Randomized Control Trial on Efficacy of Chlorhexidine Mouth Care in Prevention of Ventilator Associated Pneumonia (VAP)

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1 Randomized Control Trial on Efficacy of Chlorhexidine Mouth Care in Prevention of Ventilator Associated Pneumonia (VAP) Suresh K. Sharma, Jasbir Kaur Abstract : Ventilator associated pneumonia (VAP) is common problem among mechanically ventilated patients. However improvements in oral hygiene in these patients may prevent ventilator-associated pneumonia. The goal of this study was to determine the efficacy of 0.12% chlorhexidine gluconate mouth care to prevent the VAP among mechanically patients admitted in ICUs. A randomized control trial was carried out on 260 patients, where equal number of patients randomized in experimental (130 patients) and control group (130 subjects). Study was conducted during August to December 2010 to assess the efficacy of 0.12% chlorhexidine gluconate mouth care in prevention of VAP among mechanically ventilated patients. Study found that mouth care with 0.12% chlorhexidine twice daily was significantly effective in prevention of VAP among mechanically ventilated patients as compared to conventional method of mouth care (VAP: 5.7% vs. 35.4%) without any significant adverse event (p<0.05). Furthermore, it found that increased duration of mechanical ventilation escalates the risk of VAP; however, chlorhexidine mouth care was consistently effective with even longer duration of mechanical ventilation. Mouth care twice daily with 0.12% chlorhexidine is significantly effective in prevention of VAP among mechanically ventilated patients. Therefore, it is recommended to provide mouth care twice daily with 0.12% chlorhexidine to mechanically ventilated patients for prevention of VAP. Key words : Efficacy of Chlorhexidine, Chlorhexidine mouth care, Ventilator Associated Pneumonia Correspondence at : Dr. Suresh K. Sharma Professor, College of Nursing, Dayanand Medical College & Hospital, Ludhiana, Punjab Introduction The pathogenesis of ventilatorassociated pneumonia (VAP) involves aspiration of bacteria from the oropharynx into the lung, and subsequent failure of host defenses to clear the bacteria resulting in development of lung infection 1. In mechanically ventilated, intensive care unit patients, the major potential respiratory bacterial pathogens (PRPs) include Staphylococcus aureus, Pseudomonas 169

2 aeruginosa, Acinetobacter species, and enteric species. 2 Research confirmed that VAP develops quickly and easily in intubated patients. Any ventilated patient is at risk to develop VAP. The risk amplifies with increased length of time intubated. 3-7 Incidence reportedly occurs in up to 25% of ventilated patients. Bacteria that cause VAP occur naturally in the oral cavity and reside on the teeth and throat. Dental plaque and bacteria normally resident in the mouth and oropharynx, and colonization due to endemic antibiotic resistant organisms, are accepted sources of VAP development. The pooling of subglottal secretions and saliva, formed within the oral cavity, and associated endotracheal or nasotracheal intubation, increases risk of bacteria entering the lungs by up to twenty fold. Additional ventilated days in ICUs for patients who develop VAP overall doubles length of hospitalization, adding a financial liability for every patient Topical oral application of antiseptics such as chlorhexidine gluconate (CHX) have been evaluated for the prevention of VAP. CHX is a cationic chlorophenyl bis-biguanide antiseptic that has long been approved for use as an inhibitor of dental plaque formation and gingivitis CHX is of particular interest as an oral care and disinfectant in Mechanically Ventilated Intensive Care Unit (MV-ICU) patients because of its substantivity (the ability of CHX to bind to oral tissues with subsequent slow release and thus a relatively long period of action). Several recently published clinical trials of intra-oral disinfection with topical CHX or povidone-iodine gargle and toothbrushing 21 have demonstrated a reduction in the prevalence of oropharyngeal colonization by PRPs, as well as a reduction in the rate of VAP in MV-ICU patients. Based on these observations, recommendations for preventing VAP have included improving oral hygiene in MV-ICU patients 22,23. However, not all studies of the use of CHX have shown a reduction in the incidence of pneumonia 24. Moreover, the studies that have been published demonstrated that conventional solutions such as Hydrogen Peroxide, Potassium Permanganate (KMNO 4 ) and normal saline are used for mouth care. Thus, the goal of the present study was to determine the efficacy of the chlorhexidine as compared to conventional method of oral care as an endpoint of incidence of VAP. Objectives To assess the efficacy of chlorhexidine mouth care in prevention of VAP. Materials & Methods Patient population: This Randomized control trial was approved by the Institutional Ethical Committee. Subjects for this study were recruited from patients admitted to the Medical, Surgical and Neuro-surgery Intensive Care Units of Dayanand Medical College & Hospital (DMCH), Ludhiana, who were mechanically ventilated. DMCH is a bedded tertiary care providing hospital and is an affiliated teaching facility for the Baba Farid Univeristy of Health Sciences, Faridkot, Punjab. The average length of stay in this unit in the year before the start of the study was approximately nineteen days. Over the past 170

