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Introduction
Pneumonia remains the leading cause of death in
intensive care unit (ICU) patients, with an attributed
mortality of around 30%. Moreover, it affects the length and
cost of the ICU stay. (1) Gram-negative enteric bacilli often
multidrug resistant (MDR) to antibiotics are the most
frequent
causative
antimicrobial
pathogens.
resistance
in
the
(2)
ICUs
Thus,
increasing
has
challenged
intensivists to search for alternative therapeutic options. (3)
Since the tissue concentration at the site of infection is a
major determinant of the bacterial killing efficiency and
clinical
response,
the
use
of adjunctive
therapy with
aerosolized antibiotics (e.g. aminoglycosides, polymixins and
colistin) represents one of these. (4, 5)
Aerosolized antimicrobial agents have been used in
clinical practice since the 1950s. (6) Their administration
remains theoretically attractive for the prevention and
treatment of hospital-acquired pneumonia (HAP) because of
the ability to generate high drug concentrations at the site of
1
infection. There is renewed interest in this area because of
the shortcoming of current therapies, increasing MDR gramnegative organisms and the established use of nebulized
antibiotics
for
treatment
of
chronic
infection
with
pseudomonas areugenosa, particularly in cystic fibrosis and
bronchiectasis but with variable clinical efficacy. (7) Clinical
trials
of
aerosolized
or
endotracheally
administered
antibiotics for HAP prevention or the ventilator-associated
pneumonia (VAP) treatment in adults have generally been
positive. (8, 9)
Compared to systemic routes of administration (both
enteral
and
parenteral),
inhalation
achieves
higher
pulmonary concentrations of antibiotics, with the potential to
reduce systemic toxicity. (5, 10, 11, 12)
But, it is important to know that the penetration of
antimicrobial drugs into the respiratory tract is influenced by
both
host-related
factors,
such
as
inflammation
or
mechanical injury, and drug-related factors, such molecular
2
weight,
product
formulation
and
the
nebulizer
used
(ultrasonic or jet). (13)
The hazards of nebulized antibiotics depend on the
formula used and the dose administered. The highest local
concentrations are associated with the highest peak values
in serum and hence more systemic toxicity. (14) The use of
intravenous formulations via
a nebulizer
can lead
to
exposure to potentially irritant or toxic additives and
inappropriate pH or osmolality ranges, with the risk of
bronchospasm. (15, 16, 17) In addition, inhaled antibiotic
may be deposited poorly or may be virtually absent in
regions of the lung where airflow is minimal and where
infection is presumably greatest. (18)
Labiris and colleagues found that aminoglycosides,
including gentamycin, are considered among the most useful
classes
of
antibiotics
for
treatment
of
Gram-negative
infections. The major drawback was that in its maximum
safe intravenous dose, only low sputum concentrations are
achievable.
Inhalation
of
the
intravenous
formula
of
3
gentamycin offered the potential benefit of producing high
concentrations at the site of infection in the airways, without
the risk of systemic toxicity. (19) All these potential risks
regarding the use of inhaled aminoglycosides were found
negligible when actually studied before. (5, 17, 20)
Based on those previous experiences in the use of
inhaled antibiotics, our goal in this study was to assess the
safety and effectiveness of aerosolized gentamycin as an
adjunct to intravenous antimicrobial therapy for treatment of
pneumonia in pediatric intensive care unit (PICU).
Patients and Methodology:
This is a randomized controlled clinical trial.
Population: All children, admitted to university hospital
based pediatric ICU from September 2009 till September
2010, were enrolled if they met the following criteria:
 Presence of clinical and/or radiological evidence of
pneumonia on admission.
 Age from 2 months till 14 years.
4
Exclusion criteria: - Known asthmatic children.
- Moderate to severe renal insult (serum
creatinine above 1.5 times the upper level for
age).
Patients were subjected to initial evaluation in the form of
history
and
clinical
examination,
routine
laboratory
investigations and assessment of severity of illness on
admission using the need of mechanical ventilation or the
need of inotropes within first 24 hours. Special emphasis
was paid to the level of respiratory support needed, white
blood cell counts, cultures (blood, sputum and endotracheal)
and chest X-ray.
Intervention: The patients were randomly assigned to
Control group (CG) or Study group (SG) by using sealed
envelopes chosen blindly for each patient upon enrollment.
Controls
culture
and
received
systemic
sensitivity
if
antibiotics
cultures
were
according
to
available
on
admission. The routine protocol of the ICU, in the form of
5
double
antibiotics
as
1st
line
(Floxacillin,
Amoxicillin/clavulonic or Ampicillin/sulbactum plus Amikacin
or Cefotaxime) was otherwise given.
Study group received the systemic antibiotics by the
same concept plus nebulized gentamycin for a period of 7
days at a dose of:
 20 mg every 12 hrs in children less than 1year old.
 40 mg every 12 hrs in children from 1 year till 5
years old.
 60 mg every 12 hrs in children more than 5 years
old. (21, 22, 23)
We used the intravenous formula of the Gentamycin
according to the above dose added to 2.5ml of normal
saline. The aerosolized gentamycin was administered by
means of small-volume ultrasonic nebulizers (Atom brand).
