1. health and fitness
2. disease
3. asthma

Korean Edition
베타 차단제:
COPD에서는 너무 적게,
심근경색에서는 너무
조기에 사용하는 경향
Beta-Blockers:
Too Little in COPD,
Too Soon in MI
Bronchospasm concerns
may be ebbing.
V OL . 2 / N O . 1 / A PRIL 2013
C O N T E N T S
NEWS
베타 차단제: COPD에서는 너무 적게, 심근경색에서는 너무 조기에 사용하는 경향
COPD 진료지침, 일차의료에서 적절하게 활용되고 있는가?
아스피린 복용 시 주요 혈관의 합병증 및 정맥혈전증 재발 줄어
새로운 지침에서 제시하는 Troponin 검사의 로드맵
중증 안정 COPD에서 비침습적 양압호흡환기(NIPPV) 사용이 도움 줄 수 있어
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PULMONARY MEDICINE
이차 항결핵제에 대한 내성이 증가하고 있다
LABA 사용 중지로 천식은 악화될 수 있어
정위적방사선치료; 폐암 생존율 향상을 위한 새로운 치료전략
환자가 느끼는 호흡곤란 정도가 COPD 결과에 영향을 미쳐
Crizotinib이 진행된 ALK 양성 비소세포폐암 치료를 바꾼다
Tiotropium 추가요법이 조절되지 않는 천식환자의 악화 감소에 도움
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PEDIATRIC CHEST MEDICINE
소아에서 Budesonide 사용이 성인신장을 감소시킴
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PULMONARY PERSPECTIVES
BY BRUCE JANCIN
IMNG Medical News
ESTES PARK, COLO. – Betablockers may be underprescribed in the setting of chronic
obstructive pulmonary disease,
yet overused in the early treatment of acute myocardial infarction, recent surprising evidence suggests.
Cardiovascular disease and
COPD are closely intertwined
through the effects of smoking.
Yet the notion of prescribing
beta-blockers in patients with
COPD challenges the conventional wisdom. Most physicians
avoid the practice, even in patients with concomitant cardiovascular disease, because of
worries about triggering bronchospasm and perhaps blocking
the bronchodilating benefits of
beta-agonist inhaler therapy.
But data from a Scottish retrospective cohort study strongly suggest these concerns are
misplaced, asserted Dr. Mel L.
Anderson, chief of the hospital
medicine section and associate
chief of the medical service at
the Denver VA Medical Center. He spoke at a conference
on Internal Medicine sponsored by the University of Colorado
The NHS Tayside Respirato-
ry Disease Information System
(TARDIS) is a disease-specific
database developed 11 years
ago to help Scottish primary
care physicians and pulmonologists manage patients with
COPD. The TAYSIDE investigators recently reported on
5,977 patients above age 50 with
confirmed COPD who were
followed for a mean of 4.4
years. The study population included 819 patients on betablockers, nearly 90% of which
were relatively cardioselective
agents such as bisoprolol or
atenolol.
THE STUDY SHOULD
AT LEAST MAKE YOU
FEEL COMFORTABLE
THAT IT’S SAFE TO OFFER
BETA-BLOCKER THERAPY
TO COPD PATIENTS,
PROVIDED THEY DON’T
HAVE ASTHMA.
In a matched propensity
score analysis, patients on a
beta-blocker plus various combinations of respiratory med-
See Therapy · page 3
CHEST PHYSICIAN
Elsevier Korea LLC, 4FL, Chunwoo Bldg,
534 Itaewon-dong, Yongsan-gu, Seoul 140-861,
S. Korea
COPD에서 성별에 따른 차이점: 아직도 문제가 되는가?
11
CRITICAL CARE
급성호흡곤란: 생리학적 접근을 시도해야..
새로 개정된 패혈증 치료 지침
말기 암 환자에서 임종에 대비한 상의를 일찍 하는 것은 공격적인 치료를 줄인다
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음악칼럼
15
COPD 진료지침, 일차의료에서
적절하게 활용되고 있는가?
