Impact of BAL Data on the Therapy and

Outcome of Ventilator-Associated Pneumonia*

Carlos M. Luna, MD, FCCP; Patricia Vujacich, MD;
Michael S. Niederman, MD, FCCP; Carlos Vay , PhD; Carlos Gherardi, MD;
Josue Matera, PhD; and Enrique C. Jolly, MD

Study objective: To define the impact ofBAL data on the selection of antibiotics and the outcomes
of patients with ventilator-associated pneumonia (VAP).
Design: Prospective observation and bronchoscopy with BAL, performed within 24 h of estab-
lishing a clinical diagnosis of a new episode of hospital-acquired VAP or progression of a prior
episode of nosocomial pneumonia (NP).
Setting: A 15-bed medical and surgical ICU.
Patients: One hundred thirty-two patients hospitalized for more than 72 h, who were mechani-
cally ventilated and had a new or progressive lung infiltrate plus at least two of the following
three clinical criteria for VAP: abnormal temperature (>38°C or <35°C), abnormal leukocyte
count (> 10,000/mm3 or <3,000/mm 3 ), purulent bronchial secretions.
Interventions: Bronchoscopy with BAL within 24 h of establishing a clinical diagnosis of VAP or
progression of an infiltrate due to prior VAPor NP. All patients received antibiotics, 107 prior to
bronchoscopy and 25 immediately after bronchoscopy.
Results: Sixty-five of the 132 patients were BAL positive (BAL[ + ]), satisfying a microbiologic
definition ofVAP ( > 104 cfu/mL), while 67 were BAL negative (BAL[- ]). The BAL( +)patients had
no differences in mortality, prior antibiotic use, and demographic features when compared with
the BAL(-) patients. More of the BAL( +) patients (38/65) satisfied all three clinical criteria of
VAP than did BAL(-) patients (24/67) (p<0.05). A total of 50 BAL( +) patients received antibiotic
therapy prior to bronchoscopy, and when this prior therapy was adequate (n=16), as defined by
the results of BAL, then mortality was 38%, while if prior therapy was inadequate (n=34),
mortality was 91% (p<0.001), and if no therapy was given (n= 15), mortality was 60%. When
therapy changes were made after bronchoscopy, more patients (n=42) received adequate
therapy, but mortality in this group was comparable to mortality among those who continued to
receive inadequate therapy (n=23). A total of 46 of the 65 BAL(+) patients died, with 23 of these
deaths occurring during the 48 h after the bronchoscopy, before BAL results were known. When
BAL data became available, 37 of the 42 surviving patients received adequate therapy, but their
mortality was comparable to the patients who continued to receive inadequate therapy.
Conclusions: Patients with a strong clinical suspicion ofVAP have a high mortality rate, regardless
of whether BAL cultures confirm the clinical diagnosis ofVAP. When adequate antibiotic therapy
is initiated very early (ie, before performing bronchoscopy), mortality rate is reduced if this
empiric therapy is adequate, compared to when this therapy is inadequate or no therapy is given.
If adequate therapy is delayed until bronchoscopy is performed or until BAL results are known,
mortality is higher than if it had been given at the time of first establishing a clinical diagnosis of
VAP. When patients were changed from inadequate antibiotic therapy to adequate therapy,
based on the results of BAL, mortality was comparable to those who continued to receive
inadequate therapy. Thus, even if bronchoscopy can accurately define the microbial etiology of
VAP, this information becomes available too late to influence survival.
(CHEST 1997; 111:676-85)

Key words: antibiotic th erapy; broncboalveolar lavage; diagnosis; nosocomial pneumonia; pneumonia; ventilator-
associated pneumonia
Abbreviations: BAL(-)=BAL negative; BAL(+)=BAL positive; EPI=extrapulmonary infection; NP=nosocomial
pneumonia; PSB=protected specimen brush; VAP=ventilator-associated pneumonia

Pulmonary and Critical Care Medicine, Winthrop-University

*From the Department of Medicine, Pulmonary Diseases Divi-
sion and Critical Care Division, and from the Clinical Analysis
Laboratory, Microbiology Division, Hospital de Clfnicas "Jose de
San Martin," University of Buenos Aires, Argentina (Drs. Luna,
Vujacich, Vay, Gherardi, Matera, and Jolly), and the Division of
Hospital, Mineola, NY (Dr. Niederman ).
Manuscript received January 2, 1996; revision accepted Septem-
ber 24.
Reprint requests: Dr. Niederman, 222 Station Plaza N, Suite 400,
Mineola, NY 11501

