THERAPY

Criteria abstracted from The Users' Guides to the Medical Literature series in JAMA

Pediatr Crit Care Med. 2007 8(5):452-8.[abstract]

Review posted December 01, 2008

I. What is being studied?:

The importance of recognizing nosocomial infections as a leading cause of significant morbidity and mortality in the critically ill patient population is addressed in this study. Despite improvements in aseptic technique and directed antibiotic therapies, the authors suggest that nosocomial infections are still a significant cause for concern. In the literature, probiotics have been lauded as potential immunomodulator adjunct therapy and as facilitators in reducing bacterial translocation. Such said properties, and reported data of potential immunoprotective benefit outside of the gastrointestinal tract, have prompted the authors to further study the specific effects of probiotics on nosocomial infections in the pediatric ICU.

1. The study objective:

   To evaluate the efficacy of consistent probiotic use in decreasing the rates of nosocomial infections in the critically ill pediatric population. In particular, nosocomial infections involving the bloodstream, urinary tract, upper and lower respiratory tracts were studied.

2. The study design:

   This was a prospective, double-blinded, randomized, placebo-controlled trial that took place in a 16 bed medical and surgical PICU that is affiliated with a university children's hospital. Study length: April-Dec 2004.

3. The patients included:

   All patients admitted to the intensive care unit were evaluated upon admission to participate. There were no age or underlying medical conditions limits. Use of inotropic support did not preclude a patient from being included in this study.

4. The patients excluded:

   Those patients who were suspected or confirmed to have a gastrointestinal bowel perforation, mechanical GI obstruction, or an absolute neutrophil count ≤ 0.5 x 10 ⁹ cells/L were excluded from the study. Moreover, any patient who had been previously admitted at another institution for > 72 hours or who was felt by the admitting attending physician to be unable to tolerate the enteral volumes needed for this study were also excluded. Finally, any patient who was already enrolled in another clinical trial, had already had probiotic use within the week prior to the study, or who had lack of parental presence and or consent were excluded.

5. The interventions compared:

   Patients received either one capsule of Lactobacillus rhamnosus GG in the experimental group or one placebo capsule of insulin once a day in the control group Participants continued to receive treatment or placebo until discharge from the hospital, individual request to withdraw from study, or death. Any patient who missed 2+ doses of Lactobacillus was not restarted.

6. The outcomes evaluated:

   Blood cultures, radiographic studies, tracheal aspirates and or bronchoalveolar lavage, viral antigen studies and or cultures, and urine cultures were obtained per attending discretion. Infections (i.e. pneumonia, blood stream infection, tracheobronchitis and UTI) noted after 48 hours of study entry, based on the CDC and National Nosocomial Infection Surveillance system's guidelines, were included as data if two independent study investigators confirmed met infection criteria as set by the CDC.

II. Are the results of the study valid?

      Primary questions:

1. Was the assignment of patients to treatments randomized?

   Yes. The hospital's Investigational Drug Services randomized patients in blocks of four.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

   Yes. Six patients died, two withdrew from the study, and one had missed multiple doses and was not allowed to continue with the protocol. All patients were included in the final intent-to-treat analysis.

Was followup complete?

No, daily clinical data was collected prospectively for 48 hrs after discharge or transfer. Data collection consisted of electronic medical record surveillance of final culture results or readmissions to the hospital or affiliated emergency department or clinic visits. Some follow-up was obtained if parents voluntarily contacted the group. Otherwise, families were not contacted directly for phone follow-up, so it is conceivable that a patient could have been lost to another facility not affiliated with this institution.

Were patients analyzed in the groups to which they were randomized?

Yes. All patients were included in the final intent-to-treat analysis and there were no crossovers between groups.

      Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

   Yes, this was a double-blinded study. The capsules were indistinguishable in appearance from one another. The investigators and clinical team were not aware of the group assignments.

4. Were the groups similar at the start of the trial?

   It is uncertain as to whether both groups were truly similar at the start of the trial, as the severity of their critical illness was not scored initially. Both groups, however, were fairly well matched for age, gender, and admission diagnoses.

5. Aside from the experimental intervention, were the groups treated equally?

   Uncertain. Only limited information is provided regarding other aspects of the patients' care, and there was no mention of general management algorithms, such a mechanical ventilation or nutrition.

III. What were the results?

1. How large was the treatment effect?

   In the treatment group, 6 patients developed infections with a total number of 11 infections for that group. In the control group, 3 patients developed infections with a total number of 4 infections for that group. There were, however, four deaths in the control group versus two deaths in the treatment group. Of the total number of infections for both, 40% were Gram positives, 40% were Gram negatives, and 20% were Candida sp. With a control event rate of 0.10 and experimental event rate of 0.19 (analyzing by number of infected patients, not the total number of infections), the absolute risk increase is 9% and number needed to harm is 11. Given this interim analysis of the data and recent reports in the literature that have raised safety concerns of L. rhamnosus strain GG, this study was terminated early.

2. How precise was the estimate of the treatment effect?

   No, the result was not precise. The authors report a relative risk of developing nosocomial infections in the treatment group = 1.94 with a very wide 95%CI of 0.53-7.04. Based on the CI, there is a chance that the probiotic therapy could reduce the risk of infection to as low as half, or increase the risk as much as 7 fold comparing with placebo. The wide confidence interval likely reflects the small sample size. Of note, the mean number of infections in treatment and control groups was equal to 1.83 and 1.33, respectively, with a difference of 0.5 (p = 0.52). The calculated odds ratio for nosocomial infection in the treatment group is 2.16 (CI = 0.53-8.74).

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

   Yes, this study looked at the critically ill pediatric population. The probiotic Lactobacillus rhamnosus GG is commercially available, though not formally approved by the FDA for use.

2. Were all clinically important outcomes considered?

   Not completely, as commercial preparations of probiotic strains are not standardized nor regulated by the FDA. This lack of regulation likely results in variable safety and efficacy profiles for individual products. Furthermore, the optimal dosing of probiotics is unclear and may be dramatically different that what has been used previously in more healthy subjects in the medical arena.

3. Are the likely treatment benefits worth the potential harms and costs?

   Not only did the study fail to show clear benefit, it demonstrated potential (serious) harm. It may also be worth noting that patients on vasopressors were allowed to participate in the study, despite the concern that splanchnic perfusion could be compromised with such infusions. Nevertheless, based on potential risk of the treatment in this study, as well as the accumulated evidence from recent reports, probiotic therapy should be prohibited until a study with excellent validity has proven a large beneficial treatment effect.

Last Updated: December 01, 2008

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