Left to Primary Care,
COPD Guidelines Often Underutilized
BY SHARON WORCESTER
IMNG Medical News
ATLANTA – Regardless of disease severity, guideline-concordant treatment is not provided
to nearly half of all patients
who have stable chronic obstructive pulmonary disease
and are treated in the ambulatory care setting, findings from
an observational study suggest.
The study showed that
guideline-concordant treatment was more likely to be
provided when patients were
comanaged by a pulmonologist and a primary care physician.
Of 450 patients, 56% received guideline-concordant
care as outlined by the 2010
Global Initiative for Chronic
Obstructive Lung Disease
(GOLD) stage-specific recommendations, Dr. Gulshan Shar-
ma, FCCP, reported at the annual meeting of the ACCP.
No differences were found
in treatment level with respect
to age, gender, race, disease
severity, or comorbidities on
multivariate analysis, but patients comanaged by a primary
care physician and a pulmonologist were more likely to
receive an appropriate level of
See COPD Guidelines · page 2
2
NEWS
CHEST Physician • April 2013
Need for increased awareness
of COPD guidelines
See COPD Guidelines · from page 1
SUMMARY
care, compared to patients treated by a
primary care physician (odds ratio, 4.6),
said Dr. Sharma of the University of
Texas Medical Branch, Galveston.
Clinical practice guidelines for the
treatment of patients with COPD in the
ambulatory care setting are issued and
updated regularly. Studies have demonstrated the value of these guidelines for
improving the quality of care and for reducing exacerbations and hospitalizations.
However, the degree to which these
guidelines are implemented in clinical
practice has been unclear, Dr. Sharma
said. The study findings suggest that
they are underutilized, particularly by
미국 일차의료에서 56%의 환자만이 COPD
진료지침에 의한 치료를 받고 있다. 반면에
호흡기전문의사와 일차의료의사가 공동으로
환자를 치료할 경우 거의 모든 환자가 진료
지침에 의한 치료를 받고 있어 일차의료현
장에서 COPD 진료지침에 대한 인식재고가
필요하다.
Korean Edition
Editor-in-Chief
primary care physicians.
Study subjects were adults with a
clinical diagnosis of COPD and at least
one outpatient visit between January
and December 2010. Mean age was 67
years, 46% were women, 20% had no
comorbidities, and 75% had one or two
comorbidities. About 7% had GOLD
stage I disease, more than 46% had
GOLD stage II disease, 33% had stage
III disease, and 13% had stage IV disease.
Also, 47% were managed by a primary
care physician alone, 41% were comanaged by a primary care physician and a
pulmonologist, 10% did not have a primary care physician and received care
mainly from a specialist, and about 2%
had no regular care provider.
The findings indicate a need for increased awareness of clinical practice
guidelines and the importance of adherence to the guidelines in patients with
COPD, particularly among primary care
physicians, said Dr. Sharma, who reported having no disclosures.
유광하 건국의대 건국대병원 호흡기내과
Editors
김덕겸 서울의대 보라매병원 호흡기내과
박주헌 아주의대 아주대학교병원 호흡기내과
김태형 한양의대 한양대구리병원 호흡기내과
신경철 영남의대 영남대학교병원 호흡기내과
김영삼 연세의대 세브란스병원 호흡기내과
윤형규 가톨릭의대 여의도성모병원 호흡기내과
박용범 한림의대 강동성심병원 호흡기내과
이상엽 고려의대 고대안암병원 호흡기내과
CHEST PHYSICIAN, the newspaper of the American College of Chest Physicians, provides cutting-edge reports from clinical meetings,
FDA coverage, clinical trial results, expert commentary, and reporting on the business and politics of chest medicine. Each issue also
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published by Elsevier Korea LLC, 4FL, Chunwoo Bldg,
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ⓒ Copyright 2013, by Elsevier Inc.