676 Clinical Investigations in Critical Care

H ospital-acquired pneumonia complicates the
course of mechanical ventilation in as many as
20% of all patients and serves as the hospital-
acquired infection most likely to lead to the death of
critically ill patients_! Current management strate-
gies emphasize early diagnosis and therapy, with
antibiotics focused on the most likely etiologic or-
ganisms, usually enteric Gram-negative bacteria and
Staphylococcus au reus. Controversy remains about
the most accurate way to diagnose this infection and
the appropriate timing of antibiotic therapy in rela-
tion to the clinical suspicion of pneumonia. In some
studies, antibiotic therapy itself has b een identified
as a risk factor for both infection with highly virulent
organisms and an increased mortality rate from
YAP.2 •3
Concern that the prior use of antibiotics could
enhance the mortality of YAP, coupled with an
awareness that the clinical diagnosis of this infection
is sensitive, but not specific, has led some investiga-
tors to suggest that antibiotic therapy decisions be
guided by the results of bronchoscopically directed
sampling of lower respiratory tract secretions .4 •5
Using this approach, antibiotics are administered
only when the diagnosis of pneumonia is confirmed
microbiologically by bronchoscopic methods.4 •5 An
alternative approach is to use early and aggressive
empiric antibiotic the rapy once aclinical diagnosis of
YAP is made, not basing any decision making on the
results of bronchoscopic sampling, because of a
concern that the microbiologic diagnosis of YAP is
not sensitive enough to recognize all infected pa-
tients.6
While controversy about the most accurate way to
diagnose YAP continues, no investigator has shown
that outcome, particularly mortality, in the setting of
suspected YAP, is improved if antibiotics are pre-
scribed based on a bronchoscopic diagnosis rather
than empirically, once aclinical diagnosis of YAP has
been made. However, some previous studies have
shown that antibiotic therapy can have a favorable
impact on the outcome of YAP, with lower mortality
rates b eing observed if appropriate therapy, rather
than inappropriate therapy, is prescribed. 7 ·8 Thus, it
might be possible to evaluate the utility of bronchos-
copy in the management of YAP from a therapeutic
perspective. If bronchoscopy is valuable for the
management of YAP, then the data obtained from
quantitative bronchoscopic cultures could be used to
select the most appropriate antibiotic and this should
in turn improve survival in patients with suspected
YAP. Alternatively, e ven if bronchoscopy can pro-
vide accurate microbiologic data, it may do so too
late in the course of the illness to impact survival,
because it may be necessary to choose adequate
empmc therapy from the start, even b efore the
result of bronchoscopic cultures can be known.
To address these questions, we performed bron-
choscopy with quantitative BAL in all patients with a
clinical suspicion of YAP, within 24 h of the clinical
diagnosis of YAP or within 24 h of progression of a
previously diagnosed episode of nosocomial pneu-
monia (NP) or YAP. We looked at the adequacy of
antibiotic therapy, using bronchoscopic culture data
to define the etiology of YAP, in all patients who
satisfied both a clinical and a microbiologic definition
of pneumonia (> 104 cfu/mL). We examined the
adequacy of therapy at three time points : prior to
BAL (empiric therapy), immediately after BAL (em-
piric therapy), and after the results of BAL were
known. We examined whether the data obtained by
BAL were used to modify therapy and whether such
changes l ed to a favorable outcome.
We confirmed the previous obse rvation that ade-
quate antibiotic therapy can improve survival in
patients with YAP, but only if given early in the
course of illness, at a time when microbiologic data
were not available. When BAL results were known
and when they documented that the initial empiric
therapy was inadequate, this information did not
help patients, because the institution of adequate
therapy at this time was associated with as high a
mortality as when inadequate therapy was continued.
Thus, even if BAL can provide accurate microbio-
logic information, our data suggest that it has no
beneficial role in the selection of antibiotics, and that
the outcome in YAP can be improved only if initial
e mpiric therapy is accurate and timely.
MATERIALS AND METHODS
The study was conducted from April 1, 1992 to November 30,
1995 in the C1itical Care Unit of the "Clinicas Jose de San
Martin" University Hospital, Buenos Aires, Argentina. This is a
15-bed m edical (noncoronary) and surgical unit at a 500-bed
teaching hospital that serves as both a r eferral cente r and a
primary care hospital. During the study period, 2,588 patients
were admitted. Patients intubated and receiving mechanical
ventilation who developed a n ewor progressive infiltrate on chest
radiograph after b eing in hospital for more than 72 h were
eligible for the study if th ey fulfilled at least two of the follo\ving
criteria: (1) temperature >38°C or < 35°C; (2) leukocytes count
> l0,000/mm 3 or < 3,000/mm 3 ; and (3) purulent bronchial secre-
tions. P atients \\~th previous NP were included if they developed
a newor progressive infiltrate along vvith a clinical deterioration,
and if th ey fulfill ed the other clinical crite1ia of VAP. Severely
neutropeni c .( < 500 neutrophils ) and AIDS patients were not
eligible for the study.
The follo~~ng information was recorded prospectively: age;
sex; dates of admission and discharge from the ICU; prior trauma
or surge1y; presence of COPD or other pulmonary disease;
cardiac disease; heart failure; shock; diabetes; renal failure;
non pharmacologic consciousness depression or coma; duration of
tracheal intubation and mechanical ventilation p•ior to the
CHEST I 111 I 3 I MARCH, 1997 677
development of VAP; use of corticosteroids; use of antacids, progression of a prior stable infiltrate. In the 25 patients not
including H 2 blockers; and other underlying diseases. Shock was receiving prior antibiotics, therapy was started immediately after
defined as a systolic BP ::;go mm Hg, requirement of vasopres- performing BAL. In 64 of the 107 patients receiving prior
sors for more than 4 h, or urinary output less than 20 mUh for antibiotics, a change in therapy was done immediately after the