3 three years the incidence of VAP has ranged from 10 to 50% of all MV patients, and VAP per 1000 ventilator days has ranged from 8 to 12. Once participant eligibility was established, written informed consent was obtained from each patient, or most often from his/her next of kin. Sample size estimate: Based on previous studies, it was conservatively estimated that approximately 30% of all subjects admitted to the ICU would encounter VAP. In order to have a 95% power of detecting a difference between VAP proportions, and assuming a dose-response effect it was determined that a minimum group size would require 130 participants in experimental or control group. Thus total 260 patients were recruited in study; comprising equal number of the subject in experimental and control group. Duration of the study: Study was conducted during August 2010 to December Inclusion/exclusion criteria: Eligible patients were those admitted to the ICU, who were expected to be intubated and mechanically ventilated within 48 hours of admission, with the exception of those demonstrating the following exclusion criteria: a witnessed aspiration (to eliminate patients with chemical pneumonitis); a confirmed diagnosis of post-obstructive pneumonia (e.g. advanced lung cancer); a known hypersensitivity to CHX; absence of consent; a diagnosed thrombocytopenia (platelet count less than 40 and/or a INR above 2, or other coagulopathy); a do not intubate order; children under the age of 18 years; pregnant women; legal incarceration; oral mucositis; immunosuppression (either-hiv or drug induced (e.g. organ transplant patients or those on long term steroid therapy)); and readmission to the ICU. In addition, patients, who were not the under the regular VAP prevention bundle were also excluded. Trial design: Eligible patients, after seeking informed consent and following baseline assessment, were randomly assigned to one of the two: 1) a control arm in which patients received twice daily (AM and PM) oral care with the placebo normal saline and 2) an experimental arm in which patients received twice daily oral care with 0.12% CHX gluconate. CHX mouth care solution formula: Intervention protocol included carrying out the mouth care twice daily with 0.12% chlorhexidine gluconate; which was prepared as discussed further; 3 ml chlorhexidine gluconate 20% added to 200 ml of normal saline (0.9% NaCl); separately 5 ml essence of peppermint was mixed with 5 ml 95% ethanol, and then 15 ml glycerin. The solutions were then mixed and brought to 500 ml with normal saline. The placebo contained all ingredients, except for CHX, which was substituted with normal saline. Concealment, blocking, and randomization Subjects were randomized to the study via a web-based subject enrollment system that used protocol-specific specification files 171

4 that presented questions to site personnel to evaluate eligibility. Only subjects who met all eligibility requirements were randomized to the study. The randomization system prepared a set of Subject Identification Numbers (SID) that identified individual treatment assignments. The study nurse obtained the SID number based on the randomization when the subject was enrolled. The assigned SID number was sent to the dispenser to dispense the appropriate blinded treatment. Assignment of treatment was blinded to patients and all investigators including outcome assessors, statisticians, and care providers. Sealed envelopes containing a random number were generated in blocks of four to provide concealment of patient assignment from the investigators. Each block of four numbers were assigned corresponding boxes prepared and numbered sequentially from one to four. The dispenser prepared each box to contain two 30 oz bottles, one labeled AM and one labeled PM. For each block one of 260 possible permutations of symbols (Placebo 1(P 1 ), Placebo 2 (P 2 ), Twice a day 1 (T 1 ), Twice a day 2 (T 1 )) were selected using a random number generator, and numbers one to six were assigned based on randomly selected permutations. The oral topical treatment for each box was formulated and prepared by the designated dispenser. Training of the ICU Nurses: The study investigator trained all ICU staff nurses to perform the standardized technique for mouth care with CHX. In addition, the study investigator periodically observed ICU staff nurses for adherence to study protocol. Routine in-service sessions were held every month to review the protocol with ICU staff nurses. The study investigator collected all samples and study data and followed each enrolled subject until they were exited from the study. Intervention: Study interventions were provided using following protocol. Oral cavity was assessed for any abnormality. The ICU staff nurses performed CHX mouth care 0.12% CHX was applied using a rinsesaturated oral foam applicator twice daily (morning 7 AM and evening 7 PM). All teeth, the oral soft tissues including buccal mucosa, vestibule, gingiva, and the floor of the mouth and tongue dorsum were swabbed. Excess rinse was suctioned out of the subject s mouth after one minute. Presence of any adverse effect of solution was also determined by nurses. Deep suctioning was also performed to assist in removing oropharyngeal secretions pooled on top of the cuff of the endotracheal tube every 12 hours and following position changes. Patient data and outcome variables: Initially baseline demographic information was recorded such as age, gender, habitat, admission diagnosis and admitted from i) community, ii) hospital ward, iii) other ICU, or 172

