Original Article
A Controlled Trial in Intensive Care Units of Selective Decontamination of the Digestive Tract with Nonabsorbable Antibiotics
N Engl J Med 1992; 326:594-599February 27, 1992
- Abstract
- Abstract
Background.
Selective decontamination of the digestive tract with topical nonabsorbable antibiotics has been reported to prevent nosocomial infections in patients receiving mechanical ventilation, and the procedure is used widely in Europe. However, it is unclear whether selective decontamination improves survival.
Methods.
We conducted a randomized, double-blind multicenter study in which 445 patients receiving mechanical ventilation in 15 intensive care units were given either prophylactic nonabsorbable antibiotics (n = 220) or a placebo (n = 225). Topical antibiotics (tobramycin, colistin sulfate, and amphotericin B) or placebo was administered through a nasogastric tube and applied to the oropharynx throughout the period of ventilation. The main end points were the mortality rate in the intensive care unit and the mortality rate within 60 days of randomization.
Results.
A total of 142 patients died in the intensive care unit: 75 (34 percent) in the treatment group and 67 (30 percent) in the placebo group (P = 0.37). Mortality within 60 days of randomization was similar in the two groups (P = 0.40), even after adjustment for factors that were either unbalanced or individually predictive of survival in the two groups (P = 0.70). Pneumonia developed in 59 patients (13 percent) in the intensive care unit within 30 days of enrollment in the study (33 in the placebo group and 26 in the treatment group, P = 0.42). Pneumonia acquired in the intensive care unit and due to gramnegative bacilli was less frequent (P = 0.01) in the treatment group than in the placebo group. The total charges for antibiotics were 2.2 times higher in the treatment group.
Conclusions.
Selective decontamination of the digestive tract does not improve survival among patients receiving mechanical ventilation in the intensive care unit, although it substantially increases the cost of their care. (N Engl J Med 1992;326:594–9.)
Media in This Article
Figure 1
Overall Survival in the Two Groups.Figure 2
Comparison of the Length of Time to the Occurrence of Pneumonia Acquired in the Intensive Care Unit during the First 30 Days after Randomization in the 225 Patients Who Received Placebo and the 220 Patients Who Received Prophylactic Non-absorbable Antibiotics.Article Activity
- Article
INFECTIONS acquired in the intensive care unit are a major cause of death in hospitalized patients. Infection is also the main cause of multiple-organ failure, which usually ends in death.1 , 2 Recent reports have suggested that selective decontamination of the digestive tract can reduce the incidence of nosocomial infections in patients in the intensive care unit. The rationale for this approach is the well-documented observation that colonization of the gastrointestinal tract by gram-negative bacilli frequently occurs before the onset of infection.3 4 5 Decontamination could also help prevent the failure of multiple organ systems by reducing the bacterial load in the gastrointestinal tract and the transfer of endotoxin to the bloodstream.6 The most impressive results with decontamination have been achieved in patients who received mechanical ventilation after trauma; in these patients a combination of topical antibiotics and a short course of systemic antibiotics significantly reduced the incidence of nosocomial respiratory tract infections.7 Several other investigators have reported similar beneficial effects with8 9 10 11 12 13 14 15 16 and without17 18 19 20 the use of additional systemic antibiotics. The inferences to be drawn from these data are controversial for a number of reasons: the treatment regimens differed from one study to another, and all but two trials18 , 19 were not blinded. All were conducted in single centers, and some included only a small number of patients. None of the studies explicitly demonstrated a beneficial effect on a major index of outcome, such as mortality. Despite this, the prophylactic use of nonabsorbable antibiotics has gained wide acceptance in Europe. This trial was undertaken to study the efficacy of selective decontamination of the digestive tract with topical antibiotics in patients receiving mechanical ventilation.