more than 4 hours; cardiac failure was defined by a pulmonary BAL, while in the other 43, therapy either did not change at all
artery occlusion pressure 2o18 mm Hg or clinically (third heart or changed only after having the BAL culture results available.
sound gallop, neck vein distention and/or suggestive interstitial To perform the BAL, the bronchoscope was advanced and
edema at the chest radiograph in patients with obvious severe wedged into a distal airway in the area involved by the infiltrate,
cardiac disease) in the few patients in whom that pressure was not as seen on chest radiograph, or into a subsegment of the middle
available; consciousness was evaluated by the Glasgow Coma lobe or lingula if diffuse inflltrates were noted. After wedging, six
Scale, and postoperative respiratory failure was diagnosed when 20-mL aliquots of sterile, nonbacteriostatic saline solution (0.9%
patients were mechanically ventilated after surgery. All the NaCI) were instilled through the channel of the bronchoscope
patients who received antimicrobials for more than 24 h during and subsequently aspirated by hand. The first aliquot instilled
the 10 days preceding the episode of VAP (mean, 119 h; range, 24 was discarded, the remaining aliquots were saved, with the total
to 360 h) or those who were receiving antimicrobials for pre- amount of saline solution instilled through the bronchoscope
sumed VAP during the 24 h before the bronchoscopy were (after the first discarded aliquot) being 100 mL.
defined as receiving prior antibiotics. A total of 132 patients were Recovered BAL fluid was processed for semiquantitative cul-
studied, with 107 receiving prior antibiotics, while 25 were not ture for aerobic bacteria. Using a quantitative loop, 0.01 mL of
receiving antibiotics prior to bronchoscopy. Prior antibiotics were the BAL fluid was plated onto each of four culture media (sheep
given to 54 patients for NP, while in the other 53 patients, the blood agar, EMB Levine Agar, mannitol salt agar, and chocolate
indication was another condition (community-acquired pneumo- blood agar). After inoculation, each plate was incubated at 35°C
nia in 16 and extrapulmonary infection in 37) (Table 1). Mean in a C0 2 -enriched environment. Estimates of the number of
duration of antibiotic therapy was 8.1 ::+::5.8 days, including prior bacteria originally in the fluid were made by colony counts and
use of antibiotics. At the onset of the study, 107 patients had bee n were expressed as colony-forming units per milliliter of fluid.
receiving prior antibiotics for a mean of 5.1::+::3.0 days. Mean Since other authors found that more than 104 cfulmL correlated
duration of mechanical ventilation at the onset of the study was with the final diagnosis of VAP with a sensitivity between 80%
7.8::+::14.4 days (5.8::+::5.7 days excluding three patients who were and 100% and a specificity between 69% and 100%, 9 - 11 we chose
ventilated for more than 70 days) and from the time of bronchos- "more than 104 cfulmL" of at least one species as the cutoff point
copy to the time of death in patients who died, 6.6::+::9.1 days. for bacteriologic confirmation of the diagnosis of pneumonia.
Fiberoptic bronchoscopy examination was performed in each In patients with BAL-confirmed pneumonia (n=65), antibiotic
patient within 24 h after the development of a new inHltrate or susceptibility was tested; if the organisms present at a concentra-
tion >than 104 cfulmL were demonstrated to be sensitive to the
agent prescribed, the patient was defined as being treated with
adequate antibiotics and if they were resistant, the patient was
Table !-Clinical Features of All Patients*
defined as being treated with inadequate antibiotics. Sensitivity
Results of BAL Culture patterns in the antibiogram, and not the response of the organ-
isms to the therapy or the use of combination therapy instead of
Positive Negative monotherapy, were used to define the adequacy of therapy.
Clinical Characteristics (n=65) (n=67) Antibiotic therapy was evaluated at three different time points:
pre-BAL=before performing BAL; post-BAL=evaluating the
Age, yr 60::+::21 60::+::19
empiric therapy received immediately after performing BAL; and
Sex, M/F 41/24 40/27
postresult=evaluating the therapy choices that were guided by
Temperature, °C 38.5::+::1.1 38.6::+::1.0
the antimicrobial sensitivity data. Each patient could be rede-
Blood leukocytes/mm 3 15,006::+::7,202 14,148::+::5,390
fined at each time point as receiving adequate or inadequate
PaO/Fio2 188::+::91 202::+::99
5§ antibiotics.
Bacteremia 18
The selection of antibiotic therapy was left to the discretion of
Postoperative respiratmy failure 27 29
the attending physician and the medical staff. Although the
Consciousness altered 37 38
preferred approach of our group is to first perform the BAL and
Shock 29 25
then start antibiotic therapy empirically, at the moment of
Preexisting pulmonary disease 27 32
performing BAL, 107 of 132 patients were receiving antibiotics or
Preexisting cardiac disease 23 23
had received them for at least 24 h during the preceding 10 days.
Cardiac failure 8 6
All of the patients defined as receiving adequate therapy at the
Malignant neoplasm 14 15 pre-BAL time point were receiving this therapy at the time of
Mortality, % 7l 64 performing the bronchoscopy except for two patients who had
P1ior antibiotic 1 50 57 received antibiotics for 360 h and 120 h, and then the therapy was
For VAP, 1 54 (10) 26 (6) 28 (4)
suspended for 24 h and 96 h, respectively, prior to performing
For CAP, 16 (1) 8 (0) 8 (1)
bronchoscopy.
For EPI, 37 (2) 16 (1) 21 (1)
Blood cultures were collected within 24 h of BAL in all
No. of criteria of pneumonia patients. Bacteremia was present when two or more of each set of
Only 2 27 43 11 two or three blood cultures yielded a microorganism. In two
All3 38 2411
cases, only one of hvo bottles was positive but the bacteria were
*CAP=community-acquired pneumonia; Fio 2 =fraction of inspired also isolated from BAL and this was considered evidence of
oxygen. bacteremic VAP.
'Numbers in parentheses indicate S24 h. All patients were monitored until their discharge from the
1VAP or NP. hospital. Subsequent changes in their clinical course, chest
§p=0.005. radiograph, and modifications in antibiotic therapy were re-
llp<0.05. corded in all the cases.

