The New England Journal of Medicine <http://nejm.org>





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Original Article


Patients at High Risk of Death after Lung-Volume–Reduction Surgery


National Emphysema Treatment Trial Research Group


Notice: Because of its clinical implications, this article is being
published on August 14, 2001. It will appear in the October 11 issue of the
New England Journal of Medicine.
  _____


ABSTRACT

Background Lung-volume–reduction surgery is a proposed treatment for
emphysema, but optimal selection criteria have not been defined. The
National Emphysema Treatment Trial is a randomized, multicenter clinical
trial comparing lung-volume–reduction surgery with medical treatment.
Methods After evaluation and pulmonary rehabilitation, we randomly assigned
patients to undergo lung-volume–reduction surgery or receive medical
treatment. Outcomes were monitored by an independent data and safety
monitoring board.
Results A total of 1033 patients had been randomized by June 2001. For 69
patients who had a forced expiratory volume in one second (FEV1) that was no
more than 20 percent of their predicted value and either a homogeneous
distribution of emphysema on computed tomography or a carbon monoxide
diffusing capacity that was no more than 20 percent of their predicted
value, the 30-day mortality rate after surgery was 16 percent (95 percent
confidence interval, 8.2 to 26.7 percent), as compared with a rate of 0
percent among 70 medically treated patients (P<0.001). Among these high-risk
patients, the overall mortality rate was higher in surgical patients than
medical patients (0.43 deaths per person-year vs. 0.11 deaths per
person-year; relative risk, 3.9; 95 percent confidence interval, 1.9 to
9.0). As compared with medically treated patients, survivors of surgery had
small improvements at six months in the maximal workload (P=0.06), the
distance walked in six minutes (P=0.03), and FEV1 (P<0.001), but a similar
health-related quality of life. The results of the analysis of functional
outcomes for all patients, which accounted for deaths and missing data, did
not favor either treatment.
Conclusions Caution is warranted in the use of lung-volume–reduction surgery
in patients with emphysema who have a low FEV1 and either homogeneous
emphysema or a very low carbon monoxide diffusing capacity. These patients
are at high risk for death after surgery and also are unlikely to benefit
from the surgery.
  _____

Lung-volume–reduction surgery is a potentially valuable treatment for
patients with advanced emphysema. 1
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%2F2001&strArt=01&strNumber=3&strInstance=1#References3>   4
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=4&strInstance=1#References4>   5
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=5&strInstance=1#References5>   6
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=6&strInstance=1#References6>   7
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=7&strInstance=1#References7>   8
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=8&strInstance=1#References8>   During the
operation, 20 to 35 percent of the emphysematous lung is resected by means
of either a median sternotomy or video-assisted thoracoscopy. Generally,
lung function, exercise capacity, and the quality of life improve after
surgery, but the results vary. 9
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=9&strInstance=1#References9>   The surgical
mortality rate ranges from 4 to 15 percent, 3
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=3&strInstance=2#References3>   and one-year
mortality rates are as high as 17 percent, 10
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=10&strInstance=1#References10>   although
follow-up has often been incomplete. 11
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=11&strInstance=1#References11>   A review of
Medicare claims showed that the six-month mortality rate was 16.9 percent.
12
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=12&strInstance=1#References12>   Uncertainty
about the risk of lung-volume–reduction surgery, the magnitude and duration
of benefit, and optimal selection criteria led the National Heart, Lung, and
Blood Institute and the Center for Medicare and Medicaid Services (formerly
the Health Care Financing Administration) to sponsor a multicenter,
randomized clinical trial, the National Emphysema Treatment Trial. 13
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=13&strInstance=1#References13>
The main goal of the trial is to compare survival rates and exercise
capacity two years after lung-volume–reduction surgery with the results
obtained after medical treatment. An important goal of the trial is to
identify selection criteria for lung-volume–reduction surgery. The inclusion
criteria for the trial are broad enough to allow the evaluation of subgroups
of patients who have traditionally been considered candidates for surgery,
but who were present in only small numbers in previous studies. 10
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=10&strInstance=2#References10>   Every three
months a data and safety monitoring board reviews recent medical literature,
the quality of the data, adverse events, and outcome data from the trial.
The board is charged with periodically reviewing subgroups of patients who
may benefit from or be harmed by the procedure; as a result of such review,
a set of clinical characteristics that defines a group of patients with a
high mortality rate and little benefit after lung-volume–reduction surgery
has been identified and is described in this article. The National Emphysema
Treatment Trial has now modified the protocol to exclude these patients.
Patients who do not meet these exclusion criteria continue to be enrolled in
the trial, and their results will be reported when the trial is completed.

