ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectiveTo determine the safety and efficacy of BAY times 1351, a murine monoclonal antibody to recombinant human tumor necrosis factor (TNF)-alpha, in patients with sepsis.DesignAn international, multicenter, prospective, placebo-controlled trial in patients with sepsis, stratified into shock/nonshock groups.SettingForty acute clinical care facilities in 14 countries.PatientsOf the 564 patients enrolled in the study, 553 patients received study drug or placebo.InterventionsPatients received 15 mg/kg or 3 mg/kg of BAY times 1351, or placebo, as a single intravenous infusion.Measurements and Main ResultsThe patients were well matched for severity of illness and for risk factors known to influence the outcome of sepsis. There was no difference in 28-day mortality rates between groups (placebo group 66 [39.5%] of 167; 3 mg/kg group 57 [31.5%] of 181; 15 mg/kg group 87 [42.4%] of 205). Approximately 9 months after this study had begun, an interim safety examination of NORASEPT, a North American Sepsis Trial using the same monoclonal antibody, indicated that there was no benefit to patients in the nonshock group and further enrollment of these nonshock septic patients into INTERSEPT was stopped. The analysis therefore focused on the 420 patients in shock. The primary efficacy variable was the 28-day, all-cause mortality rate: placebo group 57 (42.9%) of 133; 3-mg/kg group 51 (36.7%) of 139; and 15-mg/kg group 66 (44.6%) of 148 (not significant). Two secondary efficacy variables were identified prospectively: shock reversal and frequency of organ failures. Life-table analysis showed that in patients who survived 28 days, there was a more rapid reversal of shock in both treatment groups compared with placebo (15-mg/kg group vs. placebo group log-rank statistic p = .007, 3-mg/kg group vs. placebo group p = .01). Similarly, in patients surviving 28 days, there was a significant delay in the time to the onset of first organ failure (log rank 15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .07), and more patients in the placebo group developed at least one organ failure: 15-mg/kg group 33 (40.2%) of 82; 3-mg/kg group 39 (44.3%) of 88; and placebo group 45 (59.2%) of 76 (15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .06). No significant adverse events were associated with the monoclonal antibody treatment.ConclusionsINTERSEPT provides additional clinical data implicating TNF-alpha as an integral mediator of septic shock. The study suggested a possible role for anti-TNF antibody as adjunctive therapy, but this possibility requires confirmation by another clinical trial.(Crit Care Med 1996; 24:1431-1440)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectiveSeveral large clinical trials have recently evaluated a variety of potential therapeutic interventions for sepsis and have yielded negative results based on analyses of intention-to-treat cohorts. The present study was undertaken to evaluate the importance of a Clinical Evaluation Committee.DesignProspective, double-blind evaluation of a prospective, controlled, double-blind, randomized, multinational trial.SettingForty medical centers.PatientsFive hundred fifty-three infused patients with severe sepsis and septic shock.MethodsAs part of an international trial (INTERSEPT) of anti-tumor necrosis factor therapy, a Scientific Extramural Review Commitee prospectively defined and excluded patients with confounding events that objectively interfered with the potential of any intervention for sepsis to exercise its therapeutic effect. These confounding events included inappropriate antimicrobial therapy, inadequate medical-surgical management, underlying disorders, and forgoing life-sustaining therapies before management had failed. Patients who met all inclusion and exclusion criteria and who had no confounding events were defined as the Scientific Extramural Review Committee group.Measurements and Main ResultsFive hundred fifty-three patients were enrolled in INTERSEPT. Seventy-seven patients did not meet inclusion and exclusion criteria. Sixty patients had confounding events, including inappropriate antimicrobial therapy (n = 28), inadequate medical-surgical management (n = 16), underlying disorders (n = 17), and forgoing life-sustaining therapies (n = 7). Four hundred sixteen patients were in the Scientific Extramural Review Committee group and their mortality rates were different from the mortality rates of the intent-to-treat cohort. In the intent-to-treat analysis among shock patients, low-dose anti-tumor necrosis factor reduced 28-day mortality by 14.5% (p = .34), whereas in the Scientific Extramural Review Committee