INTRODUCTION

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Ventilator-associated pneumonia (VAP) remains a frequent problem in most intensive care settings, its incidence ranging from 9% to more than 40% (1). VAP is thought to increase both length of stay in the intensive care unit (ICU) and mortality (6), and the costs attributed to it are therefore high (7).

Infections occurring in critically ill patients are mainly of endogenous and less frequently of exogenous origin. Infections of the lower respiratory tract are usually preceded by an abnormal carriage pattern, which consists of the presence of potentially pathogenic aerobic organisms in the oropharynx and gut. The importance of oropharyngeal carriage and subsequent entry of oropharyngeal content into the trachea in the pathogenesis of nosocomial pneumonia is well established (8, 9). The stomach and proximal intestine have been suggested to be reservoirs for retrograde colonization of the oropharynx (10). The sequence of events whereby microbes of the gut colonize the upper respiratory tract and are subsequently aspirated, leading to pneumonia, is termed secondary endogenous pneumonia, and constitutes the main target of the nonabsorbable antimicrobial agents used for selective decontamination of the digestive tract (SDD). Locally applied lethal oropharyngeal and gastrointestinal antibiotics are directed at eradicating the carriage of potentially pathogenic aerobic microorganisms, including Staphylococcus aureus, enterobacteria, pseudomonads, and yeasts (11).

Different study designs and patient populations in previous trials (12) of the efficacy of SDD in patients requiring intensive care yielded mixed results. A high prevalence and incidence rate of gram-negative VAP, with its associated morbidity and costs, prompted us to undertake the present study of whether SDD reduces morbidity and cost for mechanically ventilated, critically ill patients (15).

	METHODS

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We conducted a double-blind, randomized, placebo-controlled trial of SDD in the general ICUs of five teaching hospitals in the Madrid area. Besides the primary end point of pneumonia, we studied the incidence of nonrespiratory infections, length and total cost of ICU stay, ICU mortality, and the two microbiologic end points of carriage and bacterial resistance. The trial protocol was approved by the ethics committee of each institution. Written informed consent was required of each participating patient.

Patient Population

The five ICUs participating in the study treat medical and surgical patients. Patients with trauma and those undergoing emergency surgery comprise 30% of the units' admissions.

All patients aged 16 yr or older who were expected to require intubation for a minimum of 48 h, as assessed by the attending intensive-care physician, were considered for inclusion in the study. Severity of the patient's acute disease or underlying condition, infection present on admission, gut surgery, ileus, prior antibiotic therapy, or previous length of stay were not exclusion criteria for the study. Patients not randomized at the time of intubation were enrolled as soon as their clinical course predicted a prolonged duration of intubation. Patients were excluded if they were pregnant, allergic to study antibiotics, received an organ transplantation, or did not require a nasogastric tube.

Study Organization and Design

Baseline samples for microbiology were obtained readily after intubation. The study medications were immediately administered and given until extubation or death. Patients were randomized through a computer-generated random-number table and were stratified by center. Treatment codes were kept in individual sealed envelopes. Treatment and placebo SDD preparations were manufactured by the pharmacy department of the coordinating center, and were indistinguishable from one another in taste, color, and consistency. Severity of illness was assessed by means of the Acute Physiology and Chronic Health Evaluation (APACHE II) score (16) at intubation.

The microbiologists who examined specimens for the study were blinded to the patient groups. Results of surveillance culture were withheld from the attending physician. Results for tracheal aspirates were reported if antibiotic therapy for purulent tracheobronchitis or pneumonia was considered.

The association between SDD and colonization with methicillin-resistant S. aureus (MRSA) was evaluated in one unit during an additional 14-mo poststudy period. An identical treatment protocol was followed for all patients. Surveillance cultures were obtained for 100 consecutive patients who met the entry criteria of the study. Generally accepted patient isolation procedures were implemented following the isolation of MRSA in any of the surveillance samples, as was also done during the period of controlled study.

Selective Decontamination Regimen and Study Groups

At 6-h intervals, the oropharyngeal cavity was thoroughly cleansed with 0.1% hexetidine solution and 0.25 g of an adherent methylcellulose paste were applied with a gloved finger. Ten milliliters of active drug or placebo suspension were administered through the patient's nasogastric tube, and aspiration was interrupted for 1 h. An intravenous solution of active drug or placebo was given once daily to noninfected patients during the first three days of the protocol (Figure 1).

View larger version (29K): [in this window] [in a new window]   Figure 1.   Flow chart of enrollment of patients in the trial.