[알려드립니다]
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E-mail. [email protected] Tel. 02-6714-3151 Fax. 02-725-4388
COPD SCHOOL 2013
•일자 : 2013년 4월 20일(토)
Program
•장소 : 서울아산병원 동관 6층 소강당
14 : 00 ~ 14 : 30 등록
14 : 30 ~ 14 : 40 Opening remark
대한결핵 및 호흡기학회 이사장 유지홍
좌장 : 김원동(건국의대 내과)
Session 1
Session 2
좌장 : 김관형(가톨릭의대 내과)
14 : 40 ~ 15 : 05 Stable COPD 치료 - 한국진료지침과 GOLD 차이
황용일(한림의대 내과)
:
:
15 05 ~ 15 30 Stable COPD 치료- 흡입 스테로이드 역할
이창훈(서울의대 내과)
15 : 30 ~ 15 : 55 PDE4 inhibitor vs. theophylline in COPD treatment
김유일(전남의대 내과)
15 : 55 ~ 16 : 10 Panel Discussion; All Speakers
16 : 30 ~ 16 : 55 COPD Comorbidity - Cardiovascular disease
유광하(건국의대 내과)
16 : 55 ~ 17 : 20 COPD Comorbidity - Depression
신경철(영남의대 내과)
:
:
~
17 20 17 45 COPD Comorbidity - Osteoporosis
이영민(인제의대 내과)
17 : 45 ~ 18 : 00 Panel Discussion; All Speakers
16 : 10 ~ 16 : 30
18 : 00 ~ 18 : 10 Closing remark
COPD 연구회장 김원동
18 : 10 ~
Dinner
Coffee Break
To learn more or request trial, please contact Elsevier Sales Representative.
Tel (02)-6714-3000 | Email [email protected]
NEWS
Beta-Blockers May Be COPD Tool
See Therapy · from page 1
COMMENTARY
ications had a 22% decreased risk of allcause mortality and a 50% reduction in
the risk of hospitalizations for COPD
during the follow-up period.
The mortality benefit associated with
beta-blocker therapy proved independent of the presence or absence of overt
cardiovascular disease, as similar reductions were seen in deaths as a result of
COPD and myocardial infarction (BMJ
2011;342:d2549]).
“Yes, this is an observational study
and so you have to worry about selection bias, but if anything, it should at
least make you feel comfortable that
it’s safe to offer beta-blocker therapy to
COPD patients, provided you’re sure
Dr. Vera DePalo,
FCCP, comments:
COPD 환자의
입원율을 줄이
고 예후를 향상
시키는데 중점
을 두고 볼 때,
새로운 방법은
임상의들이 이
런 목표에 도달
하는데 도움을 주는 것으로 확인된 듯하다.
NHS TARDIS 자료 분석에서 여러 조합의 호
흡기약물과 상대적으로 심장선택적인 베타
차단제를 함께 사용해 온 COPD 환자에서
전체 사망률을 줄이고, COPD로 인한 입원
을 50% 정도 줄이는 것으로 밝혀졌다. 일
부의 선택적인 COPD 환자를 대상으로 베
타 차단제를 시작하거나 심인성 쇼크가 발
생할 위험요인을 가진 심근경색 환자에서
24시간 이내에 베타 차단제를 투여할 때는
주의 깊은 결정을 내리는 것이 권고된다.
they don’t have asthma,” Dr. Anderson
remarked.
He also highlighted another emerging
issue with regard to beta-blockers, this
one involving their widespread inappropriate use in the early treatment of MI
in patients with one or more risk factors
for cardiogenic shock.
Investigators utilized the American
College of Cardiology registry known
as ACTION Registry-GWTG to study
outcomes in 34,661 patients with ST elevation MI (STEMI) and non–ST-segment MI (non-STEMI) who received
beta-blocker therapy within the first 24
hours after MI presentation at 291 participating U.S. hospitals. The registry is
part of the American College of Cardiology’s National Cardiovascular Data
Registry.