Methods
The design and methods of the National Emphysema Treatment Trial have been
described previously 13
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=13&strInstance=2#References13>   and are
summarized below.
Screening and Base-Line Assessments
The inclusion criteria were as follows: a forced expiratory volume in one
second (FEV1) that was no more than 45 percent of the predicted value 14
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=14&strInstance=1#References14>   but that was at
least 15 percent of the predicted value among patients who were 70 years of
age or older, a total lung capacity that was at least 100 percent of the
predicted value, 15
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=15&strInstance=1#References15>   a residual
volume that was at least 150 percent of the predicted value, 15
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=15&strInstance=2#References15>   a partial
pressure of arterial carbon dioxide of 60 mm Hg or less (55 mm Hg in Denver)
while patients were at rest and breathing room air, a partial pressure of
arterial oxygen of at least 45 mm Hg (30 mm Hg in Denver) while patients
were at rest and breathing room air, an ability to walk farther than 140 m
(459 ft) in six minutes, an ability to complete three minutes of pedaling on
a bicycle ergometer without a load, and abstinence from smoking for six
months before randomization. Patients had to complete a measurement of
carbon monoxide diffusing capacity but were not excluded on the basis of the
value. 16
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=16&strInstance=1#References16>   Lung function
was tested according to the guidelines of the American Thoracic Society. 17
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=17&strInstance=1#References17>   18
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=18&strInstance=1#References18>   19
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=19&strInstance=1#References19>   Patients were
excluded if they had other medical conditions that made them unsuitable for
surgery or that might interfere with follow-up. All patients provided
written informed consent, and the study was approved by the institutional
review board at each center.
The severity and distribution of emphysema were determined from
high-resolution computed tomographic (CT) scans of the chest obtained during
full inspiration. Each lung was divided into three apical-to-basal zones,
and each zone was scored visually by a radiologist who had been trained in
the study protocol. The extent of emphysema was graded from 0 to 4, with a
grade of 0 indicating no emphysema and a grade of 4 indicating the presence
of emphysema in more than 75 percent of the lung zone. 20
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=20&strInstance=1#References20>   21
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=21&strInstance=1#References21>   22
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=22&strInstance=1#References22>   Heterogeneous
emphysema was defined as a difference in scores of at least two among the
three zones in one lung; otherwise, the distribution of emphysema was
classified as homogeneous.
The initial evaluation included six-minute walk tests, 23
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=23&strInstance=1#References23>   24
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=24&strInstance=1#References24>   lung-function
tests, bicycle ergometry to determine maximal exercise capacity, the 77-item
Quality of Well-Being questionnaire (scores can range from 0 to 1, and
higher scores indicate a better quality of life), 25
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=25&strInstance=1#References25>
echocardiography, radionuclide pharmacologic (dobutamine) stress testing,
measurement of arterial blood gases, and lung-perfusion scanning. Patients
who met the enrollment criteria had to complete 6 to 10 weeks of pulmonary
rehabilitation, after which the participating center's pulmonologist and
surgeon, in consultation with an anesthesiologist and, if necessary, a
cardiologist, had to determine whether the patient was a suitable candidate
for lung-volume–reduction surgery. Exercise testing, lung-function testing,
the Quality of Well-Being questionnaire, and six-minute walk testing were
then repeated. Patients who were randomly assigned to medical therapy
continued pulmonary rehabilitation and medical treatment. Patients who were
randomly assigned to undergo lung-volume–reduction surgery underwent
bilateral surgery by means of either a median sternotomy or video-assisted
thoracoscopy; the goal was to resect 20 to 35 percent of each lung. After
surgery, patients continued rehabilitation and medical treatment.
Pulmonary-function testing, exercise testing, the Quality of Well-Being
questionnaire, and the six-minute walk test were repeated six months after
randomization.
Statistical Analysis
We ascertained vital status as of June 2001. In the calculations of 30-day
surgical mortality rates we included only patients who actually underwent
lung-volume–reduction surgery within the trial. Other analyses were
conducted according to the intention-to-treat principle and included
patients in their assigned group regardless of the treatment received. We
used contingency tables to estimate the relative risk of death between
treatment groups, and we used the Poisson distribution to calculate 95
percent confidence intervals. 26
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=26&strInstance=1#References26>   Kaplan–Meier
survival curves from the date of randomization were compared with use of the
log-rank test. 27