Methods
Study Design
This was a prospective, randomized, double-blind, placebo-controlled, multicenter study of topical antibiotics in patients receiving mechanical ventilation. The main end points were the overall survival in the intensive care unit and the overall survival within 60 days of randomization. We also studied the acquisition of pulmonary infections in the intensive care unit by day 30 and the types of pathogens involved, the duration of mechanical ventilation, the length of stay in the intensive care unit, and the charges for antibiotic treatment. Patients with conditions in which the probability of survival and the duration of mechanical ventilation are strongly related to status on admission were excluded.
Study Organization
Fifteen medical intensive care units in 15 referral hospitals participated in the study. All aspects of the protocol were approved by two institutional review committees on human investigation. Written informed consent was obtained from the patients or their closest relatives. The study was monitored by a coordinating center (Institut National de la Santé et de la Recherche Médicale U13, Paris).
Eligibility Criteria
Patients older than 15 years who required mechanical ventilation were eligible for the trial provided that intubation was performed no more than 48 hours before randomization. Patients were excluded from the study for any of the following reasons: mechanical ventilation was discontinued less than 24 hours after a scheduled operation, mechanical ventilation was begun after an overdose of sedative drugs or alcohol, there was neutropenia (<500 polymorphonuclear cells per cubic millimeter), the simplified acute physiologic score21 was more than 24 or the Glasgow coma score was less than 4, a decision was made that only palliative treatment was to be used, or there was chronic degenerative central nervous system disease or a spinal-cord injury above the level of C-4. Patients were also excluded if they had chronic or acute severe enteropathy, were pregnant, were participating in another ongoing clinical trial, or refused to give written informed consent.
Randomization and Treatment Regimens
Within 48 hours of the start of mechanical ventilation, patients were assigned to receive either topical antibiotics or placebo, according to a randomized list of consecutive treatment assignments. Randomization was performed separately in each center. Identical drug and placebo capsules were manufactured by the Pharmacie Centrale des Hôpitaux de Paris and dispensed by each hospital's pharmacist. The oropharyngeal cavity was carefully cleaned with isotonic saline before the antibiotic or placebo was applied. Four times daily, 3 g of a sticky gel containing the placebo (nonabsorbable calcium salt) or a combination of colistin sulfate, tobramycin, and amphotericin B, each at a concentration of 2 percent, was applied to the oropharyngeal cavity. At the same time, the solutions of antibiotics (or placebo) were administered through a nasogastric tube at doses of 100 mg of colistin sulfate, 80 mg of tobramycin, and 100 mg of amphotericin B. One milliliter of the suspension was injected into each nostril. Topical antibiotics and placebo were administered throughout the period of ventilation. Gels and suspensions were made from the powders contained in the capsules. To ensure the blinded nature of the observations, antibiotics and placebo powders were made in a variety of colors. Samples for bacteriologic analysis were taken only when infection was suspected. Serum levels of tobramycin were measured twice a week to avoid renal toxicity; the results were revealed by the laboratory only if levels exceeded 2.5 mmol per liter, in which case the treatment was discontinued. Prophylactic systemic antibiotics were given only if they were required for surgical procedures.
Data Collection and Definitions
The severity of the acute illness on admission to the intensive care unit was assessed by means of the simplified acute physiologic score.21 Acute organ-system failure was diagnosed according to the definition of Knaus et al.22 at the time of enrollment in the study and every seven days thereafter. Follow-up continued until patients were sent home from the hospital. Patients who were sent home were considered to be alive on day 60 after enrollment in the study. The type and dosage of antibiotic therapy administered were scrupulously recorded throughout each patient's stay in the intensive care unit, and treatment was subdivided into that given for respiratory tract infections acquired in the intensive care unit and that given for other infections. The charges for antibiotics administered to each patient were calculated.
Respiratory tract infections diagnosed within 48 hours of admission to the intensive care unit were classified as primary. All subsequent episodes were classified as having been acquired in the intensive care unit. Pneumonia was defined by the presence of all of the following: purulent tracheal aspirate, fever (temperature, >38.5°C), and peripheral leukocytosis (>10,000 leukocytes per cubic millimeter) associated with a new and persistent infiltrate on the chest film. A fiberoptic bronchoscopy, with specimens obtained by brushing, was recommended but was not mandatory. bacteriologie documentation was not required for the diagnosis of nosocomial pneumonia because the presence of antibiotics in the bronchial tree can interfere with the accuracy of cultures.17 , 23 Tracheobronchitis was defined by the presence of clinical signs and the absence of pulmonary infiltrates on the chest film.