The relevant ACC/American Heart
Association Guidelines for Unstable
Angina/Non-STEMI (J. Am. Coll. Cardiol. 2007;50:e1-e157) and STEMI (J. Am.
Coll. Cardiol. 2008;51:210-47) recommend caution in giving beta-blockers in
the first 24 hours in patients with risk
factors for cardiogenic shock.
Yet in the ACTION Registry-GWTG
study, 45% of the STEMI patients treated
with early beta-blockers and 63% of early
beta-blocker recipients with non-STEMI
had one or more cardiogenic shock risk
factors identified in the guidelines on
the basis of findings in the earlier COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) study (Lancet
2005; 366:1,622-32).
Moreover, the ACTION Registry data
demonstrated that early beta-blocker therapy in patients with risk factors for cardiogenic shock was associated with significantly worse outcomes. For example,
the combined rate of in-hospital cardiogenic shock or death was 1.3% in betablocker recipients with no shock risk factors, 4.8% in those with one of the risk
factors, and 8.1% in those with two or
more (Am. Heart J. 2011;161:864-70).
The cardiogenic shock risk factors that
grew out of the COMMIT study are age
greater than 70 years, systolic blood pressure below 120 mm Hg at presentation,
SUMMARY
April 2013
COPD에서는 베타 차단제 사용이 저조한 반면에
급성 심근경색에서는 조기 투여로 과하게 사용하
는 경향이 있다. 천식이 없는 COPD 환자에서는 베
타 차단제 사용이 전체사망률이나 COPD 및 심근
a heart rate in excess of 110 bpm, and 12
hours or longer since symptom onset in
STEMI patients.
“I bring this to your attention because
these risk factors are not going to jump
out at you. They fit a lot of the patients
we see, but statistically they have an
excess risk for cardiogenic shock, and
you should either not use beta-blockers
early or be incredibly careful in doing
so in those patients,” Dr. Anderson advised.
Asked by a concerned audience member how physicians who decline to prescribe a beta-blocker for patients with
3
경색으로 인한 사망률을 낮추는 것으로 보고되었
다. 반면에 심인성쇼크 발생 위험인자가 있는 급성
심근경색 환자에서 24시간 이내에 조기에 베타 차
단제를 투여하는것은 예후를 악화시킬 수 있다.
acute coronary syndrome and one or
more shock risk factors can avoid taking
a hit for noncompliance with a Joint
Commission and Medicare core performance indicator, the hospitalist replied
that the key is to avoid “early” use of
the medication in patients with cardiogenic shock risk factors.
Once 24 hours have gone by and the
patient has been stabilized and has better
blood flow to the heart, prescribing a
beta-blocker may well be appropriate,
he said.
Dr. Anderson reported having no financial conflicts.
NEWS
4
CHEST Physician • April 2013
아스피린 복용 시 주요 혈관의 합병증 및 정맥혈전증 재발 줄어
정맥혈전증, 심근경색증, 뇌졸중, 출혈 또는
사망과 같은 합병증이 33% 감소
BY HEIDI SPLETE
IMNG Medical News
A
V I TA L S
100-mg daily dose of aspirin reduced by one-third the rate of
recurrent major vascular events
for patients who had one acute unprovoked venous thromboembolism and
were switched from anticoagulant therapy to either aspirin or placebo after 3
months of anticoagulant therapy.
Patients with one episode of unprovoked VTE often discontinue anticoagulant therapy due to inconvenience and
the risk of bleeding, said Dr. Timothy
A. Brighton of the University of Sydney,
Australia, and his colleagues. For those
patients, 100 mg of aspirin per day appears to be a safe alternative.
Dr. Brighton and his colleagues reported the findings based on combined
data from the ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) study and the WARFASA (Warfarin and Aspirin) study. The findings of
ASPIRE were simultaneously published
in the New England Journal of Medicine
and presented at the annual meeting of
the American Heart Association in Los
주요 결과: ASPIRE와 WARFASA 두 임상
시험의 결과를 합쳐 분석한 결과 aspirin
100 mg을 매일 복용한 군에서 정맥혈전증
의 재발률이 32% 감소하였고, 주요 혈관에
관련된 합병증의 발생빈도는 34% 감소하
였다.