The orally applied paste for the SDD-treatment group contained a 2% concentration of gentamicin, polymyxin E, and amphotericin B. The 10-ml suspension included 80 mg of gentamicin, 100 mg of polymyxin E, and 500 mg of amphotericin B. The intravenous solution contained 2 g of ceftriaxone. The control group received placebo paste and placebo suspension, and an intravenous aqueous solution of placebo.

Surveillance samples from the throat and rectum (swabs), stomach (aspirate), and tracheal aspirate (sterile unprotected catheter) were obtained twice weekly. Blood, urine, and other diagnostic samples were taken on clinical indication only. Microorganisms were identified through standard microbiologic techniques. Antibiotic sensitivity patterns were investigated with standardized disk-diffusion methods (17).

Each center followed the local antibiotic policies designed for its respective ecology. Patients were openly randomized to receive either sucralfate or alkalinizing agents to balance gut-protection medication in the different study groups (18). The enteral nutrition protocol consisted of early feeding into the stomach and swift progression to full nutritional support within 72 h. If severe gastroparesis was documented in three gastric aspirates of more than 150 ml each, taken 6 h apart, parenteral nutrition was started at the discretion of the intensive-care physician.

Infection-control Measures

Routine care, including generally recommended infection-control measures, was applied in all the participating centers (19).

Definitions

Pneumonia was defined by the presence of a compatible, new and persistent infiltrate on chest X-ray, with at least three of the following four criteria: fever (temperature > 38° C), peripheral leukocytosis (> 12,000/mm³) or leukopenia (< 3,000/mm³), purulent tracheal aspirate, and growth of a potentially pathogenic microorganism in lower-airway secretions. Because of the expected high level of administration of systemic antibiotics, no protected specimen was required (20).

A time cutoff of 48 h was chosen to distinguish primary from secondary infections. Five days or 120 h was the time criterion for the distinction between early-onset and late-onset pneumonia. Secondary endogenous infection and pneumonia were considered to be present if the bacterium causing an infection had been previously identified in surveillance cultures (21).

Index culture was defined as the first sample, for either diagnostic or surveillance purposes, yielding MRSA during the additional study of MRSA. For calculation of the incidence of MRSA, we considered all patients with one or more MRSA-positive isolates.

Cost

The ICU costs per day were $666 (at a conversion rate of 150 Spanish Pesetas to the U.S. Dollar), including fixed costs, nutrition, and all drugs except systemic and topical antibiotics. The price of the topical antibiotic powder was $4 daily per patient. All episodes of pneumonia not existing at the time of admission were considered in calculating cost. The cost for each bacterial culture of a clinical specimen was $24.30. The cost for processing of endotracheal aspirates was $40. Bronchoscopy with bronchoalveolar lavage (BAL) and a telescoping catheter, including the processing of samples, cost $227. The cost of the abdominal computed tomographic scan used for the diagnosis of abdominal infection was $140. One catheter-related infection included one multilumen intravenous catheter at a cost of $33. In the SDD-treatment group, the cost of weekly surveillance cultures (four samples) was compared with the cost of one weekly culture of endotracheal aspirate in the control group ($24.30 per culture). The ratio of the total cost in the two groups, divided by the number of survivors in each group, was considered to reflect the average cost-effectiveness.

Statistical Analysis

A sample size of 295 was calculated as necessary to demonstrate a reduction in VAP from 30% to 15%, including 10% losses, with a statistical power of 0.80, with a two-sided test at the 0.05 significance level. All data were analyzed according to the intention-to-treat principle.

Categorical variables were compared through use of the chi-square test, with Yates' correction for continuity. Fisher's exact test was used whenever required by the smallest value of the contingency (2 × 2) table. Differences in means of normally distributed variables were analyzed with Student's t test. Nonparametric variables were compared with Wilcoxon's rank-sum test.

The probabilities of survival, of remaining intubated, and of remaining free of pneumonia were estimated for each study group with the Kaplan-Meier method, and were compared with the log-rank test.

Prognostic factors for mortality were studied with a Cox proportional hazards model. The model was adjusted for the following covariates: APACHE II score on admission, study group, receiving intravenous component of the protocol (ceftriaxone), age, and center.

A value of p  0.05 or less was considered statistically significant. Statistical analyses were performed with SAS, version 6, release 6.08 (SAS Institute, Cary, NC).