Statistical Analysis
The sample size (600 patients) was calculated to allow the detection of a 25 percent reduction in mortality among the treated patients on day 60, assuming a mortality rate of 40 percent in the placebo group, an alpha error of 0.05, and a beta error of 0.20. An interim analysis was planned after the treatment of 200 patients and after the treatment of 400 patients. These analyses were performed by the coordinating center, and the investigators were unaware of the results. Enrollment was closed after the second interim analysis because the goals of the study had been achieved. The analysis was made on an intention-to-treat basis. Time-censored criteria were estimated with the Kaplan–Meier method and compared with the log-rank test.24 The comparative terms of overall survival and the length of time to the onset of nosocomial pneumonia were adjusted with the semiparametric Cox model.25 The duration of mechanical ventilation was analyzed, and the patients who died were censored. Continuous variables were compared with the nonparametric Mann—Whitney test. Qualitative variables were compared with the chi-square test, with correction for continuity when appropriate. All tests of significance were two-tailed. A P value of 0.05 or less was considered to indicate statistical significance.
Results
Recruitment
Between February 10 and June 30, 1990, 2703 patients were admitted to the 15 participating intensive care units, and 1437 (53 percent) of these patients required mechanical ventilation. Of the 1437 patients, 966 did not meet the entry criteria. The main reasons for exclusion were withdrawal of mechanical ventilation less than 24 hours after a scheduled operation (29 percent), a need for mechanical ventilation because of sedative or alcohol overdose (26 percent), a simplified acute physiologic score of more than 24 or a Glasgow coma score of less than 4 (16 percent), initiation of mechanical ventilation more than 48 hours before enrollment (11 percent), or the presence of neutropenia (4 percent). In addition, 26 eligible patients were not randomized for the following reasons: 7 died before randomization, 7 were unable to receive oropharyngeal or gastric antibiotics, and 12 were not enrolled within 48 hours of the initiation of mechanical ventilation. When recruitment was complete, a total of 445 patients had been randomly assigned to one of the two groups — 225 to the placebo group and 220 to the topical-decontamination group (treatment group).
Characteristics of the Patients
The demographic and base-line characteristics of the 445 patients are shown in Table 1Table 1
Characteristics of the 445 Study Patients in the Two Groups.*. There was a higher proportion of males in the treatment group. The two groups were comparable in terms of the number and types of underlying diseases and diagnostic categories on admission. The simplified acute physiologic score was higher in the patients assigned to receive prophylactic nonabsorbable antibiotics, and more patients in this group had failure of more than one organ system at enrollment. Fewer patients in the treatment group than in the placebo group had received one or more systemic antibiotics before randomization. The two groups were similar with respect to adjunctive treatment and prophylaxis for stress ulcers during the stay in the intensive care unit (Table 1).Discontinuation and Safety of Treatment
Topical treatment had to be discontinued before weaning from mechanical ventilation in 31 patients (15 receiving placebo and 16 receiving nonabsorbable antibiotics). In 28 cases, this was because of discomfort due to the oropharyngeal gel. In the three other patients, all of whom had renal impairment, treatment with antibiotics was interrupted because serum levels of tobramycin exceeded 2.5 mmol per liter. The average (±SD) length of treatment was 11.7±12.2 days in the placebo group and 10.5±8.2 days in the treatment group.
