THERAPY

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

Am J Respir Crit Care Med. 2006 173(12):1348-5.[abstract]

Review posted May 19, 2007

1. What is being studied?
   
   
   1. The study objective:
      
      To assess the effect of oral decontamination with chlorhexidine or chlorhexidine /colisitin on ventilator-associated pneumonia (VAP) incidence and time to development of VAP.
      
      
   2. The study design:
      
      Randomized, double-blind, placebo controlled trial with three arms: Chlorhexidine (CHX), Chlorhexidine /Colisitin CHX/COL, and placebo (PLAC)
      
      
   3. The patients included:
      
      385 patients, >18 years old, requiring mechanical ventilation for longer than 48 hours and who were started within 24 hours of being intubated and mechanically ventilated.
      
      
   4. The patients excluded:
      
      Patients were excluded if they were immunocompromised, pregnant, if investigators were unable to physically apply gel because of a patient’s condition, or because they refused.
      
      
   5. The interventions compared:
      
      Oral cleansing using CHX (CHX 2%) vs. CHX/COL (CHX/COL, 2%/2%) vs. a placebo
      
      
   6. The outcomes evaluated:
      
      Development and timing to VAP was the primary outcome measured. Although bronchoscopy is the gold standard for diagnosis, VAP was diagnosed if a patient had presence of a new, persistent or progressive infiltrate on chest radiograph and at least three of four clinical criteria:
      
      (1) Temperature > 38.0 C or < 35.5 C
      
      (2) Leukocytosis and/or left shift or leukopenia
      
      (3) Tracheal aspirate with evidence of purulent material
      
      (4) Positive tracheal aspirate culture after 48 h of mechanical ventilation
      
      VAP was diagnosed by 3 reviewers who examined case report forms. Reviewers were not aware of the treatment modality or the study center. In cases of discrepancy, phone conversations between reviewers were held to discuss diagnosis and reach consensus. Also clinical pulmonary infection scores (CPIS) were calculated daily.
      
      Secondary endpoints included oral colonization with gram-positive and gram-negative microorganisms, endotracheal colonization, length of stay, and all-cause ICU mortality.
      
   
   
2. Are the results of the study valid?
   
   Primary questions:
   
   
   
   1. Was the assignment of patients to treatments randomized?
      
      Yes. A computer randomization scheme was used and it was stratified by site.
      
      
   2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
      
      385 patients were randomized. 5 out of 6 patients were discontinued during the study secondary to non-compliance. 1 patient was discontinued secondary to developing tongue edema which was a presumed adverse reaction . The primary outcome measure was reported as being completed for all 385 patients.
      
      Was follow-up complete?
      
      Yes
      
      Were patients analyzed in the groups to which they were randomized?
      
      Yes. There was no cross-over of patients between groups.
      
      
   Secondary questions:

   
   

   3. Were patients, health workers, and study personnel "blind" to treatment?
      
      Yes. Patients were blinded to the knowledge of whether they were receiving CHX, CHX/COL or placebo. Physicians and staff were blinded to which treatment they were dispensing. Experimental and placebo pastes were tasteless and of similar odor and consistency.
      
      
   4. Were the groups similar at the start of the trial?
      
      Not sure. Although the authors reported that the groups were comparable at baseline, p atients were slightly more dominant male in the placebo groups. In the placebo group there was more infection present, higher number of past medical history of patients with cardiovascular disease and higher admission for postoperative care. Patients in the CHX group had more ulcer prophylaxis (18% in placebo vs. 27% in CHX) which has been associated with an increased rate of VAP. In the CHX/COL group more patients were intubated for a GCS <8 and were admitted for trauma. None of these were reported as being significantly different however.
      
      At the start of the study the three groups were similar in numbers of patients receiving antibiotics prior to the diagnosis of VAP. The proportion of antibiotic days was greatest for the PLAC group and lowest for the CHX/COL group. Other well known factors influencing VAP rates (e.g., minimizing ventilator circuit changes, closed endotracheal suction system) were not mentioned (1).
      
      
   5. Aside from the experimental intervention, were the groups treated equally?
      
      Not sure. Head of bed elevation in all patients, but otherwise, there is no mention of treatment strategy in the study. For instance, ventilator weaning approach was not mentioned. Patients were admitted to ICU for multiple different pathologies which generated different treatment strategies for patients enrolled in the study. The authors did mention that selective digestive decontamination and continuous aspiration of subglottic contents were not performed in any patient.
      
   
   
3. What were the results?
   
   
   
   1. How large was the treatment effect?
      
      VAP was diagnosed in 18 % of PLAC group, 10% in CHX group and 13% in the CHX/COL group. This was not statistically significant, but the timing of diagnosis of VAP was significant. The PLAC group had a significant difference in early onset VAP (defined as onset 48-96 hours) compared to the treatment groups. 13/130 patients in the PLAC group had early onset VAP, compared to 3/127 on CHX group. (P=<0.001). 9/127 in the CHX/COL group had early onset VAP, which was not significantly different.
      
      The absolute risk reduction in early VAP is about 7% for the CHX group.
      
      CHX/COL was more effective than CHX and PLAC for endotracheal colonization because CHX was less effective against gram negative colonization. Between days 1-4 colonization rates were equal. At days 5-8 colonization was lower in CHX/Col compared to CHX (16 vs. 38%) and PLAC (16 vs. 40%). After 8 days, CHX and CHX/COL both had lower colonization rates against PLAC.
      