	RESULTS

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Patients

A total of 271 patients were consecutively enrolled in the study, of whom 131 received antibiotic prophylaxis and 140 received placebo. The APACHE II score on admission was 26.6 ± 10 (mean ± SD) (Table 1); approximately 20% of the patients were in a state of shock, and one third of the patients in each study group had multiple organ failure at the time of ICU admission. Impaired consciousness was more frequent on admission in treated patients. The diagnostic category was medical in 70.5%, surgical in 12.9%, and trauma in 16.6%. Primary infection was present in 31.3% of treated and 36.4% of control patients. In the SDD-treated group, four patients died within 48 h of intubation, and five improved and were extubated. In the control group, eight patients died and eight were extubated within 48 h of intubation. Baseline characteristics (Table 1) were comparable in the two groups, except for a significantly higher percentage of patients with chronic renal failure undergoing SDD.

Infections, Morbidity, and Costs

Of 74 (27.3%) patients who were considered infection-free on admission, 35 received intravenous ceftriaxone and 39 received placebo for 3 d (Table 2). The incidence of early-onset pneumonia was 14.3% (five patients) in the treated group and 51.3% (20 patients) in the control group (p = 0.002). The overall incidence of early-onset pneumonia remained significantly lower (Table 3).

The reduction in the incidence of secondary pneumonia and nonrespiratory infection in the SDD-treated group was highly significant (Table 3). The daily incidence rate of VAP decreased from 17.3 episodes per 1,000 ventilator-days in the placebo group to 8.5 episodes per 1,000 ventilator-days in the SDD-treated group (p < 0.001). The probability of remaining free of secondary pneumonia was significantly higher in decontaminated patients than in controls (Figure 2). Given a baseline risk of 29.3% and assuming a relative risk reduction of 61%, 5.6 patients had to be treated in order to prevent 1 episode of pneumonia. Two patients in the treatment group and seven in the control group had more than one episode of pneumonia. All patients in whom there was no microbiologic proof for the clinical signs of pneumonia (n = 19), save for one control subject, were receiving systemic antibiotic therapy at the time of sampling (Table 4). The incidence of gram-negative secondary pneumonia (Table 4) was significantly lower in the SDD-treated group, as was the incidence of episodes of secondary pneumonia of endogenous origin. Two of the three cases of gram-negative secondary endogenous pneumonia were diagnosed in patients in the SDD-treated group in whom administration of the study medications had been discontinued.

View larger version (10K): [in this window] [in a new window]   Figure 2.   Comparison of Kaplan-Meier estimates of probability of remaining free of pneumonia at 3 wk of intubation (p = 0.0002 by two-sided log-rank test). SDD = selective decontamination of the digestive tract.

Nine treated patients and six in the control group did not receive gut-protection medication. In a comparison based on intention-to-treat, the incidence of VAP was 23%, versus 19.2% in patients allocated to sucralfate and an H₂-blocker, respectively (p > 0.05).

Among survivors, the probability of remaining intubated over the course of the study (Figure 3) as well as during the ICU stay (Table 3) was significantly reduced in patients undergoing SDD. Significantly fewer patients in the SDD-treated group required systemic antibiotic therapy, and the duration of antibiotic therapy was significantly shorter (Table 3). In the SDD-treated group, the mean cost of systemic antibiotics, including prophylactic ceftriaxone, was 37% lower than in the control group (Table 5), and the cost of diagnostic procedures for infection was significantly reduced. The calculations of cost of diagnosis of pneumonia that was not present at the time of admission were based on 38 episodes in the treated group and 82 episodes in the control group. There was a 21% reduction of the total cost per survivor in the SDD-treated group.

View larger version (12K): [in this window] [in a new window]   Figure 3.   Comparison of Kaplan-Meier estimates of survivors requiring ventilation at third week of ICU stay (p = 0.006 by two-sided log-rank test). SDD = selective decontamination of the digestive tract.

Mortality

ICU mortality was 38.9% (51 patients) in the SDD-treated group and 47.1% (66 patients) in the control group (p = 0.57 by the log-rank test). APACHE II score on admission was the only independent, statistically significant predictor of mortality (p = 0.0001). All other examined covariates were not independent predictors of mortality, with p values above 0.05.

Microbiology

Figure 4 shows the impact of SDD on the prevalence of gram-negative microorganisms. Baseline figures are comparable, at about 50%, and the carriage rate decreased significantly in the treated group, to 23.9% (p = 0.001) and to 13.1% of patients on Days 3 and 7, respectively, and was significantly lower throughout the study than in the placebo-control group. The prevalence of aerobic gram-negative bacilli in the oropharynx and rectum of patients undergoing SDD was significantly reduced during the study, from 30.9% to 11.4% on Day 3 (p = 0.002), and from 34% to 11.5% on Day 7 (p = 0.003), respectively, and always remained significantly lower than in the control group at both of these anatomic sites. Colonization of the lower airway with gram-negative microorganisms was significantly lower in treated patients than in controls (Table 6). A gram-negative bacillus was identified in tracheal aspirate on an average of every 22 d of intubation (45 per 1,000 ventilator-days) in decontaminated patients, and every 8.4 d (119 per 1,000 ventilator days) in the control group (p < 0.001).

