Robert F. Lodato

Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis*

ObjectiveTo determine the safety and efficacy of filgrastim (r-metHuG-CSF) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis. DesignThis study was multicenter, double-blind, and randomized. SettingIntensive care units PatientsAdult patients with bacterial pneumonia, either acquired or nosocomial, as confirmed by chest radiograph and positive culture or Gram-negative stain, and severe sepsis, defined as sepsis-induced hypotension or organ dysfunction. InterventionsStandard antibiotic therapy with or without filgrastim (300 &mgr;g/day) or placebo administered as a 30-min intravenous infusion. The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached >75.0 × 109 cells/L. Measurements and Main ResultsThe primary end point was the occurrence of mortality through day 29; secondary end points included occurrence of subsequent organ dysfunction, time to discharge from intensive care unit, number of days on mechanical ventilatory support, and time to death. Study-related observations were recorded through day 10 and included vital signs, onset of organ dysfunction, clinical laboratory variables, and adverse events. Filgrastim increased the white blood cell count to a median peak of 31.7 × 109 cells/L from a baseline of 12.3 × 109 cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events, time to death, occurrence of end-organ dysfunction, days of intensive care unit hospitalization, or days on mechanical ventilatory support. Mortality was low in both treatment groups; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups. ConclusionsThe addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe, but not efficacious in reducing mortality rates or complications from this infection.

Administration of the nitric oxide synthase inhibitor NG-methyl- L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: Results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002)

ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure ≥70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. DesignMulticentered, randomized, placebo-controlled, safety and efficacy study. SettingForty-eight intensive care units in Europe, North America, and Australia. PatientsA total of 312 patients with septic shock diagnosed within 24 hr before randomization. InterventionsPatients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Measurements and Main ResultsRequirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p = .004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. ConclusionsIn this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

Roles of IL-1 and TNF in the decreased ileal muscle contractility induced by lipopolysaccharide

Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-α (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean ± SE) from 508 ± 55 (control) to 355 ± 33 g/cm2( P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold ( P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra ( P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean +/- SE) from 508 +/- 55 (control) to 355 +/- 33 g/cm2 (P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold (P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra (P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.

A Phase 2 Randomized, Double-Blind, Placebo- Controlled Study of the Safety and Efficacy of Talactoferrin in Patients With Severe Sepsis*

Objectives:Lactoferrin is a glycoprotein with anti-infective and anti-inflammatory properties found in secretions and immune cells. Talactoferrin alfa, a recombinant form of human lactoferrin, has similar properties and plays an important role in maintaining the gastrointestinal mucosal barrier integrity. In experimental animal models, administration of talactoferrin reduces translocation of bacteria from the gut into the systemic circulation and mortality from sepsis. Our objective was to determine if talactoferrin could reduce 28-day all-cause mortality in patients with severe sepsis and to assess its safety. Design:Prospective, randomized, double-blind, placebo-controlled, multicenter phase 2 trial. Setting:Adult ICUs and emergency departments in the United States. Patients:One hundred ninety-four adults within 24 hrs of the onset of severe sepsis. Interventions:Enterally administered talactoferrin 1.5g or placebo every 8 hrs for up to 28 days or until discharge from the ICU. Measurements and Main Results:Modified intention-to-treat analysis was used to assess the primary (28-day all-cause mortality) and secondary endpoints. The all-cause mortality at 28 days was 26.9% in the placebo group and 14.4% in the talactoferrin group (two-sided p = 0.052), representing a 12.5% absolute and a 46.5% relative reduction in mortality, meeting the protocol-specified primary endpoint. Reduction in all cause mortality was sustained at 6 months (p = 0.039). These reductions in mortality were observed across a wide spectrum of subgroups. The drug was well tolerated with a safety profile similar to that of placebo. Conclusions:Enteral administration of talactoferrin reduced 28-day all-cause mortality in patients with severe sepsis. This reduction in mortality was sustained at 6 months. Talactoferrin was very well tolerated.