678 Clinical Investigations in Critical Care

Statistical Analysis
Data are expressed as means:!::SD. To assess if there was a
difference between the clinical picture of the patients with
positive and negative BAL specimens, clinical variables and
mortality in both groups of patients were compared using
Student's t test or Fisher's Exact Test. In addition, the same
variables were compared in patients with BAL positive (BAL[ +])
pneumonia taking into account whether they were receiving prior
antimicrobial therapy. Also, the frequency of finding different
etiologic microorganisms was compared between patients receiv-
ing prior antibiotics and patients not receiving p1ior antibiotics
and the relation between the etiologic agent and the a dequacy of
the pre-BAL antibiotic therapy was related to mortality, using
Fisher's Exact Test.
RESULTS
During the 44-month period of this study, 132
episodes of suspected bacterial lung infection were
evaluated by fiberoptic bronchoscopy and BAL;
however, the BAL technique was able to confirm
infection microbiologically (> 104 cfu/mL) in 62 in-
dividuals for a total of 65 episodes ( BAL[+] VAP) ,
49.2% of the clinical pneumonias (Table 1). Three
patients experienced more than one episode and
their histories and outcomes for each pneumonia
were treated as separate cases, the second episode in
those patients happening at least 9 days after the first
one. In one of these cases, the patient died after the
second episode of VAP, and thus the patient was
considered as alive for the first episode and as a
mortality for the second. All 132 episodes had a
clinical suspicion of VAP and all patients received
antibiotic therapy for a mean of 4.1 days after
performing BAL. Table 2 shows which types of
Table 2-Antimicrobials Used at Pre-BAL and Post-
BAL Times*
antibiotics were used and if monotherapy or combi-
nation therapy was chosen prior to performing BAL
and after BAL, distinguishing if therapy was given
for the VAP or for another reason.
Results of BAL Culture in the Patients Studied
Less than half of the patients (n =62) met all three
clinical criteria (of the "at least 2" required for
inclusion) for the diagnosis of bacterial pneumonia
(Table 1). Cultures of BAL were negative (<104
cfu/mL) in 67 of 132 patients (50.8%). Among these
patients with negative cultures, there was no growth
in 30 patients and growth was between 10 1 and 104
cfu in 37 others. Most of the BAL( +)patients met all
three criteria of bacterial pneumonia (38/65), while
only 24/67 BAL negative (BAL[-]) patients met
these three criteria (p<0.05).
Demographic characteristics and some laboratory
and clinical data that are markers of severity of illness
are shown in Table 1. Besides the number of clinical
criteria present, only the presence of bacteremia was
significantly more common in BAL( +) than in
BAL(-) patients (p<0.01). Bacteremia was present
in 18 patients with BAL( +) VAP; in 13 cases, the
organism was also obtained in the BAL culture.
Bacteremia was also present in five patients with
negative BAL culture, but the organism was isolated
from BAL fluid (although in a count <10 4 cfu) in
only one case.
Mortality of the 132 episodes of suspected pneu-
monia was 67%. For the BAL( +) patients, mortality
was 71% and for the BAL(-) patients, mortality was
64% (p=NS). There were no differences in age, sex,
leukocytosis, oxygenation, use of ptior antibiotics (for
treating the VAP or for other reason), or clinical
diagnoses at ICU admission, when comparing
BAL( +) and BAL(-) patients.

