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* From the Pulmonary and Critical Care Divisions (Drs. Luna, Videla, and Vujacich), the Clinical Analysis Department, Microbiology Division (Drs. Mattera, Fay, and Famiglietti), Hospital de Clínicas "José de San Martín," University of Buenos Aires, Argentina; and the Division of Pulmonary and Critical Care Medicine (Dr. Niederman), Winthrop University Hospital, Mineola, NY.
Correspondence to: Carlos M. Luna, MD, FCCP, Acevedo 1070, Banfield (CP 1828), Buenos Aires, Argentina; e-mail: cymluna{at}fmed.uba.ar
| Abstract |
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Design: Prospective observational study using BAL and blood cultures collected within 24 h of establishing a clinical diagnosis of VAP.
Setting: A 15-bed medical and surgical ICU.
Patients: One hundred and sixty-two patients receiving mechanical ventilation hospitalized for > 72 h who had new or progressive lung infiltrate plus at least two of three clinical criteria for VAP.
Interventions: BAL and blood culture performed within 24 h of establishing a clinical diagnosis of VAP.
Measurements and results: Ninety
patients were BAL positive (BAL+), satisfying a microbiological
definition of VAP (
104 cfu/mL), 72 patients were BAL
negative (BAL-). Bacteremia was diagnosed when at least two sets of
blood cultures yielded a microorganism or when only one set was
positive, but the same bacteria was present at a concentration
104 cfu/mL in the BAL fluid. Bacteremia was
significantly more frequent in the BAL+ than in the BAL- group (22/90
patients vs 5/72 patients; p = 0.006). In 6 of 22 BAL+ patients with
bacteremia, an extrapulmonary site of infection was the source of
bacteremia. Sensitivity of blood culture for disclosing the pathogenic
microorganism in BAL+ patients was 26%, and the positive predictive
value to detect the pathogen was 73%. Factors associated with
mortality were age > 50 years, simplified acute physiology score
> 14, prior inadequate antibiotic therapy,
PaO2/fraction of inspired oxygen < 205, and
use of H2 blockers. By multivariate analysis, only the use
of prior inadequate antimicrobial therapy (odds ratio [OR], 6.47) and
age > 50 years (OR, 5.12) were independently associated with higher
mortality. The rate of complications was not different in patients with
bacteremia.
Conclusions: Blood cultures have a low sensitivity for detecting the same pathogenic microorganism as BAL culture in patients with VAP. The presence of bacteremia does not predict complications, it is not related to the length of stay, and it does not identify patients with more severe illness. Inadequacy of prior antimicrobial therapy and age > 50 years were the only factors associated with mortality in a multivariate analysis. Blood cultures in patients with VAP are clearly useful if there is suspicion of another probable infectious condition, but the isolation of a microorganism in the blood does not confirm that microorganism as the pathogen causing VAP.
Key Words: bacteremia blood cultures complications diagnosis mortality nosocomial pneumonia ventilator-associated pneumonia
| Introduction |
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| Materials and Methods |
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The following information was recorded: age; gender; prior trauma or
surgery; underlying comorbid illnesses, including COPD or other
pulmonary disease and cardiac disease, with or without heart failure;
presence of shock; alteration of consciousness; duration of tracheal
intubation and mechanical ventilation prior to the development of VAP;
use of corticosteroids; and use of antacids including
H2 blockers. Dates of admission, BAL specimen
retrieval, blood culture sampling, and discharge from the ICU were
noted. All antimicrobial agents received were recorded. Patients
receiving antimicrobial drugs during the 24 h preceding the
bronchoscopy, or discontinuously for > 48 h during the 10 days
preceding the episode of VAP, were considered to have received prior
antimicrobial therapy. Blood culture and fiberoptic bronchoscopy
examination were performed in each patient within 24 h after the
development of a new infiltrate. BAL was performed by using a
fiberoptic bronchoscope, and the BAL fluid specimens were processed as
previously described.9
A value
104 cfu/mL
of at least one species was the cut-off point to confirm the diagnosis
of pneumonia. In patients with confirmed pneumonia, antibiotic
susceptibility was determined. If the organisms present at a
concentration
104 cfu/mL were demonstrated to
be sensitive to the agent prescribed, the patient was defined as being
treated with adequate antibiotics; if the organisms were resistant, the
patient was defined as being treated with inadequate antibiotics.
Adequacy of the antibiotic given prior to bronchoscopy was considered
in the definition of adequate antimicrobial therapy. The adequacy of
therapy was defined based on sensitivity patterns in the antibiogram,
and not the response of the organisms to therapy or the use of
combination therapy instead of monotherapy.