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=27&strInstance=1#References27>   We compared
functional outcomes in survivors of surgery and medically treated patients
six months after enrollment using two-sample t-tests of the mean change from
base line. To account for deaths and missing information, we used the
following scoring system to define the change in functional outcome at six
months: patients who had died were given a score of 0, patients who did not
complete the evaluation were given a score of 1, and other patients were
given a score ranging from 2 to 10, depending on the size of the change. For
bicycle ergometry, patients who could not pedal for three minutes without a
load were classified as unable to complete testing. Patients who had died
were given a score of 0 on the Quality of Well-Being questionnaire. Patients
who did not complete the questionnaire were assigned a value equal to one
half the lowest score. We compared the distributions of scores between
groups using the Wilcoxon rank-sum exact test. 28
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=28&strInstance=1#References28>   All P values
were two-sided.
Interim Monitoring
At the outset of the study, the investigators provided the data and safety
monitoring board with stopping guidelines that were to be used to identify
subgroups that benefited from lung-volume–reduction surgery as well as
subgroups whose risk was increased by the procedure. Both the investigators
and the data and safety monitoring board considered a 30-day surgical
mortality greater than 8 percent to be unacceptable; a stopping guideline
was therefore instituted to terminate randomization if the lower 95 percent
confidence limit for 30-day mortality exceeded 8 percent.
The investigators requested that the data and safety monitoring board pay
special attention to a subgroup of patients who were thought likely to have
substantial benefit from lung-volume–reduction surgery, with the
understanding that this group might have enrollment terminated early if such
benefit were found. The criteria for the group thought likely to benefit
were an age of 70 years or less, a postbronchodilator FEV1 of 15 to 35
percent of the predicted value, a partial pressure of arterial carbon
dioxide of 50 mm Hg or less (45 mm Hg in Denver), a residual volume greater
than 200 percent of the predicted value, a low radionuclide perfusion ratio
(0.2 or less), a heterogeneous pattern of emphysema on CT scanning, and
evidence of hyperinflation on chest radiography.
The data and safety monitoring board examined these seven candidate
variables and five other variables (the carbon monoxide diffusing capacity,
maximal work capacity, quality of life, race or ethnic group, and sex) added
by the investigators and approved by the data and safety monitoring board to
identify subgroups of patients who might not benefit or might be at risk
from lung-volume–reduction surgery. Exploratory analyses were conducted for
each of these variables. Continuous measures were analyzed both on a
continuous scale and in binary categories, dichotomized at the approximate
quartile for the worst prognosis.
The data and safety monitoring board reviewed subgroups of patients derived
with these candidate variables every three months for evidence of increased
risk or benefit from lung-volume–reduction surgery as compared with medical
management. The statistical significance of the subgroup differences for
each variable was determined from a test for interaction of the variable
with treatment group, with a proportional-hazards regression model for
overall mortality.
Identification of a High-Risk Group
In April 2001, these analyses suggested that a low FEV1, a homogeneous
pattern of emphysema, and a high perfusion ratio predicted an increased risk
of overall mortality. In addition, a low FEV1 and a low carbon monoxide
diffusing capacity were associated with increased 30-day mortality.
Additional analyses of patients with a low FEV1 were then requested by the
data and safety monitoring board to determine whether combination with the
three other factors could define a subgroup of patients who exceeded the
stopping guideline for 30-day mortality. The data and safety monitoring
board, recognizing that any particular cutoff value for a continuous
variable is inherently arbitrary, also requested sensitivity analyses
varying the cutoff values for FEV1 and carbon monoxide diffusing capacity.
In May 2001, the data and safety monitoring board found that the subgroup
defined by a combination of low FEV1 and either homogeneous emphysema or low
carbon monoxide diffusing capacity satisfied the stopping guidelines.
Therefore, the data and safety monitoring board recommended stopping
enrollment of these patients. The board also found that the perfusion ratio
did not add prognostic value after the other risk factors had been accounted
for. It further concluded that the selected thresholds for FEV1 and carbon
monoxide diffusing capacity were the best, given the available data.
Because several risk factors with many potential cutoff points were examined
several times, the investigators and the data and safety monitoring board
considered whether discovery of the high-risk subgroups might represent a
type I error. We concluded, however, that the present findings are unlikely
to represent a type I error. The risk factors were identified prospectively
on the basis of experience and biologic information outside the trial and
were examined with respect to stringent prespecified stopping criteria. In
addition, longitudinal views of the data suggested consistency and
increasing statistical significance over time before the actual decision
point.

