Recent onset of severe sepsis (within the past 48 hours) as defined by the Consensus Panel of the American College of Chest Physicians and the Society of Critical Care Medicine in 1991 that standardized the terminology of sepsis and its sequelae (87). Sepsis was defined as a documented infection plus the Systemic Inflammatory Response Syndrome (SIRS). Severe sepsis was defined as evidence of organ hypoperfusion in association with sepsis. All three of the following criteria must be met for a diagnosis of severe sepsis: SIRS is defined as two or more of: temperature > 38o C or < 36oC; heart rate > 90 beats/min; respiratory rate > 20 breaths/min or PaCO2< 32mmHg; white blood cell count > 12.000/mm3; < 4000/mm3; or > 10% immature (band) forms.
Presence of a suspected or proven infection. Patients with suspected infection must have evidence of an infection, such as white blood cells in a normally sterile body fluid, perforated viscus, chest x-ray consistent with pneumonia and associated with purulent sputum production, or a clinical syndrome associated with a high probability of infection (for example, purpura fulminans or ascending cholangitis). Presence of one or more sepsis-associated organ failure. The onset of the first sepsis-associated organ failure must occur within the 48-hour period immediately preceding initiation of study drug infusion. A patient must have an organ failure attributable to the sepsis episode. The organ failure must be newly developed and not explained by underlying disease processes or by effects of concomitant therapy. A nonsepsis-induced organ failure may not be used to qualify the patient for the study even if the organ failure worsens as a result of the sepsis episode. In this instance, the patient must develop a new organ failure, which is sepsis-induced, to be eligible for participation in this study. Cardiovascular: An arterial systolic blood pressure (SBP) of ≤90 mm Hg or a mean arterial pressure (MAP) ≤70 mm Hg for at least 1 hour despite adequate fluid* resuscitation, adequate intravascular volume status, or the need for vasopressors to maintain SBP ≥90 mm Hg or MAP ≥70 mm Hg. Renal: Average urine output <0.5 mL/kg/h for 1 hour despite adequate fluid resuscitation Respiratory: Evidence of acute pulmonary dysfunction PaO2/FiO2 ≤ 300 and, clinical exam or pulmonary capillary wedge pressure not suggestive of volume overload. If pneumonia is the suspected site of infection, the patient must have a PaO2/FiO2 ≤200. Hematology: Platelet count <80,000/mm3 or a 50% decrease in platelet count from the highest value recorded over the last 3 days. Unexplained metabolic acidosis: Defined by
Adequate fluid resuscitation or adequate intravascular volume is defined as either pulmonary arterial wedge pressure ≥12 mm Hg or central venous pressure ≥8 mm Hg. Vasopressors are defined as dopamine ≥5 μg/kg/min or any dose of norepinephrine, epinephrine, or phenylephrine. Dobutamine is not considered a vasopressor. |
Patients with the following conditions will not be eligible for study participation: Macrolide therapy indicated for clinical condition Allergy to macrolides Pneumococcal pneumonia as suggested by tracheal aspirate Gram stain or BINAX urinary antigen test Immunosuppression as defined by: Chemotherapy within the last 30 days Leukemia or lymphoma which is not in remission Solid organ or bone marrow/stem cell transplant Human Immunodeficiency Virus infection Chronic corticosteroid use equivalent to > 20 mg prednisone per day
Prolonged QT syndrome or on medications with increased risk of QT prolongation. Patient or family decision to limit ICU care Pregnant or nursing mothers will be excluded
The majority of the exclusion criteria have been selected as they are known to affect the immune response to infection and could substantially affect the assessment of the primary outcome. Since this is a pilot study and the primary outcome variable will be inflammatory gene expression, we are excluding immunosuppressed patients, including relatively low dose corticosteroid use. The variable inflammatory response in these patients is likely to obscure the gene expression patterns. |