Pre-BAL Results in Patients With BAL( + ) Pneumonia

Overall VAP Other Post-BAL In a total of 50 of 65 episodes of BAL( +) pneu-
Monotherapy 30 9 21 13 monia, patients received antibiotic treatment before
Combination 77 45 32 119 fiberoptic bronchoscopy was performed: 16 for an
AGS 29 17 12 36 extrapulmonary infection, eight for a previous com-
APS 34 18 16 40 munity-acquired pneumonia, and 26 for presumed
B+BI 7 3 4 4
8t
VAP or NP. Of the 26 patients receiving antibiotics
CEP 38 30 27
IMID 23 7 16 19 for VAP, six were treated for < 24 h prior to BAL,
IMP 21 14 7 63 1 and 20 were treated for > 24 h prior to BAL, but all
VAN 32 21 ll 861 had radiographic progression documented within
Others 22 9 13 20 24 h prior to BAL being performed. There was no
*AGS=aminoglycosides; APS= antipseudomonal agents; B +BI = f3-lac- significant difference in mortality between the
tam+f3-lactamase inhibitor; CEP =cephalosporins; IMID=imidazole; BAL( +) VAP patients who were receiving prior
IMP = imipenem; VAN =vancomycin; Others=macrolides, antifungal
antibiotics and those who were not receiving prior
agents; trimethoprim-sulfa; penicillins; quinolones.
1
p<0.00l =pre-BAL use of CEP for VAP vs other reason. antibiotics (37/50=74% vs 9/15=60%) (Table 3).
1p< 0.00l = use of IMP at pre- BAL time point vs post-BAL. Similarly, there were no significant differences b e-
1p< 0.001 =use of VAN at pre-BAL time point vs post-BAL. tween those BAL( +) patients receiving prior antibi-

CHEST I 111 I 3 I MARCH, 1997 679

Table 3-Features of BAL-Positive Patients in Relation Although the 50 patients who received prior anti-
to Prior Antibiotic Therapy biotics did not have asignificantly different mortality
Prior Antibioti c Th erapy than the 15 who did not receive prior antibiotics,
there were mortality differences among these pa-
Without With
Clinical Characteristics (n=l5) (n =50) tients depending on the adequacy of pre-BAL anti-
biotic choices (Fig 1). Patients who received ade-
Age, yr 53 :+: 26 62:+: 20
Sex, M/F 11/4 30/20
quate antibiotics early (prior to the BAL) had a
Te mperature, oc 38.6:+: 0.5 38.4:+: 1.6 significantly lower (p < 0.001 ) mmtality rate of 38%
Blood leukocytes/mm·3 14,080:+: 5,822 15,284:+: 7,545 (6/16) than the patients who r eceived inadequate
PaOzfFI0 2 * 203:+:95 185:+:90 antibiotics at this time and who had a mortality rate
Bacteremia 4 13
of 91 % (31134). The 16 patients receiving adequate
Postoperative respiratory failure 4 23
Consciousness altered 7 30 therapy at the pre-BAL time were being treated for
Shock 5 24 a n ew YAP (n=4 ), progression of prior YAP or NP
Preexistin g pulmonary disease 6 21 (n=9 ), or extrapulmonary infection (EPI) (n=3).
Preexistin g cardiac disease 7 16 As previously mentioned (Table 3), mortality was
Cardi ac f ailure 0 8
60% (9/15) for the group of patients who received no
Malignant neoplasm 1 13
M01tality,% 60 74 antibiotics prior to BAL. Adding these 15 patients to
No. of criteria of pn eumonia the 34 who received inadequate antibiotics prior to
Only 2 6 21 BAL, the mortality was 81.6% (40/49) , even though
Al\ 3 9 29 some patients subsequently had therapy modified to
*Fio 2 = fraction of inspired oxygen. an adequate agent, either empirically or based on
BAL culture results . The mortality rate of these
patients was significantly higher than the mortality
otics and those who were not (Table 3), with respect observed in patients receiving adequate antibiotics
to age, sex, leukocytosis, oxygenation, bacteremia, prior to BAL (p<0.005 ) (Fig 2).
clinical findings suggestive of severity of illnesses, or Antibiotic therapy was initiated immediately after
number of diagnostic clinical criteria of pneumonia performing BAL in the 15 patients not receiving
present. previous antibiotics. For the 50 patients already

!00%
p·=·N-.s·.· -- ··· ··-····
80%

~ SO%

~
c:t::
0 40%
~

20%

pre-BAL (N:66) post-BAL (N:66) post RESULT (N:42)

NO-ATB 60% (9/15)

ADEQUATE 38% (6/16) 71% (30/42) 57% (21/37)
NOT-ADEQUATE 91% (31/34) 70% (16/23) 40% (2/5)

I:2:J NO-ATB .ADEQUATE ts:J NOT-ADEQUATE

FIGURE l. Mortality rates are plotted in re lation to the adeguacy of antibiotic therapy at three diffe rent
tim es (pre-BAL, post-BAL, and postresult). Statistical diffe re nces between adequate and inad equate
the rapy are present only at the pre-BAL time, when mortality was lower for p ati ents receiving adequate
the rapy.

