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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

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169

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.8-10

brushing21 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 patients22,23. However, not
all studies of the use of CHX have shown a
reduction in the incidence of pneumonia24.
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.

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
gingivitis11-13. 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
CHX14-20 or povidone-iodine gargle and tooth-

Materials & Methods

Objectives
To assess the efficacy of chlorhexidine
mouth care in prevention of VAP.
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 1200bedded 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

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170

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 par ticipant 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 par ticipants 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
2010.
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

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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(P1), Placebo 2 (P2), Twice a day 1 (T1), Twice
a day 2 (T1)) 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


subjects 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

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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 38.4C), 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.

PaO2/FiO2: 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
repor t 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
0.05. 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 41-60 years and 51 (19.6%)
subjects were in the age group of 21-40 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

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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. Fur thermore, 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


Characteristics

N 260

Exp. group
(n=130) f (%)

Control group
(n=130)f (%)

Age (in Years)


<20
21-40
41-60
>60

12 (09.2)
24 (18.5)
37 (28.5)
57 (43.8)

09 (06.9)
27 (20.8)
43 (33.1)
51 (39.2)

2 =0.387NS

Gender
Male
Female

97 (74.6)
33 (25.4)

94 (72.3)
36 (27.7)

2 =1.456NS
d.f. = 1

Habitat
Rural
Urban

56 (43.1)
74 (56.9)

52 (40.0)
78 (60.0)

2=0.934NS

Medical diagnosis
Medical
Surgical

51 (39.2)
79 (60.8)

49 (37.7)
81 (62.3)

2 =0.456NS
d.f.=1

Admitted from
Community
Hospital ward
Nursing Home
Other ICU

22 (16.9)
26 (20.0)
63 (48.5)
19 (14.6)

19 (14.6)
27 (20.8)
66 (50.8)
18 (13.8)

2 =1.012NS
d.f. = 3

2-test

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.

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Table 2: Incidence of ventilator associated pneumonia among subjects


VAP

N = 260

Exp. group
(n=130) f (%)

Control group
(n=130)f (%)

2-test

Present

07 (05.7)

46 (35.4)

36.045*

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


48-72
71-120
>120
f (%)
f (%)
f (%)

2 - test

Experimental Group (n=7)

01 (14.3)

02 (28.6)

04 (57.1)

0.174NS

Control Group (n=46)

8 (17.4)

10 (21.7)

28 (60.9)

d.f.= 1

NS: Not significant (p>0.05)


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

VAP: Ventilator Associated Pneumonia


care to improve oral hygiene and reduce oral
colonization by potential respirator y
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

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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. Fur thermore, 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.
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