Studies-Depression (CES-D) Scale: assessment of depression in the medically ill elderly.

This study examines the use of the Center for Epidemiological Studies-Depression Scale (CES-D) in a sample of elderly, medically ill inpatients. Seventy-six individuals completed the CES-D and a psychiatric interview, from which DSM-III-R diagnoses of depression were obtained. Analyses of sensitivity and specificity indicated that use of an alternative scoring method which more closely approximates current diagnostic criteria for depression may improve the predictive power of the test. Employment of stringent cut-scores was not supported, as sensitivity was compromised. Item analyses demonstrated that seven of the CES-D items failed to discriminate major, minor and nondepressed patients, and that several of these items tapped somatic symptoms. These findings suggest that the validity of the CES-D may be compromised when used with elderly medical patients. and modifications for its use are recommended.

Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group.

OBJECTIVE: To determine the magnitude and duration of the effects of sepsis on survival. DESIGN: Cohort study. SETTING: The 10 Department of Veterans Affairs Medical Centers of the Systemic Sepsis Cooperative Studies Group, which from 1983 to 1986 conducted the Department of Veterans Affairs Cooperative Study of Corticosteroids in Systemic Sepsis. PATIENTS: The septic population consisted of 1505 patients with evaluable data from the screening log of the Cooperative Study of Corticosteroids in Systemic Sepsis. All 91830 nonpsychiatric, noninfected patients discharged from the participating medical centers between October 1, 1984, and September 30, 1985, were included in the control population. MAIN OUTCOME MEASURE: Death through 8 years after the index hospitalization. RESULTS: On the basis of a proportional hazards model constructed from the demographic and illness characteristics of the control population, the septic population was at significant risk of dying of nonseptic causes (26% predicted 1-year mortality). In the septic population, the daily risk of dying exceeded predictions from this model for 5 years, and the hazard rate rose with increasing severity of the septic episode throughout the first year (P<.05). Among 30-day survivors, sepsis reduced the remaining mean life span from a predicted 8.03 years to 4.08 years. CONCLUSIONS: Sepsis not only causes deaths acutely, but also increases the risk of death for up to 5 years after the septic episode even after comorbidities are accounted for. The risk of late death during the first year is associated with the severity of the septic episode.

The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group.

BACKGROUND: In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. METHODS: From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. RESULTS: In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. With ibuprofen therapy there was no increased incidence of renal dysfunction, gastrointestinal bleeding, or other adverse events. However, treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days (mortality, 37 percent with ibuprofen vs 40 percent with placebo). CONCLUSIONS: In patients with sepsis, treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever, tachycardia, oxygen consumption, and lactic acidosis, but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival.

Immunoprophylaxis against klebsiella and pseudomonas aeruginosa infections. The Federal Hyperimmune Immunoglobulin Trial Study Group.

To determine if passive immunization could decrease the incidence or severity of Klebsiella and Pseudomonas aeruginosa infections, patients admitted to intensive care units of 16 Department of Veterans Affairs and Department of Defense hospitals were randomized to receive either 100 mg/kg intravenous hyperimmune globulin (IVIG), derived from donors immunized with a 24-valent Klebsiella capsular polysaccharide plus an 8-valent P. aeruginosa O-polysaccharide-toxin A conjugate vaccine, or an albumin placebo. The overall incidence and severity of vaccine-specific Klebsiella plus Pseudomonas infections were not significantly different between the groups receiving albumin and IVIG. There was some evidence that IVIG may decrease the incidence (2.7% albumin vs. 1.2% IVIG) and severity (1.0% vs. 0.3%) of vaccine-specific Klebsiella infections, but these reductions were not statistically significant. The trial was stopped because it was statistically unlikely that IVIG would be protective against Pseudomonas infections at the dosage being used. Patients receiving IVIG had more adverse reactions (14.4% vs. 9.2%).

Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group.