680 Clinical Investigations in Critical Care

 100%
80%
20%
O%JL--------------
ADEQUATE
NOT-ADEQUATE or NO-ATB
.ADEQUATE ts::JNOT·ADEQUATE or NO·ATB
FIGURE 2. For the 65 patients with a positive BAL culture, the impact of the initial therapy, at the
pre-BAL time, on the outcome was evaluated. Patients receiving adequate initial antibiotic therapy had
a significantly lower mortality rate than patients receiving either inadequate antibiotic therapy or no
antibiotics.
recervmg antibiotics, therapy was changed in the
immediate post-BAL period in 33 cases while it was
not changed in the other 17. Three of 16 patients
receiving adequate antibiotics pre-BAL had a change
to inadequate antibiotic therapy at the post-BAL
time and two of these patients continued with this
therapy, even after BAL data were known, because
they were responding clinically and radiographically.
With these changes, 42 of the 65 BAL( +) patients
were receiving adequate therapy in the immediate
post-BAL time. At the time that BAL results were
known, antibiotic therapy was changed in 20 cases,
not changed in 22, and 23 patients had already died.
When BAL data were known, 37 of the 42 surviving
patients were receiving adequate therapy.
As shown in Figure 1, the prescription of adequate
antibiotics, compared with inadequate therapy, re-
duced mortality only at the pre-BAL time. At the
post-BAL time (empiric therapy) and at the post-
result time (culture-guided therapy), even though a
larger percentage of patients received adequate ther-
apy, this did not reduce the mortality when com-
pared with the outcomes observed in those receiving
inadequate antibiotics. This lack of reduction in
mortality applied even after excluding the 23 early
mortalities, and examining only the remaining 42
patients evaluated when BAL results were known.
p< 0.005
38% (6/16)
81,6% (40/49)
Thus, doing BAL and defining adequate therapy did
not significantly reduce the mortality for patients
who initially received inadequate therapy, and much
of the potentially useful bacteriologic information
became available very late, after 23 of the patients
had died.
Etiology and Outcome of BAL( +) V AP: Influence
of Previous Antimicrobial Therapy
A total of 123 microorganisms were cultured from
BAL in the 6.5 episodes of BAL( +) VAP, at a
concentration> 10 cfu/mL (1.9 microorganisms per
pneumonia). The most frequently isolated organisms
were S aureus, Acinetobacter species, Klebsiella
pneumoniae, and Pseudomonas aernginosa. They
were involved in 49%, 49%, 26%, and 20% of these
pneumonias, respectively. Twenty of the 32 isolated
organisms of S aureus were identified as methicillin
resistant. Acinetobacter species and/or S aureus (at
least one of them) were involved in 74% of the
episodes of pneumonia. There were no differences
in mortality for any specific microorganism (Table 4).
No specific pathogen (Table 4) was present signifi-
cantly more frequently in the group of patients
receiving prior antibiotics than in the group not
receiving prior antibiotics (p>0.05) .
CHEST I 111 I 3 I MARCH, 1997 681
 Table 4-Etiology, Adequacy of Antibiotic Therapy, and Mortality in 65 Cases of BAL+ VAP*

Prior Antibiotic Therapy Mortality

NO-ATB 1 ATB Total ADEQ NO-AD

General % o/o %
Microorganism (n=15) (n=50) (n=65) ATB ATB

Gram-negative bacilli 12 65 77
Acinetobacter sp 4 28 32 25/32 78 1/5 20 24/27 s9t
K pneumoniae 16 17 13/17 76 1/4 25 12/13 92§
P aemginosa 4 9 13 7/13 58 416 67 3/7 43
Proteus mirabilis 0 4 4 2/4 50 l/3 33 1/1 100
Escherichia coli 2 3 3/3 100
Neisseria sp 0 2 2 2/2
Enterobacter cloacae 1 1 2 112
Pseudorrwnas putida 0 0/1
Citrohacter sp 0 1 1/1
1-Iaemophylus injluenzae 0 1 0/l
Alcaligenes xiloxida 1 0 1/ l
Gram-positive cocci 13 29 42
S aureus 9 23 32 21/32 66 1/7 14 20/25 56t
Streptococcus viridans 2 3 5 2/5 40 1/3 33 1/2 50
Staphylococcus epidennidis 0 2 2 2/2
Streptococcus agalactiae 1 0 1/1
Corynebacterium sp 1 0 1/ 1
Enterococcus faecium 0 1/1
Fungi 0 4 4
Candida sp 0 4 4 3/4 75 0/1 0 3/3 100
Total 25 98 123
*NO-ATB=patients not receiving prior antibiotics; ATB=patients receiving prior antibiotics; Mortality=No. of cases dead/cases; ADEQ
ATB=patients receiving prior adequate antibiotics; NO-AD ATB=patients not recei\~ng prior adequate antibiotics (NO ATB+ INADEQUATE
ATB).
1p=NS; p value compares frequency of isolation of the different microorganisms in the group receiving antibiotics \vith the group not receiving

antibiotics.
tp< 0.005.
\p<0. 01; p value compares mortality related to different microorganisms in cases with adequate vs no-adequate (inadequate+ NO-ATB) pre-BAL
antibiotics.