Results
Between January 1998 and June 2001, 1033 patients underwent randomization at
17 clinical centers. One hundred forty of the patients (13.6 percent) were
in the group at high risk for death after lung-volume–reduction surgery (70
in the group assigned to surgery and 70 in the group assigned to medical
therapy). The high-risk group had a very low FEV1 and either a very low
carbon monoxide diffusing capacity or homogeneous emphysema. All 140
patients had an FEV1 that was no more than 20 percent of their predicted
value. Ninety-four also had evidence of homogeneous emphysema on CT
scanning, and 87 also had a carbon monoxide diffusing capacity that was no
more than 20 percent of their predicted value. Forty-one patients met all
three criteria. The base-line characteristics of these patients were similar
in the two treatment groups ( Table 1
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=1&strInstance=1#Table1> ).
Treatment
Sixty-nine of the 70 patients assigned to undergo lung-volume–reduction
surgery underwent the procedure and 1 declined the procedure; this patient
was alive four months after randomization. The median time from
randomization to surgery was 10 days (range, 3 to 84). Forty-seven patients
had a median sternotomy, and 22 had video-assisted thoracoscopy. Four of the
70 patients assigned to receive medical treatment underwent surgery outside
the trial. Two of these patients died: one died 22 months after
randomization and 1 year after surgery; and the other died 6 months after
randomization and 21 days after surgery. The other two patients were alive
13 months after surgery.
Mortality and Morbidity
There were no deaths in the medical-therapy group during the first 30 days
after randomization. In contrast, the 30-day mortality rate after surgery
was 16 percent (95 percent confidence interval, 8.2 to 26.7 percent; P<0.001
for the comparison with the medical group) ( Table 2
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=2&strInstance=1#Table2> ). Patients with all
three high-risk characteristics had a 30-day mortality rate of 25 percent
(95 percent confidence interval, 8.7 to 49.1 percent) after surgery. The
30-day mortality rate after surgery was similar among patients who had
undergone video-assisted thoracoscopy and those who had had a median
sternotomy (P>0.99).
The overall mortality rate was 0.43 deaths per person-year among patients
assigned to undergo surgery, as compared with 0.11 deaths per person-year
among those assigned to receive medical therapy (relative risk of death,
3.9; 95 percent confidence interval, 1.9 to 9.0) ( Table 2
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=2&strInstance=2#Table2> ). The mortality rates
during three years of follow-up are shown in Figure 1
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=1&strInstance=1#Figure1> . The cause of death
was most frequently classified as respiratory: 90 percent in the case of
patients in the surgery group and 89 percent in the case of patients in the
medical-therapy group. Sixty percent of surgical patients and 43 percent of
medical patients were receiving mechanical ventilation at the time of death
( Table 3
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=3&strInstance=1#Table3> ). Pneumonia developed
in 30 percent of the high-risk patients within 30 days postoperatively.
Although equal numbers of high-risk patients were assigned to the two
groups, more patients were assigned, by chance, to surgery early in the
trial, so that 60 such patients were included in the six-month analysis of
outcomes, as compared with 51 patients in the medical-therapy group. The
distributions of the changes from base line in the scores for functional
outcomes six months after enrollment favored neither treatment group
 Figure 2
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=2&strInstance=1#Figure2> ). The surgery group
had more deaths, but a few patients in this group had a substantial
improvement in functional status. By comparison, more patients in the
medical-therapy group were unable to undergo testing because of illness.
When the analysis was confined to survivors who completed the six-month
evaluation, the surgery group showed functional improvement in some
measures. The mean (±SD) change in exercise capacity from base line in the
surgery group was an increase of 4.5±13.0 W (measured in 34 patients), as
compared with a decrease of 4.4±14.8 W in the medical-therapy group
(measured in 23 patients) (P=0.06). The surgery group increased the distance
walked in six minutes by a mean of 14.9±63.7 m (49±209 ft) (measured in 31
patients), whereas the medical-therapy group had a mean decrease in the
distance walked of 21.6±56.7 m (71±186 ft) (measured in 24 patients)
(P=0.03). Twenty-three percent of the 31 patients in the surgery group
increased the distance walked in six minutes by more than 53.9 m (177 ft) —
the minimal clinically important difference 23
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=23&strInstance=2#References23>   — as compared
with only 4 percent of the 24 patients in the medical-therapy group
(P=0.06). Patients in the surgery group had a mean increase of 5.5±6.9
percent of the predicted FEV1 (measured in 34 patients), whereas patients in
the medical-therapy group had a mean decrease of 0.4±1.9 percent (measured
in 26 patients) (P<0.001). Thirty-five percent of the 34 patients in the
surgery group had an increase in FEV1 of at least 200 ml at six months, as
compared with none of the 26 patients in the medical-therapy group
(P=0.001). The score for the Quality of Well-Being Questionnaire had
decreased by 0.01 unit in both groups at six months (P=0.94).