In ventilated patients it was used by the mean of the
ventilator nebulizer cup. This form of administration has
been officially sanctioned by the U.S. Food and Drug
6
Administration.
Each
patient
in
the
study
group
was
monitored after the first dose of inhaled gentamycin to
detect any change in his airway resistance.
Patient’s outcome was assessed by comparing the two
groups regarding the length of stay in the ICU, days of
systemic antibiotic needs, persistence of same organism
with acquiring resistance or the development of
new
organism, development of adverse effect (as bronchospasm
or renal toxicity) and mortality rate.
Statistical Analysis:
Nominal data were expressed as frequency and were
compared using Chi square test. Numerical data were
expressed as mean and range and were compared using T
test.
Non-parametric data were compared using Mann
Whitney test. P values < 0.05 were considered significant.
Results:
7
After excluding asthmatic patients, those with renal
impairment and those without evidence of chest infection,
we studied 90 child admitted to the PICU during the duration
of the study. (Fig, 1)
After randomization using sealed
envelopes, both groups were almost the same pattern.
(Table, 1)
The age of both groups ranged from 2 months till 13
years.
The outcome of both groups regarding the length of
stay, duration of respiratory support and antibiotics used
showed no significant difference. (Table, 2)
Leucocytosis on day 7 was more common among Study
group17
patients
(37.7%)
compared
with
8
patients
(17.7%) of Control group.
Fifty five percent of the Study Group patients had day
1 positive cultures compared to 42% in Control Group, with
more gram –ve organisms 16 patients (42.2%) than gram
+ve organisms 7 patients (15.5%). The dominant organism
was pseudomonas areugenosa in 10 patients (22.2%).
8
Regarding microbiological progress between cultures
day 1 and day 7, SG had almost same number of +ve
cultures becoming –ve when compared with CG 15 (33.3%);
14
(31.1%),
respectively.
The
persistence
of
same
organism in 2nd culture was found only in one patient of the
CG (2.2%). (Table, 3)
Considering the final outcome of both groups, Control
Group had 24(53.3%) discharged patients and 21(46.6%)
deaths compared with study group 33(73.3%) discharged
patients and 12(26.6%) deaths. This difference in favor of
the SG was statistically significant, p=0.024 (figure, 2).
Discussion:
The principal goals of management of pneumonia in
any
PICU
emphasize
early,
appropriate
antibiotics
in
adequate doses, adjustment of therapy according to the
clinical response and susceptibility data, culture, and an
appropriate duration of therapy. These goals are increasingly
difficult to achieve, because of hospital-acquired gram9
negative bacteria have acquired resistance to all of the
major antibiotic classes. (24, 25) The traditional approach is
to administer antibiotics via systemic circulation. Because
the airways provide a direct pathway to the lung cells and
tissues, aerosolized delivery offers an alternative route, with
antibiotic delivery directly to the air/liquid interface in the
lung. New and improved delivery devices have made it
possible to administer precise doses of inhaled drugs, with
pulmonary delivery of 50-70% of the nominal dose. (26, 27)
Our study shows that inhaled gentamycin as an adjunct
to systemic therapy for the treatment of pneumonias in the
PICU, did not help in decreasing the days of antibiotics, the
length of stay or the mechanical ventilation days. Those
results are similar to those found in study done by Palmer et
al, 2008 (28), apart from they had significant results in the
decreased weaning days from mechanical ventilation.
Our
study
also
demonstrates
that
the
use
of
aerosolized gentamycin along with systemic therapy is
associated with clinical resolution of pneumonia similar to
10
Mohr et al, 2007 (20), but with an insignificantly longer
length of stay and duration of antibiotics between SG and
CG (p= 0.4048 and 0.4677; respectively.
Chastre et al, 2003 (29) found that neither white blood
cells
(WBCs)
nor
temperature
had
normalized;
these
parameters did not normalize until day 28 of their study.
Similar findings were described by Dennesen et al, 2001
(30) who observed that neither WBCs nor temperature
returned to normal after 14 days of therapy and by Kollef et
al, 2006 who suggested that WBCs may not normalize after
successful treatment of pneumonia as a result of multiple
inflammatory stimuli from the underlying critical illness. (31)
Our treatment approach observes that the use of inhaled
gentamycin is associated with normalization of WBCs after 7
days in 62.3% of patients compared to 82.7% of the Control
group.
The most significant result in this study is the better
outcome (discharge versus death) noticed with the inhaled
gentamycin group compared with Control group. On the
11
contrary to our findings, the results of Palmer et al, 2008
(28) demonstrates that the mortality rate in both groups
was similar.
This
study
demonstrates
the
safety
of
inhaled
aminoglycosides, without adverse effects reported for either
groups (SG and CG). In particular, there is no demonstrated
renal toxicity and no reported pulmonary complications. The
development of ototoxicity in our patients is not assessed as
long-term follow up is lacking.
Our study has several limitations, including the small
size of the studied groups and the absence of a scoring
system to compare the severity of the patient’s conditions
on admission.
In
conclusion,
inhaled
gentamycin
are
safe
in
conjugation with parenteral antibiotics. Moreover, inhaled
gentamycin do not foster bacterial resistance and appear to
play a role in eradication of pneumonia and better outcome
in PICU.
12
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