Effects of dobutamine on oxygen transport and consumption in the adult respiratory distress syndrome

ObjectiveTo determine if oxygen consumption (VO2) in patients with adult respiratory distress syndrome (ARDS) is dependent on, and thus limited by, oxygen transport (TO2) rather than O2 demand.DesignProspective study.SettingIntensive care unit of a tertiary referral center.Patients12 patients with ARDS and sepsis syndrome.InterventionsRoutine intensive care unit monitoring including pulmonary and radial artery catheters.MeasurementsDobutamine was used to increase cardiac output, thereby directly varying TO2 under conditions of constant O2 demand. After baseine measurements of TO2 and VO2, dobutamine was infused intravenously at progressively increasing doses of 5, 10, 15 and 20 μg/kg/min and measurements of TO2 and VO2 were repreated after 30 min at each dose.ResultsDobutamine increased TO2 in 8 of the 12 patients, by 29% at 5 μg/kg/min and by 45% (net) at 10 μg/kg/min, but not at higher doses. In these 8 patients dobutamine also increased VO2 by 15% at 5 μg/kg/min, but did not further increase VO2 at higher doses. There was no correlation between baseline blood lactate concentration and the response of either TO2 or VO2 to dobutamine.ConclusionsIn some but not all patients with ARDS and sepsis syndrome, short-term infusion of low-dose dobutatmine can increase both TO2 and VO2. Achievement of a TO2-independent level of VO2 could not be convincingly demonstrated in any individual patient. The response of TO2 and VO2 to dobutamine could not be predicted from baseline blood lactate concentration. Determination of the impact on patient outcome of a more prolonged infusion of dobutamine requires further study.

Hemodynamic evaluation of recombinant human tumor necrosis factor (TNF)-α, TNF-SAM2 and liposomal TNF-SAM2 in an anesthetized dog model

Summary We have evaluated the hemodynamic effects of systemically administered recombinant human tumor necrosis factor (TNF)-α, TNF-SAM2 and liposome-bound TNF-SAM2 in an anesthetized mongrel dog model. A dose of 10 μg TNF protein/kg of each formulation was injected in a peripheral vein and mean systemic arterial pressure (SAP), heart rate (HR) and cardiac output (CO) were measured. TNF-α induced a marked drop in SAP in all three dogs (mean decrease = 59.3 ± 5.2 mm Hg; to 61.5% of baseline; p = 0.008); whereas TNF-SAM2 caused a smaller and transient drop in SAP in four dogs (mean decrease = 25.5 ± 10.1 mm Hg; to 81.2% of baseline; p = 0.086). In three dogs administered liposome-bound TNF-SAM2, which retains antitumor activity in vivo, a net slight hypertensive phase and sustained elevated CO occurred, followed by a return to an essentially normotensive state (101.0% of baseline SAP). This model demonstrates that the principal acute systemic toxicity of TNF, i.e., hypotension, can be markedly attenuated by liposomal formulation of a second-generation TNF.

Increased survival with hypotensive resuscitation in a rabbit model of uncontrolled hemorrhagic shock in pregnancy

AIM We sought to compare the effects of conservative hypotensive and aggressive normotensive resuscitation strategies on blood loss, fluid requirements, blood lactate and survival rate in a clinically relevant model of uncontrolled hemorrhagic shock in pregnancy. METHOD 60 anesthetized New Zealand white rabbits at late gestation underwent uncontrolled hemorrhagic shock by transecting a small artery in the mesometrium, followed by blood withdrawal via the carotid artery, to a mean arterial pressure (MAP) of 40-45mmHg. They were randomly divided into six groups (n=10 per group): sham shock (group SS); shock without resuscitation (group SH); hypotensive resuscitation in the simulated prehospital phase with Ringers solution to MAP of 50, 60, or 70mmHg, respectively (groups RE50, RE60, RE70); and aggressive resuscitation in the prehospital phase with Ringers solution to MAP of 80mmHg (group RE80). Finally, in the simulated hospital phase, animals in the resuscitated groups underwent surgical control of bleeding and were fully resuscitated with half of the heparinized shed blood and Ringers solution to MAP of 80mmHg. RESULTS Hypotensive resuscitation significantly decreased blood loss and subsequent volume infusion, leading to higher hematocrit, lower lactate concentration, and shorter prothrombin time and activated partial thromboplastin time. Median survival time in group RE60 (4.3+/-0.6 days) was significantly longer than that in groups RE50 (2.7+/-0.4 days), RE70 (2.3+/-0.3 days), and RE80 (1.7+/-0.3 days) (P<0.05). CONCLUSIONS We conclude that in this rabbit model of uncontrolled hemorrhage in pregnancy, hypotensive resuscitation to MAP of 60mmHg may be an optimal target MAP before hemorrhage can be controlled by surgical intervention.