BACKGROUND: A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human tumor necrosis factor (TNF) receptor and the Fc portion of IgG1 (TNFR:Fc) binds and neutralizes TNF-alpha and prevents death in animal models of bacteremia and endotoxemia. METHODS: To evaluate the safety and efficacy of TNFR:Fc in the treatment of septic shock, we conducted a randomized, double-blind, placebo-controlled, multicenter trial. A total of 141 patients were randomly assigned to receive either placebo or a single intravenous infusion of one of three doses of TNFR:Fc (0.15, 0.45, or 1.5 mg per kilogram of body weight). The primary end point was mortality from all causes at 28 days. RESULTS: There were 10 deaths among the 33 patients in the placebo group (30 percent mortality), 9 deaths among the 30 patients receiving the low dose of TNFR:Fc (30 percent mortality), 14 deaths among the 29 receiving the middle dose (48 percent mortality), and 26 deaths among the 49 receiving the high dose (53 percent mortality) (P = 0.02 for the dose-response relation). Baseline differences in the severity of illness did not account for the increased mortality in the groups receiving the higher doses of TNFR:Fc. CONCLUSIONS: In patients with septic shock, treatment with the TNFR:Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality.

Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Society of Critical Care Medicine.

OBJECTIVE: The development of practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit (ICU) setting for the purpose of guiding clinical practice. PARTICIPANTS: A task force of more than 40 experts in disciplines related to the use of analgesic and sedative agents in the ICU was convened from the membership of the American College of Critical Care Medicine (ACCM) and the Society of Critical Care Medicine (SCCM). EVIDENCE: The task force members provided the personal experience and determined the published literature (MEDLINE articles, textbooks, pharmacopeias, etc.) from which consensus would be sought. Published literature was reviewed and classified into one of four predetermined categories, according to study design and scientific value. CONSENSUS PROCESS: The task force met several times as a whole, and numerous times in smaller groups by teleconference, over a 1-yr period to identify the pertinent literature and arrive at consensus recommendations for the whole task force to discuss. Consideration was given to the relationship between the weight of scientific information and the experts' viewpoints. Over the next year, draft documents were composed by a task force steering committee and debated by the task force members until consensus was reached by nominal group process. The task force draft was then reviewed, assessed, and edited by the Board of Regents of the ACCM. After steering committee approval, the draft document was reviewed and approved by the SCCM Council. DATA SYNTHESIS: To facilitate rapid communication of the six recommendations contained within the complete and unabridged practice parameter document, an executive summary was prepared for publication by the ACCM Board of Regents, and this executive summary was approved by the task force steering committee and the SCCM Executive Council. CONCLUSIONS: A consensus of experts provided six recommendations with supporting data for intravenous analgesia and sedation in the ICU setting: a) morphine sulfate is the preferred analgesic agent for critically ill patients; b) fentanyl is the preferred analgesic agent for critically ill patients with hemodynamic instability, for patients manifesting symptoms of histamine release with morphine, or morphine allergy; c) hydromorphone can serve as an acceptable alternative to morphine; d) midazolam or propofol are the preferred agents only for the short-term (< 24 hrs) treatment of anxiety in the critically ill adult; e) lorazepam is the preferred agent for the prolonged treatment of anxiety in the critically ill adult; f) haloperidol is the preferred agent for the treatment of delirium in the critically ill adult. This executive summary selectively presents supporting information and is not intended as a substitute for the complete document.

Practice parameters for sustained neuromuscular blockade in the adult critically ill patient: an executive summary. Society of Critical Care Medicine.

OBJECTIVE: The development of practice parameters for achieving sustained neuromuscular blockade in the adult critically ill patient for the purpose of guiding clinical practice. PARTICIPANTS: A task force of more than 40 experts in disciplines related to the use of neuromuscular blocking agents in the intensive care unit was convened from the membership of the American College of Critical Care Medicine (ACCM) and the Society of Critical Care Medicine (SCCM). EVIDENCE: The task force members provided the personal experience and determined the published literature (MEDLINE articles, textbooks, pharmacopeias, etc.) from which consensus would be sought. Published literature was reviewed and classified into one of four predetermined categories, according to study design and scientific value. CONSENSUS PROCESS: The task force met several times as a whole, and numerous times in smaller groups by teleconference, over a 1-yr period to identify the pertinent literature and arrive at consensus recommendations for the whole task force to discuss. Consideration was given to the relationship between the weight of scientific information and the experts' viewpoints. Over the next year, draft documents were composed by a task force steering committee and debated by the task force members until consensus was reached by nominal group process. The task force draft was then reviewed, assessed, and edited by the Board of Regents of the ACCM. After steering committee approval, the draft document was reviewed and approved by the SCCM Council. DATA SYNTHESIS: To facilitate rapid communication of the three recommendations contained within the complete and unabridged practice parameter document, an executive summary was prepared for publication by the ACCM Board of Regents, and this executive summary was approved by the task force steering committee and the SCCM Executive Council. CONCLUSIONS: A consensus of experts provided three recommendations with supporting data for achieving sustained neuromuscular blockade in critically ill patients: a) pancuronium is the preferred neuromuscular blocking agent for most critically ill patients; b) vecuronium is the preferred neuromuscular blocking agent for those patients with cardiac disease or hemodynamic instability in whom tachycardia may be deleterious; c) patients receiving neuromuscular blocking agents should be appropriately assessed for the degree of blockade that is being sustained. This executive summary selectively presents supporting information and is not intended as a substitute for the complete document.