5 iv) nursing home. Then the clinical pulmonary infection score system (CPIS) used is based on five different elements: Partial pressure of arterial oxygen (PaO2), Fraction of inspired oxygen (FiO2); Infiltrate on chest radiograph; Leukocytosis; Purulent secretions; and Fever. The CPIS score was calculated as follows: Fever: 0 (36.5 to 38.4 C), 1 (38.5 to 39.0), 2 (>39.0). Leukocytosis: 0 (4000 to 11,000 WBC/ cumm), 1 (11,000 to 17,000), 2 (>17,000). New infiltrate: 0 = None, 1 = Patchy, 2 = Localized. Secretions: 0 = None to minimal, 1 = moderate, 2 = large amount. PaO 2 /FiO 2 : 0 = more than 330 and 2 = less than 330. If CPIS score was 6 or more than deep endotracheal tube suctioned catheter tip was send for culture. The following variables were assessed at the time of patient discharge: Days of ICU stay and Total day of mechanical ventilation. In addition, all subjects were monitored for potential adverse events, which included intraoral events (mucositis, thrush, tooth staining, alterations in taste, tooth hypersensitivity) and systemic adverse events (mortality). Data management & Analysis: Once subjects were enrolled to the study site, the investigator completed protocol specific case report forms according to the study evaluation schedule. The case report forms were entered into statistical software i.e. SPSS-18. Computerized data checks were run on the data as it was entered into the database. These computerized checks were tracked for resolution. The study investigator also carried out a Manual Quality Assurance checks for inconsistent data. Inconsistent data items were queried by the investigator, which were followed to resolution. Significance of effect or difference was established at the level of Baseline comparisons between groups were performed using the chi-squared test. Results: During study period total of 863 patients were admitted in selected Intensive Care Units, out of them 367 patients were mechanically ventilated. Where 260 patients met inclusion criteria of the study, which were randomly recruited under experimental and control group (130 patients in each group). Table 1 presents the sociodemographic profile of the subjects. It was found that significant number of patient (108; 41.5%) were in the age group more than 60 years, followed by 80 (30.8%) subjects were in the age group of years and 51 (19.6%) subjects were in the age group of years. However, very few number of subjects below the age of 20 years. Furthermore, it was found that majority of the subjects (191; 73.5%) were males, while female patients were only of the one fourth of the total strength. In present study, urban dwelling subjects were slightly more (152; 58.5%) than the rural dwellers (108; 41.5%). In addition, patients 173

6 with surgical diagnosis were more (160; 61.5%) than the patients with medical diagnosis (100; 38.5%). Only few patients were admitted directly from the community, while half of the subjects were referred from different nursing homes. However, some of the patients were shifted from other wards (48; 18.5%) or intensive care unit (37; 14.2%) of the same hospital. Furthermore, both experimental and control group were found to be statistically identical in reference of their socio-demographic characteristics (P>0.05). Table 1: Socio-demographic characteristics of the patients N 260 Characteristics Exp. group Control group (n=130) f (%) (n=130)f (%) χ 2 -test Age (in Years) <20 12 (09.2) 09 (06.9) χ 2 =0.387 NS (18.5) 27 (20.8) (28.5) 43 (33.1) d.f. = 3 >60 57 (43.8) 51 (39.2) Gender Male 97 (74.6) 94 (72.3) χ 2 =1.456 NS Female 33 (25.4) 36 (27.7) d.f. = 1 Habitat Rural 56 (43.1) 52 (40.0) Urban 74 (56.9) 78 (60.0) χ 2 =0.934 NS Medical diagnosis Medical 51 (39.2) 49 (37.7) χ 2 =0.456 NS Surgical 79 (60.8) 81 (62.3) d.f.=1 Admitted from Community 22 (16.9) 19 (14.6) Hospital ward 26 (20.0) 27 (20.8) Nursing Home 63 (48.5) 66 (50.8) χ 2 =1.012 NS Other ICU 19 (14.6) 18 (13.8) d.f. = 3 NS: Non-significant (p>0.05) It was found that significantly more number of subjects developed VAP in control group (46; 35.4%) as compared to experimental group (7; 5.7%); which may be perused form Table 2 (p<0.05). Further, it was observed that in control and experimental group none of the subject experienced any adverse event during intervention period. 174