Discussion
This report identifies the characteristics of patients who are at high risk
for death after lung-volume–reduction surgery and who also derive little
benefit from the procedure. These patients had an FEV1 that was no more than
20 percent of their predicted value and either homogeneous emphysema or a
carbon monoxide diffusing capacity that was no more than 20 percent of their
predicted value. Within 30 days after surgery, 16 percent of the patients in
this group had died. After six months, only 33 percent of the patients in
the surgery group had an improvement in exercise capacity; 23 percent had
either no change or a decrease in exercise capacity, 8 percent were unable
to complete testing, and 35 percent had died. The health-related quality of
life improved in only 28 percent of these patients, with 72 percent either
dying or having no change or a decrease in the quality of life. The
medical-therapy group had a higher percentage of poor functional outcomes
but fewer deaths.
Our analysis of functional outcomes took into account deaths and missing
data. We used this approach because studies that fail to consider patients
who have died or who are unable to complete testing can have biased results.
12
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=12&strInstance=2#References12>   29
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=29&strInstance=1#References29>   In our study,
more surgical patients died, whereas more medical patients were unable to
perform functional testing. Patients who did not complete testing but
provided no information about why they missed the test were assigned the
same functional status as those who were known to be too ill to complete the
test. When we accounted for deaths and missing information, there was no
significant difference in the distribution of functional outcomes between
groups. When we analyzed survivors only, there was a small improvement in
FEV1, exercise capacity, and the distance walked in six minutes in the
surgical group.
Our findings have clear importance for the selection of patients for
lung-volume–reduction surgery. No single characteristic adequately defines a
group of patients for whom the surgery poses a high risk. Sensitivity
analyses using different thresholds for FEV1 and carbon monoxide diffusing
capacity and combinations of variables suggest that our criteria for
high-risk patients are nearly optimal. In selecting patients for surgery, we
used clinical tests available to community practitioners. The presence of
these characteristics should not be considered absolute contraindications to
the surgery. In borderline cases, other clinical factors, including the
willingness of the patient to accept the risk, should be used to make
decisions about the suitability of lung-volume–reduction surgery.
Nonetheless, because of the generally unfavorable outcomes, the National
Emphysema Treatment Trial no longer enrolls such patients in the clinical
trial, and caution should be exercised in performing lung-volume–reduction
surgery in such patients.
Our findings are not the result of poor patient selection or a high
mortality rate at only a few centers. The high-risk patients were enrolled
at all 17 participating clinical centers, and the deaths occurred in the
surgery group at 13 of the 17 centers. Although the results of subgroup
analyses should be interpreted with caution because of the large number of
possible subgroups and the potential for false positive results, such errors
are unlikely in this analysis because of the prespecification of variables
of interest and stopping guidelines, the magnitude of the effect, and the
plausibility of the findings.
Published information identifying patients at highest risk after
lung-volume–reduction surgery is based mainly on small, uncontrolled case
series and is contradictory. Some series suggest that a very low FEV1 is
associated with an increased risk of death postoperatively, 30
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=30&strInstance=1#References30>   whereas others
do not. 10
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=10&strInstance=3#References10>   31
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=31&strInstance=1#References31>   32
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=32&strInstance=1#References32>   Some case
series suggest that a very low carbon monoxide diffusing capacity increases
the risk, 33
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=33&strInstance=1#References33>   34
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=34&strInstance=1#References34>   whereas others
have not confirmed this finding. 32
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=32&strInstance=2#References32>   35
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=35&strInstance=1#References35>   36
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=36&strInstance=1#References36>   37
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=37&strInstance=1#References37>   38
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=38&strInstance=1#References38>   A recent trial
of lung-volume–reduction surgery involving 48 patients stopped enrolling
participants who had a carbon monoxide diffusing capacity that was less than
30 percent of their predicted value or who were unable to walk 150 m (492
ft) on the shuttle-walking test, because 5 of the first 15 patients died (3
in the surgical group and 2 in the medical group). 4
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=4&strInstance=2#References4>   The cause of the
high mortality rate among patients with a low carbon monoxide diffusing
capacity may be related to impaired gas exchange. In a rabbit model of
emphysema, a reduction in the diffusing capacity was the physiological
factor that limited the amount of lung that could be removed during
lung-volume–reduction surgery. 39
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=39&strInstance=1#References39>   In patients
with a low carbon monoxide diffusing capacity in association with a low
FEV1, resection of lung tissue may restrict the pulmonary vasculature or
surface area available for gas exchange enough to cause pulmonary
hypertension or worsen hypoxemia, thereby compromising survival. 40
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=40&strInstance=1#References40>
Although the presence of homogeneous emphysema is associated with less
improvement in pulmonary function after lung-volume–reduction surgery than
is the presence of heterogeneous emphysema, 3
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=3&strInstance=3#References3>   32
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=32&strInstance=3#References32>   41
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=41&strInstance=1#References41>   42
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=42&strInstance=1#References42>   43
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=43&strInstance=1#References43>   44
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=44&strInstance=1#References44>   45
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=45&strInstance=1#References45>   46
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=46&strInstance=1#References46>   47
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=47&strInstance=1#References47>   48
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=48&strInstance=1#References48>   it has
infrequently been cited as a risk factor for surgical mortality. 49
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=2001/20011011/f
eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01&strNumber=49&strInstance=1#References49>   In patients
with homogeneous disease, lung-volume–reduction surgery involves resection
of functional lung tissue. After the removal of functional lung tissue,
patients with a very low initial FEV1 may not derive enough benefit from the
surgery to survive postoperative pulmonary complications.
Other factors such as advanced age, hypercapnia, and a low value on the
six-minute walk test increase the mortality rate associated with
lung-volume–reduction surgery. Although these characteristics are associated
with increased death rates, they did not clearly identify patients in our
study for whom surgery posed a substantially higher risk than medical
treatment.
Our experience in this high-risk group of patients shows that the increased
mortality rate persists beyond the 30-day postoperative period. Because
ventilatory and circulatory support can maintain life for prolonged periods
in patients with severe physiological derangement, it is important to assess
the postoperative mortality rate for longer than 30 days and to have as a
comparison group a similar group of patients who did not undergo surgery.
Patients in both treatment groups had high rates of death from respiratory
failure, and many were receiving mechanical ventilation at the time of
death.
In conclusion, we have identified a combination of physiological and
radiographic characteristics in a group of patients with emphysema that
places them at high risk of death after lung-volume–reduction surgery and
who also are unlikely to have large improvements in functional status or the
quality of life as a result of this procedure. Caution is warranted in the
use of lung-volume–reduction surgery in such patients.
Figure 1. Kaplan–Meier Estimates of the Probability of Death among High-Risk
Patients, According to Whether They Were Randomly Assigned to Undergo
Lung-Volume–Reduction Surgery or Receive Medical Therapy.
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01#FigureRef1Instance1>  ]