출처: ASPIRE trial에 등록된 성인 822명과
WARFASA trial에 등록된 402명에 대한 임
상시험 결과를 분석하여 나온 결과.
Angeles. The findings of WARFASA
were previously published in the same
journal.
ASPIRE examined the effect of a 100mg daily dose of aspirin in patients who
had a history of a first-ever unprovoked
VTE and had completed initial anticoagulation therapy. The study population included 822 adults who were randomized to a placebo or aspirin at 56
sites in five countries from May 2003
and August 2011. Roughly half of the
patients were men; 56% had a proximal
deep-vein thrombosis as an index event;
29% had a pulmonary embolism as an
index event, and 14% had both conditions as an index event (N. Engl. J. Med.
2012 Nov. 4 [doi: 10.1056/NEJMoa1210384]).
Overall, VTE recurred in 57 patients
(14%) in the aspirin group, compared
with 73 patients (18%) in the placebo
group (rates of 5% and 7% per year, respectively, a nonsignificant difference).
However, the rates of two secondary
composite outcomes were significantly
reduced in patients who took aspirin
compared with those on placebo, the
researchers noted.
The rate of a composite outcome including VTE, myocardial infarction,
stroke, or cardiovascular death was reduced by 34% in aspirin patients (5%
per year for aspirin vs. 8% per year for
placebo). The rate of a composite outcome including VTE, myocardial infarction, stroke, major bleeding, or death
from any cause was reduced by 33% in
aspirin patients (6% per year for aspirin
vs. 9% per year for placebo).No signifi-
cant differences in serious adverse events
or in the rates of major or clinically relevant nonmajor bleeding were observed
between the aspirin and placebo groups,
researchers noted.
The findings were limited by the low
number of patients in the study, however. The ASPIRE data alone were not adequately powered to show a significant
reduction in the recurrence of VTE.
To address the issue, researchers combined the ASPIRE data with data from a
similar population of 402 patients in the
WARFASA (Warfarin and Aspirin) study
(N Engl J Med 2012; 366:1959-67). In
this multicenter, double-blind study, patients with first-ever unprovoked venous
thromboembolism completed 6-18
months of oral anticoagulant treatment
and were randomly assigned to aspirin,
100 mg daily, or placebo for 2 years.
VTE recurred in 28 of the 205 patients
who received aspirin and in 43 of the
197 patients who received placebo
(6.6% vs. 11.2% per year; hazard ratio,
0.58). One patient in each treatment
group had a major bleeding episode.
Adverse events were similar in the two
groups.
Using the combined data from both
studies, the researchers found “a highly
significant reduction of 32% in the rate
of recurrence of venous thromboembolism and a reduction of 34% in the
rate of major vascular events with no
excess of bleeding.” Therefore, the combined results of the two studies support
the use of low-dose aspirin to prevent
both recurrent VTE and major vascular
events in patients who have had a first
episode of unprovoked VTE, the researchers said.