7 Table 2: Incidence of ventilator associated pneumonia among subjects N = 260 VAP Exp. group Control group (n=130) f (%) (n=130)f (%) χ 2 -test Present 07 (05.7) 46 (35.4) * Absent 123 (94.9) 84 (64.6) d.f.= 1 * Significant (p< 0.05); VAP: Ventilator Associated Pneumonia The effect of time period of mechanical ventilation on the incidence of ventilator associated pneumonia among the subjects is depicted in Table 3. It was observed that duration of mechanical ventilation was found significantly affecting the occurrence of ventilator associated pneumonia; where more than half of the cases developed pneumonia after having greater then 120 hours of mechanical ventilation. However, the patter of effect of duration on mechanical ventilation on incidence on ventilator associated pneumonia was not found to different in experimental and control group (p>0.05). Therefore, it was inferred that effect of chlorhexidine mouth care in prevention of ventilator associated pneumonia was identical during early as well as late periods of mechanical ventilation. Table 3: Hours of mechanical ventilation and incidence of VAP among subjects Presence of VAP Hours of mechanical ventilation χ 2 - test >120 f (%) f (%) f (%) Experimental Group (n=7) 01 (14.3) 02 (28.6) 04 (57.1) NS Control Group (n=46) 8 (17.4) 10 (21.7) 28 (60.9) d.f.= 1 NS: Not significant (p>0.05) VAP: Ventilator Associated Pneumonia Discussion As VAP continues to be a common complication of critical care, development of preventive approaches are essential to reduce the incidence of this infection. The purpose of the study was to assess and compare the efficacy of the two different solutions for mouth care to improve oral hygiene and reduce oral colonization by potential respiratory pathogens in intubated MV patients admitted to the ICUs. The strengths of this study include the well-controlled randomized design, and the fact that the intervention was provided by staff nurses, thus allowing for the test of the intervention under real world 175

8 conditions. The results show that the use of 0.12% Chlorhexidine for mouth care markedly reduced incidence of VAP among the ICU patients. A number of published studies suggest that topical Chlorhexidine twice-three times daily prevents VAP. One possibility is that Chlorhexidine inhibits the viability of the bacteria in the oral secretions. The subsequent reduction in the number of viable bacteria in the secretions thus reduces the number of viable organisms aspirated into the lower airway and therefore will prevent subsequent infection. Alternatively, the virulence potential of the bacteria may be reduced by Chlorhexidine. Previous studies have suggested that Chlorhexidine is able to bind to bacterial components such as lipopolysaccharide and proteases. Such interactions may diminish the biologic activity of such components to reduce the virulence potential of bacteria. It is also possible that concomitant use of other oral care products such as toothpaste might reduce Chlorhexidine efficacy. Adverse events have rarely been reported in clinical trials of Chlorhexidine in ICU patients. A meta-analysis of seven clinical trials found that adverse effects were not reported in any of these studies. A recent clinical trial of 2% Chlorhexidine versus saline found that 9.8% in the Chlorhexidine group had mucosal irritation versus 0.9% in saline controls (P=0.001). The present study using 0.12% Chlorhexidine found no adverse effects (mucosal irritation or tooth staining), except mucosal irritation while application in two subjects. Furthermore, in present study it was found that Chlorhexidine mouth care does have persistent latent effect on prevention of VAP among mechanically ventilated patients. Present study found that 0.12% chlorhexidine mouth care twice daily was significantly effective in prevention of ventilator associated pneumonia among mechanically ventilated patients without any significant adverse event. Furthermore, it found that increased duration of mechanical ventilation escalates the risk of VAP; however, chlorhexidine mouth care was consistently effective with even longer duration of mechanical ventilation. Therefore, it is recommended that along with VAP prevention bundle 0.12% chlorhexidine mouth care twice a daily must be carried out for mechanically ventilated patients for prevention of VAP. Conclusion: Mouth care twice daily with 0.12% chlorhexidine is significantly effective in prevention of VAP among mechanically ventilated patients. Therefore, it is recommended to provide mouth care twice daily with 0.12% chlorhexidine to mechanically ventilated patients for prevention of VAP. References: 1. Verghese A, Berk SL. Bacterial pneumonia in the elderly. Medicine (Baltimore) 1983, 62: Scannapieco FA, Stewart EM, Mylotte JM. Colonization of dental plaque by respiratory pathogens in medical intensive care patients. Crit Care Med 1992, 20:

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