group, the study drug reduced mortality by 26.5% (p = .16). More patients in the high dose anti-tumor necrosis factor treatment arm (31/176) were in the invalid Scientific Extramural Review Committee group than in the other two arms (16/157 and 13/143, respectively, p < .05).ConclusionsIn large trials of sepsis, in addition to analyzing the intent-to-treat cohort, patients in compliance with the protocol and with no confounding events should also be analyzed. These results should assist in determining whether treatment groups are comparable and provide a greater likelihood of demonstrating the potential efficacy of a new therapy for sepsis. A Clinical Evaluation Committee is important to properly assess a clinical sepsis trial.(Crit Care Med 1996; 24:1441-1447)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectiveTo test the hypothesis that significantly higher concentrations of interleukin-8 (IL-8) are found in the pulmonary edema fluid and plasma of patients with a septic vs. a nonseptic etiology of acute respiratory distress syndrome (ARDS).DesignProspective measurement of IL-8 concentrations in previously collected edema fluid and plasma.SettingAdult intensive care units at a university medical center.PatientsThere were 27 patients with ARDS (16 patients with a septic etiology and nine patients with a nonseptic etiology) plus eight control patients with hydrostatic pulmonary edema.Measurements and Main ResultsIL-8 was present in the pulmonary edema fluid of all patients with ARDS, but the median IL-8 concentration was higher in the edema fluid of patients with ARDS associated with sepsis (84.2 ng/mL, n = 16) compared with the ARDS patients without sepsis (14.8 ng/mL, n = 11) (p < .05). In patients with cardiogenic edema, IL-8 concentration (5.0 ng/mL, n = 8, p < .05) was significantly lower than those values in patients with ARDS. Median plasma concentration of IL-8 was increased in septic individuals (1.3 ng/mL), but these concentrations were not significantly higher than in patients with a nonseptic etiology of ARDS (0.35 ng/mL) (p = .14) or those patients with cardiac failure (0.21 ng/mL).ConclusionsThe high concentrations of IL-8 in pulmonary edema fluid, coupled with the relatively low concentrations of IL-8 in the plasma, suggest that the lung was the primary source of IL-8 in the patients with ARDS. The markedly increased concentrations of IL-8 in the pulmonary edema fluid of patients with ARDS from sepsis suggests that this group of patients may be particularly suitable for potential trials directed at inhibiting the activity of this important chemokine.(Crit Care Med 1996; 24:1448-1454)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectivesTo investigate a possible relationship between plasma erythropoietin and interleukin-6 (IL-6) in critically ill children with sepsis or septic shock. To examine the modulatory effects of plasma from these patients on erythropoietin production in vitro, employing a cell culture system that uses the erythropoietin-producing Hep 3B cell line.DesignA prospective, controlled clinical and laboratory study.SettingA pediatric intensive care unit and research laboratory facility at a children's hospital.PatientsChildren admitted to the pediatric intensive care unit with the diagnosis of sepsis or septic shock (n = 16), and control patients without infection or anemia (n = 16) were admitted to the study.InterventionsNone.Measurements and Main ResultsBlood samples were obtained from 16 children with sepsis or septic shock, and 16 age-matched controls. Plasma erythropoietin and IL-6 concentrations were measured using an enzyme-linked immunoassay. Plasma erythropoietin concentrations were significantly higher in children with sepsis or septic shock (120 +/- 26 mIU/mL) than in controls (10 +/- 2 mIU/mL) (p < .001). Plasma IL-6 concentrations were greater in children diagnosed with sepsis or septic shock (12,405 +/- 6662 pg/mL) than in control patients (7 +/- 1 pg/mL) (p < .001), and higher in septic shock patients (27,469 +/- 13,647 pg/mL) than sepsis patients (688 +/- 258 pg/mL) (p = .03). Hep 3B cells were incubated under hypoxic conditions in media containing plasma from control patients, or patients diagnosed with sepsis or septic shock. Media concentrations of erythropoietin were measured using an enzyme-linked immunoassay. Hep 3B cells incubated with plasma from patients diagnosed with sepsis or septic shock produced more erythropoietin (216 +/- 23 mIU/mL) than Hep 3B cells incubated under the same conditions in media containing plasma from control patients (152 +/- 11 mIU/mL) (p = .04). Hypoxic Hep 3B cell erythropoietin production in media incubated with plasma from patients diagnosed with sepsis or septic shock correlated significantly (although weakly) with plasma IL-6 values from these same patients (p = .03, r2= .28).ConclusionsPlasma erythropoietin and IL-6 values are increased in critically ill children with sepsis or septic shock in comparison with controls. The data indicate that one or more plasma factors are responsible for stimulation of hypoxia-induced erythropoietin production in the Hep 3B cell line and suggest a possible role for IL-6 in the regulation of erythropoietin production in critically ill children with sepsis or septic shock.