Survival
Of the 445 patients, 170 died in the hospital: 88 in the treatment group and 82 in the placebo group. One hundred forty-two of these deaths occurred in the intensive care unit: 75 in the treatment group and 67 in the placebo group (P = 0.37 by the chi-square test). Forty-one patients were discharged from the hospital more than 60 days after entering the study. Two hundred thirty-four patients were discharged within 60 days of entering the study: 104 in the treatment group and 130 in the placebo group. One hundred fifty-eight deaths occurred within 60 days of enrollment: 82 in the treatment group and 76 in the placebo group (P = 0.40 by the log-rank test) (Fig. 1Figure 1
Overall Survival in the Two Groups.). The 15-day and 30-day survival rates were 80 percent and 74 percent, respectively, in the placebo group and 76 percent and 66 percent in the treatment group. The estimated risk of death was 1.14 times higher in the treatment group (95 percent confidence interval, 0.87 to 1.67). The comparison of survival in the groups was adjusted for 13 base-line variables that were either unbalanced between the two groups or individually predictive of survival (Table 2Table 2
Prognostic Value of Several Characteristics Determined at Admission.*). The variables at the time of admission that were predictive of survival were age, the number of underlying diseases, admission from other wards, the simplified acute physiologic score, the number of organ-system failures, and the presence of infection with the human immunodeficiency virus, cancer, trauma, chronic respiratory failure, sepsis, and pneumonia. The adjusted comparison gave similar overall survival estimates in the two groups (P = 0.70 by the log-rank test), with a risk of death 1.06 times higher in the placebo group (95 percent confidence interval, 0.72 to 1.42).Organ-System Failure
The number of organ-system failures that occurred in the intensive care unit was calculated each week from entry into the study until discharge or death. This number did not change between entry and death for 118 of the 142 patients who died in the intensive care unit (60 in the control group and 58 in the treatment group); it decreased for 2 patients in each group and increased for 5 patients in the placebo group and 15 in the treatment group.
Respiratory Tract Infection
Primary pneumonia occurred in 14 patients (9 in the placebo group and 5 in the treatment group; P = 0.30 by the chi-square test). Pneumonia developed within 30 days of enrollment in 59 of the 445 patients (13 percent; 33 in the placebo group and 26 in the decontamination group; P = 0.42 by the two-sided log-rank test) (Fig. 2Figure 2
Comparison of the Length of Time to the Occurrence of Pneumonia Acquired in the Intensive Care Unit during the First 30 Days after Randomization in the 225 Patients Who Received Placebo and the 220 Patients Who Received Prophylactic Non-absorbable Antibiotics.). The Kaplan–Meier estimates at 15 days were 8.2±1.97 percent (mean ±SE; the standard error was estimated with Greenwood's formula) in the treatment group as compared with 12.7±2.3 percent in the placebo group. The comparison of the time to the occurrence of pneumonia was also adjusted for seven base-line variables that were unequal in the two groups or predictive at the 10 percent level of the occurrence of pneumonia; the latter included the presence of underlying disease, the need for antibiotic therapy, and admission for trauma. The adjustment for these variables did not change the estimated risk of pneumonia significantly (P = 0.32 by the log-rank test). The causative organisms were isolated from specimens obtained by bronchial brushing during bronchoscopy in 33 of the 59 patients whose first episode of pneumonia occurred in the intensive care unit. In a further 21 cases, the pathogens were isolated from either bronchial secretions obtained with a distally wedged catheter (n = 16) or tracheal aspirates (n = 5). No pathogen was isolated in the remaining five patients. "Gram-negative bacilli were significantly less common in patients receiving prophylactic nonabsorbable antibiotics than in those receiving placebo (P = 0.01 by the chi-square test). However, a trend toward an increase in the rate of staphylococcal pneumonia was observed in the treatment group (P = 0.06 by the chi-square test) (Table 3Table 3
Causes of the First Episode of Pneumonia Acquired in the Intensive Care Unit in the Two Groups.). Five patients in the placebo group had a second episode of pneumonia in the intensive care unit, and all cases were due to gram-negative bacilli. Nine other patients (six in the placebo group and three in the treatment group) received antibiotics for tracheobronchitis.Duration of Mechanical Ventilation and Stay in the Intensive Care Unit
A Kaplan–Meier estimate of the duration of mechanical ventilation revealed no difference between the two groups (P = 0.70 by the log-rank test). The mean length of stay in the intensive care unit was also similar in the groups: 19±16 days in the placebo group as compared with 18± 19 days in the treatment group.