Relationships among age, exercise, health, and cognitive function in a British sample.

This study was designed to evaluate the association of age, self-rated health, and walking activity with four measures of cognitive functioning in 6,979 men and women (age range: 18-94 years) randomly selected from British electoral registers. Assessments included a face-to-face interview regarding health and health beliefs as well as cognitive testing (including simple reaction time [SRT] and choice reaction time [CRT]. Hierarchical regression analyses indicated that faster reaction time (RT) speed was associated with both younger age and better self-rated health. There were also significant interactions of Age by Self-Rated Health and of Health Rating by Walking Activity for CRT, as well as an interaction of Age by Walking Activity for both SRT and CRT. Exercise and health may have an interactive effect on RT speed, and both exercise and health may modify age-related changes in RT.

A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group.

OBJECTIVE: To evaluate the safety and efficacy of E5, a murine, monoclonal antibody directed against endotoxin, in the treatment of patients with Gram-negative sepsis. DESIGN: A multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Fifty-three hospitals across the United States, including university medical centers, Veterans Affairs Medical Centers, and community hospitals. PATIENTS: 847 patients were randomized into this study. Enrolled patients met criteria for three conditions: a) known or suspected Gram-negative infection; b) clinical evidence of sepsis; and c) signs of end-organ dysfunction. Patients with refractory shock were excluded from the study. INTERVENTIONS: Two doses of E5 (2 mg/kg/day by intravenous infusion 24 hrs apart), or placebo that was identical in appearance were administered. In addition, all patients received standard supportive therapy and broad-spectrum antibiotics. MEASUREMENTS AND MAIN RESULTS: The primary end point was mortality over 30 days. Secondary outcome measures included the resolution and prevention of organ failure in the same two populations. Additionally, the safety of E5 was evaluated. There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo (n = 530; p = .21). In addition, E5 did not improve survival for patients with Gram-negative sepsis and organ failure (n = 139; p = .3). However, a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received E5, compared with those patients who received placebo (n = 139; 48% E5 vs. 25% placebo; p = .005). This result extended to all patients who entered the study with one or more major organ failures, regardless of the etiology of the infection (n = 225; 41% E5 vs. 27% placebo; p = .024). E5 also provided protection against the development of some organ failures, but significant prevention was only observed for adult respiratory distress syndrome (p = .007) and central nervous system dysfunction (p = .050). Hypersensitivity reactions attributable to E5 occurred in 2.6% of patients. An asymptomatic antibody response occurred in 44% of the E5-treated patients and in 12% of the patients who received placebo. CONCLUSIONS: In this study, E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure. However, E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis. This benefit extended to those patients with suspected Gram-negative etiology. This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results. In addition, E5 resulted in the prevention of adult respiratory distress syndrome and central nervous system organ failure. However, more studies are needed to determine if this result can be extended to organ failure in general. E5 is safe as a treatment for patients with Gram-negative sepsis.

Comparative effectiveness of social problem-solving therapy and reminiscence therapy as treatments for depression in older adults.

Compared the effects of 2 psychotherapies based on divergent conceptualizations of depression in later life. Seventy-five older adults diagnosed with major depressive disorder were assigned randomly to problem-solving therapy (PST), reminiscence therapy (RT), or a waiting-list control (WLC) condition. Participants in PST and RT were provided with 12 weekly sessions of group treatment. Dependent measures, taken at baseline, posttreatment, and 3-month follow-up, included self-report and observer-based assessments of depressive symptomatology. At posttreatment, both the PST and the RT conditions produced significant reductions in depressive symptoms, compared with the WLC group, and PST participants experienced significantly less depression than RT subjects. Moreover, a significantly greater proportion of participants in PST versus RT demonstrated sufficient positive change to warrant classification of their depression as improved or in remission at the posttreatment and follow-up evaluations.