Two or more sets of blood cultures were obtained from different sites
and at different times from each patient, at the same time or within
24 h of performing bronchoscopy and BAL for a clinically defined
episode of VAP. Blood cultures were drawn from peripheral extremity
veins at sites cleansed with an iodophor solution. Bacteremia was
diagnosed when two or more of each set of blood cultures yielded a
microorganism, or when only one of the sets was positive but the same
bacteria was isolated in a concentration
104
cfu/mL in the BAL culture.
All patients were monitored until their discharge from the hospital. Subsequent changes in their clinical course, chest radiograph findings, and modifications in antibiotic therapy were recorded in all cases.
Statistical Analysis
Data are expressed as mean ± SD. To assess whether there were
differences between the clinical picture in patients with positive or
negative BAL specimens and in patients with positive or negative blood
cultures, clinical features and mortality in both groups of patients
were compared by using Student's t test for continuous
variables and the
2 test (or Fisher's Exact
Test) for categorical variables. The influence of several variables on
the mortality rate was evaluated by univariate analysis using the
2 test (or Fisher's Exact Test); thereafter,
a multiple logistic regression model was applied to the variables found
to be significantly associated with death (p < 0.05, patients who
died vs survivors). Multiple logistic regression permitted an estimate
of the odds ratio (OR) of dying and a calculation of the 95%
confidence interval (CI). The statistical analysis was performed using
appropriate computer software (Primer of Biostatistics; McGraw Hill;
New York, NY; and SPSS for Windows; SPSS; Chicago, IL).
The sensitivity and positive predictive value of positive blood
cultures were calculated by using a decision matrix.
| Results |
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1 prior episodes of VAP; these
subsequent episodes involved other areas and developed at least 9 days
after the patient had improved from the prior episode. Each pneumonia
episode in a single patient was treated as a separate case. If the
patient died after a subsequent VAP episode, the outcome was considered
survival for the prior episode(s) and mortality for the last one.
Some demographic and clinical characteristics associated with severity
of illness and outcome are shown in Table 1
. Data from patients with VAP confirmed by BAL (n = 90) were compared
with data from those who did not fulfill the microbiological criteria
(n = 72). The presence of bacteremia (22 of 90 patients vs 5 of 72
patients; p = 0.006) was the only feature observed at a different
rate in patients with VAP confirmed by BAL, compared with those in whom
pneumonia could not be established bronchoscopically. Among the 72
patients with clinical pneumonia and negative BAL, 21 patients had
microorganisms isolated from the BAL culture at a concentration of
< 104 cfu/mL but
103
cfu/mL, and 2 of these 21 patients had positive blood cultures. Thus,
of the 27 patients with positive blood cultures, 22 were among the 90
patients whose BAL fluid yielded
104 cfu/mL,
2 were among the 21 patients whose BAL fluid yielded
< 104 cfu/mL but
103
cfu/mL, and 3 were among the 51 patients whose BAL fluid yielded
< 103 cfu/mL.
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Pathogens isolated from blood cultures in those five BAL- patients
were as follows: in two cases, the same microorganism that was present
in BAL culture at a concentration of < 104
cfu/mL but
103 cfu/mL (one was
Pseudomonas aeruginosa and the other was Acinetobacter sp);
Bacteroides sp in a patient with Staphylococcus aureus and
Proteus mirabilis at a low count in the BAL culture; and
Staphylococcus epidermidis and Streptococcus
pneumoniae in two patients.
Results of Cultures in Patients With VAP Confirmed by BAL
One hundred sixty-two microorganisms were isolated from the BAL
fluid culture at a concentration of at least 104
cfu/mL in the 90 episodes of VAP confirmed by BAL (1.8 microorganisms
per episode). The most commonly isolated pathogens were Acinetobacter
sp (31%), S aureus (28%), Klebsiella pneumoniae
(14%), and P aeruginosa (12%; Table 2
). In 22 episodes of VAP, bacteremia was confirmed by the presence of at
least one pathogen in the blood culture. The predominant microorganisms
in the blood cultures were the same (with the slight trend of a higher
prevalence of S epidermidis as those observed in the BAL
culture (Table 2)
. Looking at the correlation between the adequacy of
antibiotic therapy and results of blood cultures, we observed that
blood cultures were positive in 6 of 23 patients with adequate
antibiotics, 5 of 18 patients not receiving antibiotics, and 11 of 49
patients receiving inadequate antibiotics before bronchoscopy.