Charges for Antibiotic Treatment
The daily charge for the antibiotics used for selective decontamination of the digestive tract was $66.50 per patient (according to information provided by the Pharmacie Centrale des Hôpitaux de Paris, and assuming a conversion rate of 5.5 French francs to the U.S. dollar), and the mean total charge (±SD) per patient was $694±544. There was no significant difference between the two groups in the mean total charge for systemic antibiotics during the stay in the intensive care unit ($577±1,051 in the placebo group and $593±1,015 in the treatment group). The mean charge per patient for the systemic antibiotics used to treat all episodes of respiratory tract infections acquired in the intensive care unit (44 in the placebo group and 29 in the treatment group) was higher in the placebo group ($158±691 vs. $53±202), but the difference was not significant (P = 0.21). The mean total charge for antibiotics (topical and systemic) was 2.2 times higher in the treatment group than in the placebo group ($1,287±1,368 vs. $577±1,051; P<0.001).
Discussion
Selective decontamination of the digestive tract with oral nonabsorbable antibiotics has been widely used to prevent infection in patients with neutropenia.26 Stoutenbeek et al.7 reported that the use of such a regimen in patients in the intensive care unit produced a six-fold reduction in the incidence of nosocomial infections in two successive groups of patients with trauma. Numerous investigators have confirmed this beneficial effect on nosocomial infection rates.8 9 10 11 12 13 14 15 16 17 18 19 20 However, the results of controlled trials have been much less consistent with regard to the mortality rate; only one study has shown a significant improvement in survival.13 Although infection-related deaths were examined separately in three trials and found to be significantly reduced in the group receiving prophylactic nonabsorbable antibiotics, none of these studies were blinded and the authors did not list their selection criteria.9 , 13 , 17 Similarly, in a large study Ledingham et al. reported improved survival among a subgroup of 25 patients with trauma,8 whereas Godard et al.18 found that the mortality rate was lower in treated patients with disease-severity scores in the middle range. These results were, however, obtained in groups determined retrospectively, thus precluding any assignment of statistical significance. The results of our study, which were adjusted to avoid the possibility of bias due to differences in prognostic factors, showed similar overall mortality rates in the treatment and placebo groups, with no significant differences in any specific subgroup. In previous studies, a large proportion of patients were referred after trauma or surgical procedures, whereas most (72 percent) of our patients were admitted for preexisting conditions. The presence of underlying disease and the reason for admission to the intensive care unit may have had a great influence on outcome. Thus, our findings do not completely rule out the possible efficacy of decontamination of the gut in patients referred after trauma or surgery.
Prognosis was recently found to be strongly related to the number of organ-system failures.27 The failure of multiple organs may involve the transfer of intestinal endotoxin to the bloodstream.6 Selective decontamination of the digestive tract may reduce the production of endotoxin by diminishing gut colonization by gram-negative bacilli. Van Saene et al. reduced the pool of fecal endotoxin in healthy volunteers undergoing decontamination of the gut.28 However, in our trial, topical decontamination did not reduce the occurrence of multiple-organ failures.
Pneumonia acquired in the intensive care unit is another important cause of death29 30 31; the incidence of pneumonia in our placebo group was low (15 percent), and the mortality rates were similar in the two groups. The rate of nosocomial pneumonia varies depending on the type of hospital unit studied and the presence of underlying disease.29 Differences in diagnostic criteria for nosocomial pneumonia may also explain why its rate in most decontamination trials was higher (>40 percent) than in our trial.7 , 9 , 11 , 16 , 17 Diagnosis was blinded in our study and most often included the results of cultures of specimens obtained by bronchial brushing or catheterization. Two recent studies that also used protected specimens obtained by bronchial brushing18 , 30 reported rates of pneumonia in patients receiving mechanical ventilation in the intensive care unit that were similar to the rate that we observed. Pneumonia should not be diagnosed solely on the basis of culture results, since the presence of antibiotics in the bronchial tree after decontamination17 , 23 may lead to an underestimation of the actual incidence of disease.