Figure 1. Kaplan–Meier Estimates of the Probability of Death among High-Risk
Patients, According to Whether They Were Randomly Assigned to Undergo
Lung-Volume–Reduction Surgery or Receive Medical Therapy.
This intention-to-treat analysis shows the overall results for the high-risk
group (Panel A), the subgroup of patients with an FEV1 that was no more than
20 percent of their predicted value and a homogeneous distribution of
emphysema on CT scanning (Panel B), and the subgroup of patients with an
FEV1 that was no more than 20 percent of their predicted value and a carbon
monoxide diffusing capacity that was no more than 20 percent of their
predicted value (Panel C). For each analysis the difference between groups
was significant (P<0.001, P<0.001, and P=0.005, respectively) by the
log-rank test.



Figure 2. Changes from Base Line to the Six-Month Follow-up Assessment in
the Maximal Workload Achieved on Bicycle Ergometry (Panel A), FEV1 (Panel
B), the Distance Covered during the Six-Minute Walk Test (Panel C), and
Scores on the Quality of Well-Being Questionnaire (Panel D) among 60
High-Risk Patients Who Were Assigned to Undergo Lung-Volume–Reduction
Surgery and 51 Who Were Assigned to Receive Medical Therapy.
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eature.asp?strXMLFilename=2001/20011011/01101101&%09%09strDate=%09%0910%2F11
%2F2001&strArt=01#FigureRef2Instance1>  ]