View larger version (11K): [in this window] [in a new window]   Figure 4.   Prevalence of aerobic gram-negative bacilli (AGNB) at all sites (oropharynx, trachea, stomach, and rectum). SDD = selective decontamination of the digestive tract.

Baseline levels of gram-positive cocci (Figure 5) were comparable in the treatment and control groups, but in decontaminated patients the prevalence increased significantly over the study period. The level of carriage of MRSA, coagulase-negative staphylococci, and enterococci was significantly higher in the SDD-treated group (p < 0.001, individually, for each microorganism), whereas methicillin-sensitive S. aureus was carried in a similar proportion in both groups.

View larger version (11K): [in this window] [in a new window]   Figure 5.   Prevalence of gram-positive cocci (GPC), including methicillin-sensitive and methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, and enterococci, at all sites (oropharynx, trachea, stomach, and rectum). SDD = selective decontamination of the digestive tract.

The incidence of MRSA was 27.6% during the study itself and 8% during the follow-up period. The median and mean times of index cultures were identical during each of the two periods. The mean number of gram-positive cocci cultured from all four sampling sites decreased from 547 per 1,000 ventilator-days to 73 per 1,000 ventilator-days.

Adverse Effects

No adverse effects were attributed to the study preparations.

	DISCUSSION

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The principal finding of this randomized double-blind study was that routine SDD reduces both the rate of VAP and the costs of caring for intubated, mechanically ventilated, critically ill patients. Although mortality was not significantly affected by SDD, the sample size of this multicenter trial, performed in a general ICU setting, was not sufficient to permit detection of a significant difference with SDD (12, 22).

Infection rates mainly reflect severity of underlying disease (23). For example, a randomized French trial of SDD found a 9% infection rate of the lower airways in control patients with a low severity score, of whom less than 60% required ventilation (24). In contrast, the lower-airway infection rate was more than 90% in a Dutch trial of SDD enrolling only ventilated patients with an APACHE II score above 14 (25). The category of ICU (i.e., medical, surgical, trauma) constitutes another factor influencing the risk of infection. Medical patients, who are in general older and more often suffering from chronic debilitating diseases, are thought to be at higher risk than surgical and trauma patients (1, 6). Although length of ICU stay and days of mechanical ventilation again reflect the severity of underlying disease, a change in denominator from a patient-based to a device-associated infection rate is thought to facilitate meaningful comparisons among trials of SDD (26, 27). Among all randomized SDD trials so far reported, the mean APACHE II score of 26.6 in our trial is the highest, suggesting that ours were a critically ill subset of ICU patients. Moreover, more than 70% were medical patients. In our control group, the overall infection rate, the percentage of patients developing secondary pneumonia, and the median rate of VAP were 50%, 32%, and 17.3 per 1,000 ventilator-days, respectively. These figures are similar to those reported for comparable patient populations from Spain (1), Europe (3, 4), and the United States (2, 5, 26). The use of SDD, as described in this protocol, was highly effective. The overall infection rate, secondary-pneumonia rate, and number of pneumonias per 1,000 ventilator-days were 25%, 10%, and 8.5 pneumonias per 1,000 ventilator-days (p < 0.005). Moreover, our data show that the chance of critically ill ICU patients with a mean APACHE II score of 26.6 of remaining free of pneumonia after 3 wk of ventilation is significantly higher with SDD than with the traditional approach. Our data are consistent with four recent metaanalyses (12, 22). In addition, a significant reduction in ventilator-days for patients who underwent SDD and survived was observed in this multicenter study.

The substantial impact of SDD on infectious morbidity in critically ill ICU patients in this trial was associated with a lower total treatment cost. Incremental analysis was therefore not applicable (28). A significant 37% reduction of systemic antibiotic cost was observed for decontaminated patients, which is similar to findings in other studies (29). However, because more than 90% of the mean total costs in both study groups were fixed, the savings and increased cost-effectiveness associated with SDD in the present study were mainly a function of reduction of length of stay (33). The cost of SDD (32, 34) can be substantially reduced if generic antibiotic powders instead of commercial preparations are used, if preparations for SDD are manufactured in the hospital pharmacy, and if gentamicin is used instead of tobramycin. Although in vitro data show a relatively higher degree of inactivation of gentamicin than of tobramycin by feces (35), the combination with polymyxin E proved to be effective in vivo in this and previous trials (29, 36).