(Crit Care Med 1996; 24:1455-1459)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectivesTo describe the sequential changes in the circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins in critically ill patients. To determine whether critical illness is associated with induction of a specific protease directed against insulin-like growth factor binding protein 3 and to relate these changes to outcome.DesignProspective, descriptive study.SettingIntensive care unit (ICU) of a university hospital.PatientsEighteen heterogeneous critically ill patients, requiring ventilatory support.InterventionsSerial daily blood samples were collected until death or discharge from the ICU. In five patients, samples were also obtained on the ward before discharge from the hospital.Measurements and Main ResultsSerum concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins 1, 2, and 3 were measured by radioimmunoassay. After 5 days, insulin-like growth factor binding protein 3 concentrations were measured on alternate days. Alterations in binding of insulin-like growth factor-I to insulin-like growth factor binding protein 3 and the presence of protease activity directed against insulin-like growth factor binding protein 3 were investigated by Western ligand blotting.Circulating concentrations of insulin-like growth factor-I and insulin-like growth factor-II were low and remained low throughout the 7-day study period. Insulin-like growth factor binding protein 1 concentrations were initially increased to within the fasting range, but subsequently decreased. There was considerable variability in insulin-like growth factor binding protein 2 concentrations, but generally, concentrations were at the upper end of the normal range throughout. Insulin-like growth factor binding protein 3 concentrations were consistently low and Western ligand blotting at the nadir of the insulin-like growth factor-I concentration demonstrated the presence of a protease directed against insulin-like growth factor binding protein 3. The last recorded concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein 3 were higher in survivors than in nonsurvivors (p < .05). Two patients were also studied for a prolonged period. In one patient, a survivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 were low initially, but later increased in association with recovery and cessation of protease activity over a period of 33 days. In another patient, a nonsurvivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 remained low and protease activity persisted until the patient died 38 days after admission to the ICU.ConclusionsCritical illness is associated with low circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein 3 and these low values are associated with induction of protease activity specifically directed against insulin-like growth factor binding protein 3. In survivors, recovery is associated with increasing insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations and cessation of protease activity. The therapeutic effects of exogenous growth factors are likely to be influenced by these changes.(Crit Care Med 1996; 24:1460-1466)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectiveTo establish the value of the67Gallium (Ga) pulmonary leak index, a marker of increased permeability edema of the lungs, in assessing the severity and course of the adult respiratory distress syndrome (ARDS).DesignProspective observational study.SettingMedical intensive care unit of a university hospital.PatientsSeventeen consecutive, mechanically-ventilated ARDS patients. Eleven patients (recovering from ARDS) improved, as defined by the ability to taper the level of positive end-expiratory pressure (PEEP) to 0 cm H2O at a median of 7 days after admission. Ten patients survived. Six patients did not recover and died a median of 3.5 days after admission.InterventionsNone.Measurements and Main ResultsThe pulmonary leak index (i.e., upper limit of normal 14.1 times 10 sup -3/min) was measured within 72 hrs after admission, and repeated within 48 hrs at the time of recovery in recovering patients. At