The study was supported by grants
from the National Health and Medical
Research Council (Australia), the Health
Research Council (New Zealand), the
COMMENTARY
Aspirin Cuts Recurrence of Vascular Events, VTEs
Dr. TheodoreWarkentin comments:
수술 후 정맥혈전증의 예방에 있어 항응고
제의 효과는 잘 알려져 있어서 aspirin의 효
과가 과소 평가되어 왔다. 최근에 시행된
무작위 임상시험인 ASPIRE와 WARFASA
trial의 연구결과에 의하면 aspirin이 정맥혈
전증을 예방하는 효과가 있다고 추측할 수
있다. Warkentin은 원인 없이 정맥혈전증
이 발생한 환자에서 장기간에 걸쳐 정맥혈
전증이 재발하는 위험에 대해 다음과 같이
언급하였다. 평생 항응고제를 복용하는 대
신 아스피린을 사용하면 정맥혈전증의 재
발을 예방할 수 있고, 동맥혈전증의 발생
도 줄일 수 있다는 장점이 있다. ASPIRE
와 WARFASA 두 가지 임상연구결과를 합
쳐 분석한 결과 아스피린을 복용하면 정맥
혈전증의 재발이 방지되고, 주요 혈관에서
색전증과 관련되어 나타나는 합병증의 발
생빈도 역시 감소한다. Dr. Warkentin은 이
두 가지 임상시험의 결과를 바탕으로, aspirin을 실제 임상에서 사용하는 방법에 대
해 다음과 같이 설명하였다. 원인 모를 정
맥혈전증이 발생한 환자에서 aspirin을 처
방하기에 앞서 최소 3개월 이상 효과가 증
명된 항응고요법을 시행하여 초기에 많이
발생하는 재발을 방지하는 것이 중요하다
. 항응고제를 계속 복용하기 원하지 않는
환자에게 하루 100 mg의 aspirin을 복용하
게 하면 정맥혈전증의 재발을 1/3 가량 감
소시킬 수 있을 뿐만 아니라 주요 동맥에
서 생길 수 있는 폐쇄 관련 합병증의 발생
도 예방할 수 있고, 경구 항응고제의 복용
을 중단한 직후에 자주 나타나는 혈전증의
발생을 감소시킬 수 있다. 게다가 가격이
저렴하고 약물 농도를 확인하기 위한 혈액
검사를 할 필요도 없고 신장 기능이 저하
되어 있는 환자에서도 약물 대사물이 축적
되지 않아 안심하여 사용할 수 있다는 추
가적인 장점이 있다.
National Heart Foundation of Australia,
Bayer HealthCare (Germany), and the
Australasian Society of Haematology
and Thrombosis.
NEWS
April 2013
5
새로운 지침에서 제시하는 Troponin 검사의 로드맵
B Y A L I C I A A U LT
IMNG Medical News
A
COMMENTARY
s the sensitivity of troponin testing improves, so
must clinicians refine the way they order and interpret such tests, according to a new consensus
statement issued by seven professional societies.
Clinicians have used troponin as a biomarker for
myocardial infarction since the early 1990s. However,
while an elevated level indicates myocardial necrosis,
it does not necessarily mean that a myocardial infarction has occurred. There can be other myriad reasons
for an increase in troponin.
The consensus statement – written by a 14-member
group of experts – reviews the most recent research
on troponin testing and its clinical applications. It also
Dr. Jun Chiong, FCCP,
comments:
급성 심근경색을 진단하거나 배제
하기 위한 심장 troponin 검사의 알
고리즘은 매우 다양하다. 최근에
출판된 troponin 지침은 임상의사
들이 언제, 또 왜 troponin 검사를
지시해야 하는지 감별하는데 도움
이 될 것이며, 현재의 건강관리 체
계에서는 언제 troponin 검사가 필
수적이 아닌지를 이해하는 것도 똑같이 중요하다. 위험도가
낮은 인구 혹은 개연성이 적은 상황에서 troponin 검사의 비
용 효과 관계를 평가하는 연구들이 요구된다.
addresses frequently asked questions on what an elevated troponin level means, when the test should be
ordered, and prognosis with a positive test.
The statement also gives a schematic look at potential
causes of a positive troponin test. The schematic is divided into ischemic and nonischemic causes, and then
further broken down.
“We need to be thinking about why we are ordering
the troponin test before we order it,” said Dr. L. Kristin
Newby, who is the cochair of the writing committee for
the American College of Cardiology Foundation 2012
Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations.
“We hope this document provides a road map to
help clinicians be more deliberate when ordering these
tests and interpreting the results,” said Dr. Newby,
who is a professor of medicine in the division of cardiovascular medicine at Duke University Medical Center, Durham, N.C.