Acute lung inflammatory response and injury after hemorrhagic shock are more severe in postpartum rabbits.

Objective: The acute respiratory distress syndrome may complicate postpartum hemorrhagic shock and resuscitation, but its mechanisms are not yet well defined. We studied the lung inflammatory response to postpartum hemorrhagic shock and resuscitation in a rabbit model and the role of the nuclear factor-&kgr;B pathway. Design: Randomized, controlled, prospective study. Setting: University hospital laboratory. Subjects: Nonobstetric (not pregnant nor postpartum) and obstetrical (within 2 hrs postpartum) rabbits. Interventions: Nonobstetric and obstetric female New Zealand white rabbits underwent fixed-pressure or fixed-volume hemorrhagic shock for 30 mins and then were rapidly resuscitated with the shed blood and Ringer’s solution. Finally, they were either monitored for survival time or euthanized by exsanguination for lung tissue examination 24 hrs after hemorrhage. Measurements and Main Results: After hemorrhagic shock and resuscitation, median survival time in obstetric rabbits (3 days) was significantly shorter (p < .05) than that in nonobstetric rabbits (5 days). Compared with nonobstetric rabbits, obstetric rabbits had more severe lung injury as indicated by alveolar and interstitial fluid accumulation and marked neutrophil sequestration and greater lung injury score, myeloperoxidase activity, expression of intercellular adhesion molecule-1, serum tumor necrosis factor-&agr; levels, and nuclear factor-&kgr;B activation, and lower serum interleukin-10 levels (p < .05 for all). Conclusions: After hemorrhage and resuscitation, obstetric rabbits had significantly shorter survival time and more severe lung injury than nonobstetric rabbits. The mechanism may be through upregulation of the signal transductions of the nuclear factor-&kgr;B pathways.

Effects of Normobaric Hyperoxia on Hemodynamics and O2 Utilization in Conscious Dogs

Normobaric hyperoxia decreased resting whole-body O2 consumption in conscious dogs by equal (Fick) contributions from decreases in cardiac output and in the arterial-venous difference in O2 content. The decrease in O2 consumption was fully developed by 20 min, was maintained for at least 1 h, and was both reversible and reproducible. Hyperoxia also decreased heart rate, right and left ventricular work rates (and therefore, presumably myocardial O2 consumption), and pulmonary vascular resistance; and increased systemic vascular resistance and right atrial pressure. Paradoxically, hyperoxia did not change O2 delivery. This latter observation together with the decrease in O2 consumption produced a unique vertical orientation to the O2 consumption-delivery relationship induced by hyperoxia. It is concluded that hyperoxia may decrease metabolic rate and substantially alter hemodynamics, which may have important implications for understanding the metabolic regulation of oxygen utilization and for the medical and nonmedical uses of oxygen.

Hemodynamic Changes With Manual and Automated Lateral Turning in Patients Receiving Mechanical Ventilation

BACKGROUND Lateral turning of critical care patients receiving mechanical ventilation can adversely affect hemodynamic status. OBJECTIVE To study hemodynamic responses to lateral turning. METHOD A time-series design with automated signal processing and ensemble averaging was used to evaluate changes in heart rate, mean arterial pressure, and pulse pressure due to lateral turning in 13 adult medical-surgical critical care patients receiving mechanical ventilation. Patients were randomly assigned to the manual-turn or the automated-turn protocol for up to 7 consecutive days. Heart rate and arterial pressure were measured every 6 seconds for more than 24 hours, and pulse pressure was computed. RESULTS A total of 6 manual-turn patients and 7 automated-turn patients completed the study. Statistically significant changes in heart rate, mean arterial pressure, and pulse pressure occurred with the manual turn. Return of the hemodynamic variables to baseline values required up to 45 minutes in the manual-turn patients (expected recovery time ≤ 5 minutes). However, clinically important changes dissipated within 15 minutes of the lateral turn. The steady-state heart rate response on the right side was slightly greater (3 beats per minute) than that on the back (P = .003). Automated turning resulted in no clinically important changes in any of the 3 variables. CONCLUSIONS In medical-surgical critical care patients receiving mechanical ventilation, manual lateral turning was associated with changes in heart rate, mean arterial pressure, and pulse pressure that persisted up to 45 minutes.