Although the overall incidence of pneumonia acquired in the intensive care unit was similar in the treatment and placebo groups, the number of respiratory tract infections caused by gram-negative bacilli was lower in the treated patients. In contrast, staphylococci were isolated in a higher proportion (60 percent) of patients with pneumonia in the treatment group, a finding that is in keeping with reports of increased oropharyngeal colonization by staphylococci after selective decontamination of the digestive tract.10 11 12
Although selective decontamination of the digestive tract originally included treatment with intravenous cefotaxime to prevent primary pneumonia due to indigenous flora,7 more recent studies17 18 19 20 have reported beneficial effects with the use of the topical regimen alone. Few cases of primary pneumonia occurred in our trial, and 72 percent of the patients were receiving systemic antibiotics at the time of randomization, so the addition of cefotaxime would probably not have substantially changed our results.
One might expect that lowering the incidence of sepsis would reduce the need for curative systemic antibiotic treatment, but there was no substantial difference between the two groups in terms of the total charges for systemic antibiotics during the stay in the intensive care unit. On the contrary, topical decontamination was substantially more expensive. The antibiotics used to treat respiratory tract infections acquired in the intensive care unit in the patients in the treatment group cost less than those used in the placebo group, but this reduction was not significant. In two nonblinded trials, the same amounts of systemic antibiotics were administered to the treatment and control groups9 , 13; in the trial by Ledingham et al., there was a 20 percent reduction in the use of systemic agents, including cefotaxime, in the treatment group as compared with the placebo group.8
We conclude that although selective decontamination of the digestive tract with topical antibiotics can prevent pneumonia due to gram-negative bacilli in the intensive care unit, the overall benefit is limited and is achieved at an increase in cost. The results of this study do not support the routine use of topical antibiotics for selective decontamination in patients in an intensive care unit.
Address reprint requests to Dr. Gastinne at the Service de Réanimation, Hôpital Universitaire Dupuytren, 2 ave. Alexis-Carrel, 87042 Limoges CEDEX, France.
Supported in pan by grants from Lilly France and the Commission de la Recherche Clinique de l'Assistance Publique Hôpitaux de Paris.
We are indebted to the nursing staff of all the intensive care units, who made this study possible; to N. Sauteret, C. Lecocq, and C. Balagaert for assistance with the preparation of the manuscript; and to P. Jelazko and D. Young for technical assistance.
Source Information
* The French Study Group on Selective Decontamination of the Digestive Tract included the following: C. Richard. M.D., J. Depret, M.D., A.M. Taburet, Ph.D., J.M. Boles, M.D., B. Garo, M.D., A. Primualt, Ph.D., J.P. Bedos, M.D., A. Certain, Ph.D., D. Dreyfuss, M.D., K. Djedaini, M.D., C. Giraud, Ph.D., R. Boiteau, M.D., A. Tenaillon, M.D., M. Willoquet, Ph.D., B. Clair, M.D., P. Moine, M.D., I. Jolivet, Ph.D., F.P. Savy, M.D., F. Carron, Ph.D., C. Martin, M.D., L. Papazian, M.D., C. Penot-Ragon, Ph.D., P. Damas, M.D., M. Delporte, Ph.D., D. Villers, M.D., C. Bonin, M.D., F. Vincent-Ballereau, Ph.D., C. Camus, M.D., Y. Letulzo, M.D., M. Javaudin, Ph.D., B. Guidet, M.D., G. Offenstadt, M.D., A. Daguenel, Ph.D., F. Fraisse, M.D., G. Moret, M.D., M. Talbert, Ph.D., B. Misset, M.D., J. Carlet, M.D., J. Huchet, Ph.D., G. Nitenberg, M.D., B. Leclercq, M.D., and J. Alarcon, Ph.D.
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