admission and recovery, respiratory variables were recorded and a lung injury score was calculated. At admission, the pulmonary leak index was increased in each patient to 32.3 (range 15.6 to 52.4) and 28.7 (range 26.0 to 40.8) times 10 sup -3/min in recovering and nonrecovering patients, respectively (NS). Groups did not differ with respect to the oxygenation ratio, the level of PEEP, radiographic abnormalities, and the lung injury score. At recovery, the pulmonary leak index in recovering patients had decreased in each patient and had normalized in four patients, averaging 15.2 (range 5.6 to 25.9) times 10 sup -3/min, concomitantly with an increased oxygenation ratio, less radiographic abnormalities, and a decreased lung injury score (p < .01 vs. admission). For pooled recovering and nonrecovering patient data, the pulmonary leak index directly related to the lung injury score (p < .005).ConclusionsThe67Ga pulmonary leak index may be a clinically useful tool to quantify the severity and course of ARDS, since clinical recovery from the syndrome may be characterized by amelioration of increased microvascular permeability.(Crit Care Med 1996; 24:1467-1472)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectiveTo assess the pharmacokinetics and pharmacodynamics of propofol sedation of critically ill, mechanically ventilated infants and children.DesignA prospective clinical study.SettingA pediatric intensive care unit (ICU) in a university hospital.PatientsClinically stable, mechanically ventilated pediatric patients were enrolled into our study after residual sedative effects from previous sedative therapy dissipated and the need for continued sedation therapy was defined. Patients were generally enrolled just before extubation.InterventionsA stepwise propofol dose escalation scheme was used to determine the steady-state propofol dose necessary to achieve optimal sedation, as defined by the COMFORT scale, a validated scoring system which reliably and reproducibly quantifies a pediatric patient's level of distress. When in need of continued sedation, study patients received an initial propofol loading dose of 2.5 mg/kg and were immediately started on a continuous propofol infusion of 2.5 mg/kg/hr. The propofol infusion rate was adjusted and repeat loading doses were administered, if needed, using a coordinated dosing scheme to maintain optimal sedation for a 4-hr steady-state period. After 4 hrs of optimal sedation, the propofol infusion was discontinued and simultaneous blood sampling and COMFORT scores were obtained until the patient recovered. Additional blood samples were obtained up to 24 hrs after stopping the infusion and analyzed for propofol concentration by high-performance liquid chromatography.Measurements and Main Resultsor=to27) after stopping the propofol infusion was rapid, averaging 15.5 mins in 23 of 24 evaluable patients. In 13 patients who were extubated after stopping the propofol infusion, the time to extubation was also rapid, averaging 44.5 mins. Determination of the blood propofol concentration at the time of recovery from propofol sedation was possible in 15 patients. The blood propofol concentration was variable, ranging between 0.262 to 2.638 mg/L but <or=to1 mg/L in 13 of 15 patients. Similarly, tremendous variation was observed in propofol pharmacokinetics. Propofol disposition was best characterized by a three-compartment model with initial rapid distribution into a small central compartment, V1, and two larger compartments, V2and V3, which are two- and 20-fold greater in volume, respectively, than V1. Redistribution from V2and V3into V1was much slower than ingress, underscoring the importance of the propofol concentration in V1as reflective of the drug's sedative effect. Propofol was well tolerated. Two patients experienced an acute decrease in blood pressure which resolved without treatment.ConclusionsWe conclude that a descending propofol dosing strategy, which maintains the propofol concentration constant in the central compartment (V1) while drug accumulates in V2and V3to intercompartmental steady-state, is necessary for effective propofol sedation in the pediatric ICU. Our proposed dosing scheme to achieve and maintain the blood propofol concentration of 1 mg/L would appear effective for sedation of most clinically stable, mechanically ventilated pediatric patients.