The use of adequate pre-BAL antibiotics for in-
fections with Acinetobacter species, K pneumonia,
and S aureus (Table 4) led to a lower mortality rate
than the use of inadequate antibiotics for these
organisms.
DISCUSSION
Bacterial infection of the lung is a common com-
plication of mechanical ventilation and most re-
searchers have adopted or modified the clinical
definition of pneumonia used by Johanson et alt 2
(radiographic appearance of a new or progressive
pulmonary infiltrate; fever; leukocytosis; and puru-
lent tracheobronchial secretions). However, several
studies have demonstrated that the same clinical
picture can occur without bacterial pneumonia, mak-
ing this definition sensitive, but not specific. Contro-
versy has therefore developed over whether a clinical
definition of pneumonia should be used to guide
decisions about the initiation or continuation of
antibiotic therapy. Some investigators have proposed
that antibiotic decisions be guided by microbiologic
confirmation of the clinical diagnosis of pneumonia,
relying on quantitative cultures obtained from bron-
choscopic techniques, including BAL and the pro-
tected specimen brush (PSB), because these meth-
ods have been reported to accurately confirm or
exclude the diagnosis of pneumonia.l3-16
While emotions run high in this area, no investi-
gator has demonstrated that bronchoscopic data can
favorably influence the outcome of patients with
established NP. Therefore, we examined the initial
and subsequent choices of antibiotics, and the im-
pact of BAL data (collected within 24 h of the clinical
diagnosis of a new or progressive pneumonia), on the
course and outcomes in 132 episodes of clinically
suspected YAP. In this study, pneumonia was con-
firmed microbiologically (> 104 cfu/mL on BAL) in
65 episodes, and the bacteriology of BAL cultures
and antimicrobial susceptibility patterns were used
to determine if antibiotic therapy was adequate or
inadequate. These designations were made for each
episode at three different times: pre-BAL, when the