Figure 2. Changes from Base Line to the Six-Month Follow-up Assessment in
the Maximal Workload Achieved on Bicycle Ergometry (Panel A), FEV1 (Panel
B), the Distance Covered during the Six-Minute Walk Test (Panel C), and
Scores on the Quality of Well-Being Questionnaire (Panel D) among 60
High-Risk Patients Who Were Assigned to Undergo Lung-Volume–Reduction
Surgery and 51 Who Were Assigned to Receive Medical Therapy.
The designation “Unable” indicates patients who were too ill to complete the
procedure, as well as patients who declined to complete the procedure but
who did not explain why they did not complete the procedure. The designation
“Dead” indicates patients who died during the first six months of follow-up,
even though some of these patients had completed the six-month evaluation
before death. Scores on the Quality of Well-Being Questionnaire can range
from 0 to 1, with higher scores indicating a better quality of life. To
convert values from feet to meters, divide by 3.28.



Table 1. Characteristics of the High-Risk Patients at Base Line.
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Table 1. Characteristics of the High-Risk Patients at Base Line.



Table 2. Mortality Rates among High-Risk Patients.
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%2F2001&strArt=01#TableRef2Instance1>  ]

Table 2. Mortality Rates among High-Risk Patients.



Table 3. Causes of Death and Mechanical-Ventilation Status at the Time of
Death in High-Risk Patients.
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%2F2001&strArt=01#TableRef3Instance1>  ]

Table 3. Causes of Death and Mechanical-Ventilation Status at the Time of
Death in High-Risk Patients.





Source Information

The writing committee of the National Emphysema Treatment Trial (Alfred
Fishman, M.D., University of Pennsylvania, Philadelphia; Henry Fessler,
M.D., Johns Hopkins University, Baltimore; Fernando Martinez, M.D.,
University of Michigan, Ann Arbor; Robert J. McKenna, Jr., M.D.,
Cedars–Sinai Medical Center, Los Angeles; Keith Naunheim, M.D., St. Louis
University, St. Louis; Steven Piantadosi, M.D., Ph.D., Johns Hopkins
University, Baltimore; Gail Weinmann, M.D., National Heart, Lung, and Blood
Institute, Bethesda, Md.; and Robert Wise, M.D., Johns Hopkins University,
Baltimore) takes responsibility for the content of this article. Address
reprint requests to Dr. Piantadosi at the NETT Coordinating Center, 615 N.
Wolfe St., Rm. 5010, Baltimore, MD 21205.
Supported by contracts with the National Heart, Lung, and Blood Institute
(N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106,
N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112,
N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119),
the Center for Medicare and Medicaid Services (formerly the Health Care
Financing Administration), and the Agency for Healthcare Research and
Quality.

Footnotes
The members of the National Emphysema Treatment Trial Research Group are
listed in the Appendix.
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%2F2001&strArt=01#FnoteInstance1>  ]

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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.