(Crit Care Med 1996; 24:1473-1481)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectiveTo evaluate in vitro and in vivo the efficacy of covalent end point-attached heparin to single-lumen polyurethane central venous catheters in reducing microbial adherence and colonization.DesignIn vitro study: A controlled bench study. In vivo study: A prospective, randomized, double-blind, clinical trial.SettingIntensive care unit in a 1200-bed teaching hospital.InterventionsIn vitro study: Adhesion of 17 radiolabeled clinical isolates of Staphylococci to catheters was examined in vitro. In vivo study: The outcome of heparinized and control catheters was compared in vivo in patients receiving long-term parenteral nutrition. Fifty-five adult patients were prospectively, blindly randomized to heparinized or control central venous catheters. The catheters, removed on clinical grounds, were analyzed with semiquantitative and quantitative cultures. Blood cultures were done at catheter removal.Measurements and Main ResultsIn vitro study: Coagulase-negative Staphylococci adhered less in vitro to heparinized catheters than to control catheters (p < .05). In vivo study: Among 32 central venous catheters, or patients who completed the study, catheter-associated bacteremia or fungemia was observed in five patients in the control group (n = 19) and in no patient with a heparinized catheter (n = 13) (p = .047). Four of 13 catheters in the heparin group were colonized compared with 14 of 19 in the control group (p = .03). Coagulase-negative Staphylococci were the most frequent microorganisms in both groups. The numbers of organisms found on colonized catheters were larger in the control group than in the heparin group.ConclusionsCovalent end point surface heparinization appears to have a great impact on both in vitro and in vivo bacterial colonization of central venous catheters. Such heparinization can be a practical and economical approach to the prevention of catheter-associated bacteremia or fungemia.(Crit Care Med 1996; 24:1482-1489)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

ObjectivesMilrinone is a phosphodiesterase F-III inhibitor with positive inotropic and vasodilating activities. We investigated the hemodynamic response and pharmacokinetics of intravenous milrinone in patients with acute heart failure.DesignDouble-blind studies: a prospective, multicenter, double-blind, dose-finding study and a placebo-controlled, double-blind, comparative study.Settingor=to18 mm Hg), who were hospitalized in the cardiac care units of 33 institutes in Japan, were entered into the study.PatientsFifty-four patients with acute or decompensated heart failure in the dose-finding study and 52 patients in the placebo-controlled, double-blind, comparative study.InterventionsThe present multicenter study consisted of a double-blind, dose-finding study (50-micro gram/kg intravenous loading dose, followed by 0.25, 0.5, or 0.75 micro gram/kg/min of a continuous infusion of milrinone for 6 hrs, n = 54), and a placebo-controlled, double-blind, comparative study (50-micro gram/kg loading dose, followed by 0.5 micro gram/kg/min of a continuous infusion of milrinone vs. placebo treatment, n = 52). We investigated the effects on cardiovascular hemodynamics, subjective symptoms, physical findings, and the pharmacokinetics of intravenous milrinone in a total of 106 patients with acute heart failure.Measurements and Main ResultsIn the double-blind, dose-finding study, dose-dependent inotropic/vasodilating hemodynamic effects were documented for percent changes in cardiac index (+21.2%, +25.8%, and +30.9%, respectively) and pulmonary artery occlusion pressure (-12.8%, -17.0%, -41.3%, respectively) vs. plasma drug concentration at the equilibrium state (6 hrs after starting continuous infusion; 97 +/- 13, 197 +/- 22, and 284 +/- 28 ng/mL, respectively). Throughout the 6-hr infusion period, subjective symptoms were improved in 40%, 46.2%, and 70% of patients, respectively, for the three continuous infusion rates (0.25, 0.5, and 0.75 micro gram/kg/min). In the placebo-controlled, double-blind, comparative study, the milrinone group exhibited marked improvement in cardiovascular hemodynamics (pulmonary artery occlusion pressure: from 26 +/- 6 to 15 +/- 3 mm Hg; cardiac index: from 2.6 +/- 0.9 to 3.3 +/- 1.1 L/min/m2) within 15 mins after starting drug administration. However, the placebo group showed no significant hemodynamic changes. Subjective symptoms and physical findings of acute heart failure improved in 47.6% and 40%, respectively, of patients within 60 mins after starting milrinone. The placebo group, however, showed no improvement providing inotropic/vasodilating (both 0%).ConclusionContinuous infusion of milrinone (0.25 to 0.75 micro gram/kg/min) after a 50-micro gram/kg loading dose is effective for inotropic/vasodilating hemodynamic support in patients with acute or decompensated heart failure.(Crit Care Med 1996; 24:1490-1497)

ISSN:0090-3493    

出版商:OVID    

年代:1996

数据来源: OVID