Troponin may be elevated because of heart failure,
surgery, trauma, kidney disease, or pulmonary embolism, among other conditions.
The biomarker may also show up in patients who
have sepsis or those who are taking certain chemotherapies, such as anthracyclines and cyclophosphamide,
which are known to cause cardiac damage.
“If we are indiscriminate in how we order these
tests or we aren’t paying attention to the clinical scenario before us, we may miss something important,”
said Dr. Newby.
Further complicating testing, the statement warns
clinicians that “all troponin assays are not created
equal,” and that there “is a wide spectrum of assay
quality in practice.”
The measurement of cardiac troponin is also not
standardized, though there have been recommenda-
“2012 Expert Consensus Document on Practical Clinical
Considerations in the Interpretation of Troponin Elevation”은 7개 전문가 협회의 협의 발표로서 troponin 증가가 의
미하는 것, troponin 검사의 적응증 및 troponin 검사 양성 시
예후는 어떤지 기술하고 있다. 또한, troponin 검사 양성의 경
우 먼저 허혈성 및 비허혈성, 그리고 그 이후 좀더 세밀한 추
정 원인을 밝히는 단계적 과정을 보여준다.
tions by the National Academy of Clinical Biochemistry
on how to achieve standardization.
Most assays, however, are “able to selectively detect
cardiac troponin to the exclusion of troponin from
other tissues,” according to the statement.
The statement also documents that elevated troponin
deserves investigation because it is associated with
worse outcomes.
“If you have a pulmonary embolism or end-stage renal disease and your troponin is elevated, your prognosis – how you are expected to do – is worse,” said
Dr. Newby.
According to the statement, for clinicians, the “best
value of troponin testing remains in the diagnosis of MI.”
But even with that use, “it is important to understand
the clinical context as treatment may vary considerably.”
The 37-page statement was developed by the ACCF,
the American Association for Clinical Chemistry, the
American College of Chest Physicians, the American
College of Emergency Physicians, the American College of Physicians, the American Heart Association,
and the Society for Cardiovascular Angiography and
Interventions.
The statement was published online in the Journal
of the American College of Cardiology (JACC 2012;60)
and is available on the ACC’s website at (http://content.onlinejacc.org/article.aspx?articleid=1389700).
중증 안정 COPD에서 비침습적 양압호흡환기
(NIPPV) 사용이 도움 줄 수 있어
NIPPV Benefits Severe Stable COPD
BY SHARON WORCESTER
IMNG Medical News
COMMENTARY
ATLANTA – Long-term nocturnal use
of noninvasive positive pressure ventilation significantly reduced the likelihood
of intensive care unit admission in patients with severe stable chronic obstructive pulmonary disease, according to
findings from a systematic review of 582
patients in 13 randomized, controlled
clinical trials.
After 1 year, noninvasive positive
pressure ventilation (NIPPV) was associated with a significant decrease in
ICU admissions (odds ratio, 0.41) compared with standard medical therapy.
Patients using NIPPV for more than
3 months also had improvements in
oxygenation (mean difference of –2.43
mm Hg), reduction in Pco2 (mean difference, –2.96 mm Hg), and an improvement in 6-minute walk distance
(mean difference 45.15 m), Dr. Monali
Patil said at the annual meeting of
the American College of Chest Physicians.
A trend toward improved mortality
at 1 year did not reach statistical significance, and no significant improvements
in lung function were noted, according
to Dr. Patil, of the University at Buffalo
(N.Y.).