682 Clinical Investigations in Critical Care

 pneumonia was first recognized (early empiric ther-
apy); post-BAL when the bronchoscopy was com-
pleted (empiric therapy); and postresult, when BAL
data were known (culture-guided therapy). At each
successive time point, alarger percentage of patients
received adequate therapy, but the use of adequate
th erapy was only significant (p<0.001) , compared
with inadequate therapy, if it was given at the
pre-BAL time (Fig 1). If adequate therapy was given
at the post-BAL or postresult time, mortality was
higher than if adequate therapy had been given
earlier. In addition, at these later times, mortality
was comparable whether patients received adequate
or inadequate therapy. We also found that among
the 46 patients who died, 23 died within the first 48 h
after bronchoscopy, a time before BAL data were
available to guide therapy. Thus, definitive bacterio-
logic data often became available too late to be
clinically useful, and there was no evidence that the
information provided by BAL could be used to
reduce mortality in these seriously ill patients. Ade-
quate antibiotic therapy did have benefit for some
patients, but this benefit was most clear if therapy
was initiated empirically at the earliest possible time
after the clinical recognition of infection.
When the 65 BAL( +) patients were compared
with the 67 BAL(-) patients (Table 1), mortality
rates were comparable and the two groups differed
only with the finding that significantly more BAL( + )
patients had all three clinical criteria of pneumonia
present and more were bacteremic. Thus, when VAP
was confirmed by BAL culture, patients were more
likely to have three clinical criteria present than to
have only two such criteria, while the opposite
situation was found in patients whose pneumonia
was not confirmed by BAL (p<0.05 ). These data
suggest some value in carefully observing the clinical
features of VAP, even though some investigators
have suggested that these clinical features are overly
sensitive for the diagnosis of VAP and thus of little
value.l 0·13 · 16 ·li However, others have found , as we
did, that the clinical definition of pneumonia does
correlate with BAL data, reporting a higher fre-
quency of clinical pneumonia in BAL( + ) patients
than in BAL(- ) patients. 18
One limitation to the use of bronchoscopy in
critically ill patients is the finding that prior antibiotic
therapy can lead to fals e-negative microbiologic data,
even though some studies have collected quantitative
cultures in patients receiving antibiotics. 11 · 16 In the
present study, BAL was done regardless of whether
the patient was receiving antibiotics and the overall
clinical picture in the 65 BAL( +) patients was
similar regardless of whether the patient was receiv-
ing antibiotic therapy (Table 3). In fact, 50 of these
65 patients with microbiologically confirmed pneu-
monia were receiving antibiotic therapy at the time
that BAL was performed. The high rate of positive
BAL results in these patients may be a reflection of
the fact that only 16 individuals were receiving
adequate therapy.
Previous studies have suggested that prior antimi-
crobial therapy can cause a change in the distribution
of infecting pathogens , le ading to infection with
organisms that are associated with a high mortality
rate. 2,17,19 In the present study, we did not observe
significant changes in the distribution of any specific
pathogen as a result of prior use of antibiotics (Table
4). In addition, mortality in the BAL( +) patients was
not higher for patients receiving antibiotics com-
pared with those not receiving antibiotics, even when
taking into account the time that antibiotics were
given (>24 h pre-BAL vs ::::;24 h pre-BAL) and the
reason that antibiotics were prescribed (VAP vs other
causes) (Tables 1 and 3).
Although we observed only a small, nonsignificant
difference (71 % vs 64%) in mortality between
BAL( + ) and BAL(- ) patients, previous studies have
reported that the mortality of patients with microbi-
ologically confirmed VAP (using BAL or PSB ) is
higher than the mortality of patients with clinical
pneumonia but negative BAL or PSB cultures.l 1·20
Our findings may reflect ahigh rate of false (-) BAL
results , possibly as a consequence of the fact that 57
of the 67 BAL(-) patients received prior antibiotic
therapy. It is difficult to comment on the rate of
false-negative results in the BAL(- ) patients, al-
though some of these patients probably were treated
with adequate therapy. For example, one patient had
two of two blood cultures positive for Acinetobacter
species but was BAL(- ), with < 104 cfu/mL for
Acinetobacter species, while receiving adequate an-
tibiotic therapy for that microorganism. It is possible
that other BAL(-) patients also had false-negative
results as a result of antibiotic therapy or had
negative BAL data as a reflection of the inherent
limitations of bronchoscopic cultures. Alternatively,
both BAL( +) and BAL(-) patients could have
comparable, and high, mortality rates because of a
lack of attributable mortality of VAP in this popula-
tion of individuals with a high degree of severe
illness.
The greatest impact of prior antibiotic therapy on
mortality was related to whether that therapy was
adequate for the organisms that were subsequently
identified b y BAL. The following were the most
common bacteria in our study: S aureus (most of
the m m ethicillin resistant) ; Acinetobacter species; K
pneumoniae, and P aeruginosa. Although we did not
find overall differences in mortality related to spe-
cific etiologic pathogens, we did observe that the use
of adequate therapy led to an improved outcome for
CHEST I 111 I 3 I MARCH, 1997 683
certain pathogens (Table 4). For the group as a
whole, as well as with certain organisms, when
adequate therapy was given prior to performing BAL
(at the time that pneumonia was clinically recog-
nized), mortality was lower than if adequate therapy
or no therapy had been given (Fig 2). However, our
data did have a trend toward the finding that when
pneumonia was first recognized, the use of inade-
quate empiric therapy may have been worse than the
use of no therapy (Fig 1). Even when therapy was
later modified to reflect bronchoscopic data, mortal-
ity did not fall when compared with continued
inadequate therapy (Fig 1).
These data fit well with the findings of Montravers
et al 2l who showed that microbiologic evaluation
using a PBS after 3 days of antibiotic therapy can
define a bacteriologic failure, but that the recogni-
tion of such a microbiologic nonresponse did not
lead to modifications in therapy that could improve
outcome. Others have also suggested that the use of
adequate antibiotic therapy cannot affect outcome in
VAP,22,23 but they did not stratify the timing of
adequate therapy in the same way that we did,
looking specifically at early vs late time points.
Our study has a number of limitations that are a
reflection of the fact that the data, although collected
prospectively, were observational, and patients were
not managed with a specific therapeutic protocol.
Other limitations include the following: (1) there was
a high mortality of both BAL( +) and BAL(-)
patients, which might be related to the fact that the
patients in this study were predominantly old and
seriously ill, although comparable mortality rates
have been reported by other investigators, particu-
larly in patients receiving prior antibiotics; 24 (2) most
of the patients were receiving antibiotics prior to
BAL so that the adequacy of therapy of BAL(-)
patients could not be assessed; and (3) many patients
receiving prior antibiotics were being treated for
previous pneumonia or for EPI. Paradoxically, 12 of
16 patients getting adequate therapy at the pre-BAL
time point had developed a new or progressive
infiltrate, with microorganisms susceptible to the
antibiotics used despite >24 h of adequate therapy.
Future studies are needed to confirm our findings
and to determine if they can be generalized to other
critical care settings. In our study, many patients
were infected with potentially resistant Gram-nega-
tive bacteria, and our observations may not apply to
a population with more easily treated organisms. In
addition, our initial antibiotic therapy was often
inadequate, reflecting a need to modify our empiric
approach, although it was impossible to comment on
whether our initial therapy choices in BAL(-) pa-
tients were correct. In addition, we had a surprisingly
high early mortality rate in our patients, which may
684
have been multifactorial and not entirely related to
the presence of pneumonia.
Quantitative bronchoscopic cultures of BAL and
PSB may permit more precise etiologic diagnosis of
pneumonia and must be considered a reference
standard in confirming or ruling out infection in
cettain clinical investigations or epidemiologic sur-
veys ofVAP. Nevertheless, some authors believe that
invasive diagnostic methods do not currently repre-
sent an accepted standard for routinely treating
patients suspected of having VAP. 25 In our study,
BAL permitted us to know the etiology of YAP, but
this knowledge did not help reduce mortality or lead
to an improvement in outcome for any patient group.
Thus, it may be necessary to use appropriate empiric
therapy from the time pneumonia is first recognized,
and if this therapy is adequate, outcome may im-
prove. Our data suggest that if initial therapy is
incorrect, the results of BAL cultures cannot be
relied on to modify therapy and to lead to a favorable
outcome.
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.-\ M E RI C A N CO l l E G E O F

PHY S I C I AN S

Mechanical
~ntilation
The First Annual Symposium and
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June 26-28, 1997
San Diego, California
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CHEST /111 /3/ MARCH, 1997 685