The combined finding of more survivors at lower cost generates the attractive economic message that it is cheaper to produce a survivor in an ICU by implementing SDD than it is with a traditional approach. There were more survivors in the SDD-treated group in our study (80 of 131; 61%) than in the control group (74 of 140; 53%). Because of the limited sample size, the difference in mortality (p = 0.57) was not significant. A recent metaanalysis, including 5,727 patients in 33 randomized trials, found a significant reduction of mortality in the subset of 3,581 patients in 16 trials who were treated with the full protocol (22). In addition, the findings in the present study support a very recent analysis which found that the more ill the ICU patient (APACHE II score: 26.6), the more effective is SDD in reducing mortality (37). The greater number of survivors, even if not significant, supported the favorable cost- effectiveness findings previously reported by Rocha (30) and Korinek (31). Our findings are also consistent with the findings in other trials (1) that the severity of underlying disease determines outcome. However, our study failed to show that pneumonia independently contributes to ICU mortality (6).

Surveillance samples from the throat and rectum are taken with the purpose of detecting the carrier state. Carriage of aerobic gram-negative bacilli (AGNB) is abnormal and reflects severity of underlying disease. Two recent French studies showed that severity of illness and infection on admission were two independent risk factors for the development of abnormal bacterial carriage (38, 39). Half of our mainly medical population carried AGNB on entering the present trial, supporting the observation that our study population belonged to a severely ill subset of patients. Apart from their value for identification of patients at high risk for secondary infection with an abnormal carrier state of AGNB, surveillance cultures are an integral part of the SDD strategy (27) for three reasons: (1) to monitor compliance with and efficacy of SDD; (2) to distinguish exogenous (without previous carriage) from endogenous infections; and (3) to detect antimicrobial resistance in an early stage.

AGNB, methicillin-sensitive S. aureus, and yeasts are the target microorganisms of SDD. The effective eradication of AGNB carriage reflects good compliance. By design, SDD will not affect the indigenous flora, including coagulase-negative staphylococci and enterococci. Inevitably, SDD will exert selective pressure on potentially pathogenic microorganisms (PPM) such as MRSA that are intrinsically resistant to polymyxin E, gentamicin, and amphotericin B, and cause the observed associated increase in colonization with coagulase-negative staphylococci, enterococci, and MRSA. The topical antimicrobial agents used in our study were carefully chosen for their propensity to leave largely undisturbed the indigenous flora, which are thought to play a role in the resistance to colonization by PPM (40). However, although coagulase-negative staphylococci and enterococci rarely cause lower airway infections, MRSA is a serious PPM known to be responsible for infections of both endogenous and exogenous origin. Although of no clinical relevance in the present study, MRSA was significantly more prevalent in the SDD-treated group. The 14-mo follow-up period did not show an increase in colonization with MRSA, but this finding requires confirmation after prolonged use of SDD. Some studies of SDD found endemic MRSA during their prevention phases (41). This is a substantial (4) and complex issue, and requires further evaluation (47).

The emergence of microorganisms resistant to the antimicrobials used for SDD could reduce the long-term effectiveness of SDD in routine clinical practice. The traditional experience is that the extensive use of antimicrobials inevitably leads to resistance. However, there is a fundamental difference between the conventional use of parenteral agents only (48) and the full SDD protocol, combining short-term systemic antibiotics with long-term nonabsorbable antibiotics. Resistant strains generally emerge first in the gut, following overgrowth. These resistant strains have been successfully abolished by polymyxin E and gentamicin. Resistance developing in a patient who is free of PPM is thought to be unlikely. University hospitals (11, 46) that have used SDD for more than 10 yr have not detected an increase in the frequency of such resistant infections. The significant reduction of systemic antibiotic usage found in the present and other studies (29) could be a contributory factor in controlling the incidence of resistance among both gram-negative and gram-positive microorganisms. The reduced antibiotic usage may be partly responsible for the absence of resistant gram-negative bacilli in previous trials of SDD and in long-term follow-up studies (46, 49), and for the absence of an increase in colonization or infection with MRSA during observational periods by Hammond and colleagues (46) as well as in the present trial.

In conclusion, we found that SDD was highly effective in preventing secondary infections in a mixed population of ventilated patients at high risk for infection. The associated significant reductions in use of systemic antibiotic therapy and length of stay account for a lower cost in the SDD-treated group of patients in the study. We observed no resistant gram-negative bacilli or superinfections following failures of SDD. However, colonization, although not infection, with intrinsically resistant gram-positive cocci was increased in the treated group, and close microbiologic surveillance is therefore mandatory with the use of SDD.