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In the 90 BAL+ patients, blood cultures were drawn the same day as bronchoscopy in 70 cases just before BAL fluid retrieval; in 12 patients, blood cultures were drawn within 24 h prior to bronchoscopy; and in 8 patients, cultures were drawn within 24 h after bronchoscopy. Five of 22 positive blood cultures were obtained either in the 24 h prior (4 cultures) or in the 24 h after bronchoscopy. Two patients in whom blood cultures were drawn within 24 h before bronchoscopy had a pathogen isolated that was not present in the BAL culture (the difference from patients in whom blood and BAL cultures were drawn was not statistically significant).
Potential prognostic factors were evaluated by univariate analysis in
the 90 BAL+ patients (Table 4
). Positive blood cultures were not demonstrated to be a factor
associated with higher mortality. Age > 50 years, SAPS
14,
PaO2/FIO2 < 205
mm Hg, use of H2 blockers, and use of inadequate
prior antibiotic therapy were the only factors associated with a
significantly higher mortality. Multivariate analysis by multiple
logistic regression confirmed that only inadequate prior antibiotic
therapy and age > 50 years remained significantly associated with
mortality (Table 5
).
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| Discussion |
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Positive blood cultures are used to define the presence of bacteremia, but some authors have suggested that finding certain pathogens in blood culture or isolating organisms in less than two of two or two of three bottles suggests contamination rather than infection.20 For example, the presence of S epidermidis in blood cultures usually raises concern about the possibility of contamination; however, this pathogen is increasingly being found in ICU patients and is capable of causing infections of the bloodstream, the lower respiratory tract, and the urinary tract.21 Thus, one approach has been to base the definition of contamination on clinical findings.22 The presence of bacteremia in patients with community-acquired pneumonia is considered to have a high positive predictive value for defining the etiology. However, in patients with nosocomial pneumonia, the relationship of bacteremia to pneumonia etiology is less certain, particularly since some of these patients can have multiple sites of infection simultaneously. Overall, bacteremia has been reported in patients with nosocomial pneumonia at a rate between 10% and 31%3 6 9 21 23 24 .
The clinical course of pneumonia, the presence of complications, and the mortality rate have been related to the presence of bacteremia in patients with both community-acquired and nosocomial pneumonia. In patients with community-acquired pneumonia, a more complicated course and higher mortality rate have been observed for those patients with bacteremia.25 Taylor et al26 described a high 7-day mortality rate in 168 episodes of bacteremic nosocomial infection in both ICU and non-ICU patients, whereas Chendrasekhar7 found an association between bacteremia and severity of anatomic injury, and also found that bacteremia independently increased length of stay. Roberts et al23 also found prognostic significance of bacteremia in 178 patients with pneumonia (nosocomial and community-acquired pneumonia were considered together in this study). Fagon et al8 found that nosocomial bacteremia was associated with an increased mortality risk in ICU patients (OR, 2.51), and that nosocomial pneumonia itself also was associated with an increased mortality rate (OR, 2.08). They did not analyze whether mortality was increased in patients who had nosocomial pneumonia and bacteremia compared with patients who had nosocomial pneumonia without bacteremia.
We demonstrated in this study that bacteremia was more frequent among
patients who eventually were confirmed to have VAP by the BAL culture
compared with those who did not have the diagnosis of VAP confirmed by
BAL culture (Table 1)
. This difference may be due to the fact that the
presence of antibiotic therapy prior to the performing the cultures was
more common (but not statistically different) in BAL- patients than in
BAL+ patients (62 of 72 patients vs 72 of 90 patients). It is also
possible that some of these BAL- patients might actually not have
pneumonia at all. It is interesting that the incidence of bacteremia
with the same organism that was detected in BAL was 0% in 51 patients
(44 patients with prior antibiotics) with BAL cultures at a
concentration of < 103 cfu/mL; 9.5% (2 of 21
patients; 18 with prior antibiotics) in patients with BAL cultures one
log below the diagnostic threshold (
103 but
< 104 cfu/mL); and 17.8% (16 of 90 patients;
72 with prior antibiotics) in patients with positive BAL cultures at or
above the diagnostic threshold. Thus, patients with "borderline"
BAL results had a higher coincidence of blood culture and BAL culture
results than did patients with lower bacterial counts in BAL fluid.
This observation raises the possibility that using a BAL threshold for
the diagnosis of VAP that is one log below the standard may be
appropriate for some patients, particularly those who have received
prior antibiotics, an intervention that was more common in BAL-
patients than in BAL+ patients.