      Oral colonization with gram negatives was more prevalent in the CHX and PLAC groups when compared with the CHX/COL group.
      
      ICU mortality, duration of mechanical ventilation and lengths of ICU/hospital stay were comparable for all 3 groups.
      
      
   2. How precise was the estimate of the treatment effect?
      
      In patients receiving mechanical ventilation, it is 95% certain that there was somewhere between a 21 to 84% relative risk reduction of a patient developing early VAP when patients were pretreated with CHX. (RRR=65 % (hazard ratio [HR] = 0.35 ; 95% confidence interval [CI], 0.16 , 0. 791; p =0.01 )
      
      When using CHX/COL, it is 95% certain that there was somewhere between a 7 to 77% relative risk reduction in developing VAP. (RRR=55% (HR = 0.454; 95% CI, 0.22 , 0. 93; p = 0.030). Keep in mind that the authors define p < 0.025 as significant for this study.
      
   
   
4. Will the results help me in caring for my patients?
   
   
   1. Can the results be applied to my patient care?
      
      Uncertain. This study was conducted on adults and it is plausible that the data can be translated to teenagers and children. Most of our patients do not have as many coexisting diagnoses such as heart disease or diabetes which were well represented in this study. It would be reasonable to assume that these techniques would benefit our patients .
      
      
   2. Were all clinically important outcomes considered?
      
      Mostly. Timing to VAP has not previously been determined to be an important variable, but seems to make clinical sense. By delaying VAP, patients may be able to be extubated sooner. However, this study failed to show increased vent days or LOS in the patients who got VAP early. It is therefore u nclear on how to interpret the clinical significance of this metric . There was no mention of tracheostomy rates. The patient population was very heterogeneous. This intervention may have been more effective in certain types of ICU patients. Applicability to children is unclear.
      
      
   3. Are the likely treatment benefits worth the potential harms and costs?
      
      Maybe. While there is a risk of COL resistant strains, the use of CHX alone has little risk of developing resistant bacterial strains. There was clear advantage in adults in reducing the incidence of VAP in both CHX and CHX/COL arms. ICU mortality, duration of mechanical ventilation and lengths of ICU/hospital stay were comparable for all 3 groups which suggests that although this intervention may reduce the costs and morbidity associated with the development of VAP it doesn’t lessen the burden of time or familial hardship.
      
      Although multiple studies have shown the advantage of an oropharyngeal cleansing protocol in prevention of VAP there is no current protocol which recommends oral rinses. In 2004, Annals of Internal Medicine published a guideline for prevention of VAP. It suggested the following: “1) Orotracheal route of intubation 2) Changes of ventilator circuits for new or dirty circuits 3) Closed endotracheal suction systems 4) Heat and moisture exchangers unless contraindicated 5) Change heat and moisture exchangers every week 6) Place patient in semi-recumbent positioning 6) Consider subglottic secretion drainage and kineticbeds.� (1). The CDC 2003 guidelines for preventing healthcare associated pneumonia do not currently recommend chlorhexidine or topical antimicrobials (2). The Institute for Healthcare Improvement’s 100,000 Lives Campaign suggests the ‘Ventilator Bundle’ approach to prevention of VAP. Of the key components, only elevation of the head of the bed, daily “sedation vacations�, and assessment of readiness to extubate are VAP prevention techniques (3). Oropharyngeal cleansing with a specific product or protocol is not clearly suggested by any of the published protocols.
      
      The Sage product is currently a standard being used for oral cleansing. It consists of: 0.05% cetylpyridinium chloride, 1.5% hydrogen peroxide, 0.12% chlorhexidine gluconate, vitamin E, coconut oil, and an alcohol free mouthwash. A meta-analysis of 7 randomized controlled trials including 1,650 patients looked at topical chlorhexidine applied to the oropharynx vs. placebo or standard care in prevention of VAP. It revealed that topical chlorhexidine is efficacious, especially for cardiac patients, in preventing VAP. There is still no current evidence of topical chlorhexidine in preventing mortality associated with VAP but it was shown to be cost effective (4). Gentamicin/ colistin/vancomycin 2% in Orabase was studied and was shown to be effective in prevention of oropharyngeal colonization and VAP in a prospective, randomized, placebo-controlled, double-blind study, but risk of microbial resistance is still an issue with its use (5).
      
   
   
   

References:

1. Dodek P, Keenan S, Cook D, Heyland D, Jacka M, Hand L, Muscedere J, Foster D, Mehta N, Hall R, Brun-Buisson C: Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia. Ann Intern Med 2004, 141:305-313.
2. CDC Guidelines for Preventing Health-Care--Associated Pneumonia, 2003 CDC, MMWR. March 26, 2004;53(RR03);1-36
3. Gosfield AG, Reinertsen JL. The 100,000 lives campaign: crystallizing standards of care for hospitals. Health Aff (Millwood). 2005 Nov-Dec;24(6):1560-70.
4. Chlebicki MP, Safdar N. Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med. 2007 Feb;35(2):595-602.
5. Bergmans DC, Bonten MJ, Gaillard CA, Paling JC, van der Geest S, van Tiel FH, Beysens AJ, de Leeuw PW, Stobberingh EE. Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2001 Aug 1;164(3):382-8

Last Updated: May 19, 2007

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