Aerosolized Ceftazidime for Prevention of Ventilator-Associated Pneumonia and Drug Effects on the Proinflammatory Response in Critically Ill Trauma Patients

G. Christopher Wood, Pharm.D., Bradley A. Boucher, Pharm.D., FCCP, Martin A. Croce, M.D., Scott D. Hanes, Pharm.D., Vanessa L. Herring, B.S., Timothy C. Fabian, M.D.

Disclosures

Pharmacotherapy. 2002;22(8) 

In This Article

Methods

The protocol for this randomized, double-blind, placebo-controlled clinical trial was approved by the University of Tennessee's institutional review board before patient enrollment. The study took place at the Presley Memorial Trauma Center located in the Regional Medical Center at Memphis, Memphis, Tennessee. Patients aged 16 years or older were considered for study inclusion if they were admitted to the trauma ICU, were expected to require at least 7 days of mechanical ventilation, and had one or more of the following known risk factors for posttraumatic pneumonia[12]: severe traumatic brain injury (Glasgow Coma Scale score 4-8), Injury Severity Score[29] of 25 or greater, pulmonary contusion, several rib fractures, spinal cord injury, emergency laparotomy, or emergency femur fixation. Exclusion criteria included poor prognosis (Glasgow Coma Scale score of 3 or not expected to survive more than 48 hours), allergy to -lactam antibiotics, preexistent lung disease requiring long-term inhalation drug therapy, current treatment for a lower respiratory tract infection, long-term therapy with corticosteroids or immunosuppressive drugs, pregnancy, human immunodeficiency virus infection, cancer, or white blood cell count less than 4 103/mm3. Written informed consent was obtained from each patient or his or her legally authorized representative before randomization.

Patients randomly were assigned to receive either ceftazidime 250 mg (Fortaz; GlaxoWellcome, Research Triangle Park, NC) or placebo (normal saline for injection) every 12 hours for 7 days by nebulization. Randomization was determined by computer, with each block of 10 patients equally distributed between the ceftazidime and placebo groups. Assignments to receive ceftazidime or placebo were kept in sealed envelopes and opened on patient enrollment. Study treatment began within 48 hours of hospital admission and was discontinued early if the patient was extubated or developed VAP before receiving 7 days of treatment. Patients were considered eligible for evaluation if they received at least 3 days of study treatment. The diagnosis of VAP was defined as growth of at least 105 colony-forming units (cfu)/ml of an organism from bronchoalveolar lavage (BAL) in addition to Society of Critical Care Medicine-American College of Chest Physicians criteria for the systemic inflammatory response syndrome.[30,31] Bronchoalveolar lavage was performed for diagnosis of VAP at any time as clinically indicated by the attending physician.

Study-drug administration was performed by respiratory therapists according to recommendations for optimizing aerosolized drug delivery in patients receiving mechanical ventilation.[32,33] Specifically, each dose was administered by means of a disposable jet nebulizer with a median mass aerosol diameter of 1-5 µm (Airlife Misty-Neb; Baxter Healthcare, Deerfield, IL) filled with 4 ml of ceftazidime solution (62.5 mg/ml) or normal saline for injection. The nebulizer was connected to the inspiratory loop of the ventilator tubing 30 cm from the endotracheal tube. During administration, the ventilator (Puritan Bennett 7200 series; Nellcor Puritan Bennett, Pleasanton, CA) was set to nebulize only during inspiration, using a high nebulizer airflow rate (7.5 L/min). Ventilator humidification was turned off during administration. Study-drug doses were prepared in syringes every 48 hours in the hospital pharmacy with use of an aseptic technique in a laminar flow hood. All ceftazidime doses were prepared in normal saline for injection (final pH 7.0).

Bronchoalveolar lavage was performed before starting study treatment (baseline) and once again during days 4-7 (follow-up) for analysis of TNF- , IL-1 , IL-6, IL-8, ceftazidime, and urea. At the time of BAL, blood samples also were collected for analysis of TNF- , IL-1 , IL-6, IL-8, ceftazidime, and urea. Urea concentrations were measured to correct for the dilutional effect of BAL fluid on the analytes, by using the following equation[34]:

Concentration corrected = Concentration measured (Urea plasma/Urea BAL)

For this study, BAL was performed with a nonbronchoscopic catheter (BAL Cath; Ballard Medical Products, Draper, UT) advanced through the endotracheal tube into a distal airway of the left lung, per the manufacturer's instructions. In patients with bilateral chest trauma, the catheter was advanced into the lung on the side of the chest with the more severe injury. Bronchoalveolar lavage consisted of five aliquots of 20 ml of normal saline for irrigation with minimal dwell time in the lung for each aliquot. Recovered lavage fluid was pooled immediately, filtered through sterile gauze to remove mucus, centrifuged for 7 minutes, and frozen at -70°C until analysis. If a patient required a bronchoscopic BAL as part of clinical care at a time when a study BAL was also indicated, the lavage fluid from the bronchoscopic lavage was used for study analysis with the same technique. Serum and plasma samples also were stored at -70°C until analysis. Cytokines were analyzed with commercial enzyme-linked immunosorbent assay kits (R&D systems, Minneapolis, MN, and Endogen, Inc., Woburn, MA). Urea was analyzed with a spectrophotometric kit (Sigma Diagnostics, St. Louis, MO). Ceftazidime was analyzed with a previously reported high-performance liquid chromatography assay.[35] Modified versions of these assays were developed and validated for measuring analytes in BAL fluid. Microbial culture and sensitivity testing were performed by the hospital microbiology laboratory. An antibiogram compiled by the hospital microbiology department was used to determine overall ceftazidime sensitivity patterns of gram-negative organisms in the study ICU.[36]

The primary outcome variable was the development of VAP at day 7, 14, and for the ICU stay. Secondary variables were changes in pulmonary and plasma TNF- , IL-1 , IL-6, and IL-8 in each group. Logistic regression analysis was used to assess the relationship between cytokine concentrations and VAP development. Discrete variables were analyzed with the 2 statistic or Fisher exact text, as appropriate. A Kaplan-Meier estimation was performed to analyze VAP development over time, with death or ICU discharge used as the censoring variable. Continuous variables were analyzed with the Student t test or Mann-Whitney U test, as appropriate. Continuous data are presented as mean ± SD or median with interquartile range. Differences were considered statistically significant at a p value less than 0.05. A power analysis performed a priori determined that 40 patients were needed to detect a 65% reduction in the frequency of VAP if the baseline frequency of VAP was 65% ( = 0.05, = 0.2).

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