In the present study, we observed that mortality in patients who had
confirmed VAP did not differ from mortality in those who had clinical
signs of VAP without bronchoscopic confirmation. In addition, in those
with VAP, the presence of bacteremia did not increase the risk of
mortality in a multivariate analysis. However, there was a higher
mortality in those VAP patients who had bacteremia from a nonpulmonary
source (83%; 5 of 6 patients) than in those with pneumonic bacteremia
(56%; 9 of 16 patients). Univariate analysis showed that factors
associated with higher mortality were age
50 years, SAPS index
14, the presence of prior inadequate antibiotic therapy,
PaO2/FIO2
< 205, and use of H2 blockers. In multivariate
analysis, only the prior use of inadequate antimicrobials (OR, 6.47)
and age > 50 years (OR, 5.12) were independently associated with
higher mortality. The relationship between inadequate therapy and
mortality is a complex one, and it may reflect the fact that patients
who died were infected with organisms that were more difficult to
treat, leading to the coincidence of inadequate therapy and mortality.
However, if we examine the data relating bacteriology to mortality with
Acinetobacter sp, there is no apparent relationship. In patients with
bacteremic Acinetobacter pneumonia (Table 2)
, mortality was 50% (3 of
6 patients), and mortality for all bacteremic patients with
Acinetobacter in BAL cultures was 75% (9 of 12 patients). These
results do not differ overall from the mortality seen in all bacteremic
patients (64%) or in all BAL+ patients (71%). In addition, as shown
in Table 6
, mortality was clearly related to the adequacy of therapy
for both Acinetobacter and non-Acinetobacter infections, and if
adequate therapy was given, mortality was similar regardless of the
bacteriology of the infection.
We demonstrated that the positive predictive value of blood culture for detecting the etiologic organism of VAP (as confirmed by BAL) was only 73%. Bryan and Reynolds3 found that, in 99 cases of bacteremic nosocomial pneumonia, the pathogen isolated from the sputum coincided with the bacteria isolated in the blood in 75% of cases, ie, 25% of the pathogens isolated from blood were not present in sputum, a figure that is very similar to the data presented in this paper.
The outcome in bacteremic patients has been related to the source of infection (GI tract, multiple sources, pneumonia); the type of microorganism (yeast, Serratia sp, Pseudomonas sp, and mixed); the antibiotic therapy chosen; and the presence of severe underlying disease.23 We found that in patients with VAP, mortality was related to the severity of illness and the adequacy of therapy, but not directly to the presence of bacteremia or to the etiologic organism. In addition, although the number of patients was small, mortality was increased if the bacteremia was from an extrapulmonary infection complicating VAP. Inadequate therapy in VAP patients with severe underlying conditions, and not the presence of bacteremia, had the strongest influence not only on mortality, but also on length of stay and the incidence of complications.
In patients with VAP, blood cultures do not improve identification of the etiologic pathogen over bronchoscopy alone, but may have a complementary role for two purposes. First, blood cultures can detect the presence of extrapulmonary infection complicating VAP. Second, they can detect respiratory pathogens (confirming the presence of pneumonia) in patients who have "borderline" negative quantitative BAL results. However, blood cultures do not reflect the polymicrobial nature of VAP. As seen in Table 2 , only six patients with BAL+ VAP had a blood culture showing the exact same results as the BAL. In all others who had bacteremia, either the BAL findings were discordant with the blood cultures (n = 6) or the BAL showed multiple bacteria while the blood culture showed only one of the BAL organisms (n = 10). Because adequate therapy was an important risk factor for survival, if therapy had been based only on positive blood culture data, it would have resulted in inadequate therapy in seven cases of Acinetobacter pneumonia and seven cases of S aureus pneumonia.
One limitation of this study is that the final etiologic diagnosis was defined by the result of BAL culture (a highly specific and sensitive method, but not the standard to define a pathogen of pneumonia as definitive). We also recognize that the findings of this study might not have practical applicability to ventilated patients who are not as severely ill as those presented by us. Less severely ill patients with VAP (such as trauma patients, younger people, or those presenting with the early-onset type of VAP) usually have a better outcome, and thus the presence of bacteremia may have a different significance, possibly leading to a worse outcome. We also recognize that catheter-related sepsis is one of the most common causes of bacteremia in ICU patients and may have accounted for some cases of bacteremia that could have been attributed to VAP. This cause of bacteremia could not always be excluded, even if some organisms were isolated from both blood and BAL fluid, because we did not draw cultures simultaneously from intravascular catheters, nor did we do quantitative cultures of these catheters.27 Finally, in the future, a quantitative blood culture technique may demonstrate utility to measure the intensity of bacteremia, and this intensity might correlate with mortality.
| Acknowledgements |
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| Footnotes |
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Abbreviations: BAL- = BAL negative; BAL+ = BAL positive; CI = confidence interval; FIO2 = fraction of inspired oxygen; OR = odds ratio; SAPS = simplified acute physiology score; VAP = ventilator-associated pneumonia
Received for publication June 19, 1998. Accepted for publication March 11, 1999.
| References |
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