Dr. Patil selected the 13 trials from a
review of more than 700 studies conducted between 1991 and 2011. The
Dr. Darcy D. Marciniuk, FCCP, comments:
이산화탄소 저류가 있는 중증 안정 COPD환자를 대상으로 한 소규모
의 무작위대조연구들에 대한 리뷰에서, 장기적으로 야간에 NIPPV를
적용하는 것이 유의하게 병원입원율을 감소시키고, 가스교환 개선이
있으며, 6분 보행 거리를 늘리는 것으로 밝혀졌다. NIPPV가 COPD
급성 악화에서 기본적인 치료로 자리잡은 것처럼 호흡부전이 동반된
중중의 안정된 COPD에서도 NIPPV가 도움을 줄 수 있다. 다양한 임
상, 삶의 질 및 경제적 이득 등을 목표로 한 대규모 무작위대조연구
가 뒤따라야 할 것이다.
analysis included only randomized, controlled trials of COPD patients who had
an FEV1 less than 50% of predicted and
a Pco2 greater than 45 mm Hg and were
receiving bilevel positive airway pressure
(BIPAP).
The patients in the studies were aged
18-75 years, and had no COPD exacerbations within 2 weeks prior to study
enrollment.
SUMMARY
언제, 어떻게 troponin 검사를
이용할 것인가?
SUMMARY
In New Guideline, A Road Map to Troponin Testing
13개 무작위대조연구를 분석한 연구에서 중
증 안정 COPD에 장기간 야간에 적용한
NIPPV가 통상적인 내과적 치료와 비교하여
ICU 입원 위험을 낮추고, 산소포화도를 향상
시키며, 이산화탄소 저류를 개선하고, 6분 보
행 거리를 늘리는 것으로 나타났다. 중증 안
정 COPD 관리를 위한 보조 치료로 NIPPV가
사용될 수 있을 것이다.
The long-term use of NIPPV in patients with severe stable COPD has been
controversial, but these findings demonstrate significant benefits.
“So NIPPV can be used as adjuvant
treatment for management of severe
stable COPD patients,” she concluded.
Dr Patil reported having no financial
disclosures.
6
PULMONARY MEDICINE
CHEST Physician • April 2013
이차 항결핵제에 대한 내성이 증가하고 있다
BY MICHELE G. SULLIVAN
IMNG Medical News
N
early 44% of multidrug-resistant tuberculosis
cases tested in eight countries were also resistant to at least one second-line tuberculosis
drug, according to results of an international prospective cohort study.
Extensively drug-resistant (XDR) strains were unexpectedly prevalent as well, particularly in South Korea
and Russia, reported Tracy Dalton, Ph.D., of the Centers
for Disease Control and Prevention, Atlanta, and colleagues. The report was published in The Lancet. These
XDR isolates were detected in 6.7% of patients overall,
with prevalence in South Korea (15%) and Russia (11%)
exceeding the current World Health Organization global estimate (9.4%). The risk of XDR disease was four
times greater in previously treated patients, and previous
treatment with second-line drugs was consistently the
strongest risk factor for resistance to these drugs (Lancet
2012 Aug. 30 [http://dx.doi.org/10.1016/ S01406736(12)60734-X]).
Multidrug-resistant (MDR) tuberculosis is resistant
to at least rifampicin and isoniazid, and accounts for
3·6%-4·8% of new tuberculosis cases worldwide. XDR
tuberculosis is resistant to at least rifampicin, isoniazid,
and one or more of the second-line antituberculosis
drugs. XDR tuberculosis has been reported in 77 countries.
While the numbers varied between nations, investigators with the international Preserving Effective TB
Treatment Study (PETTS) saw a concerning pattern:
The prevalence of drug-resistant strains correlated with
the time that the second-line drugs had become available through the Green Light Committee, a World
Health Organization program designed to increase access to second-line antituberculosis agents.
“[Second-line drugs] had been available for 10 years
or less in Thailand (7 years), the Philippines (9 years),
and Peru (10 years), and
these countries had the lowest rates of resistance,” wrote
Dr. Dalton of the Centers for
Disease Control and Prevention. “By contrast, South Korea and Russia had the
longest histories of availability (more than 20 years) and
the highest rates of resistance.”
PETTS was launched in
2003 to determine the risk
factors for and frequency of
acquired resistance to second-line therapies in people
with MDR tuberculosis. In
2005, in light of burgeoning
numbers, the program was
modified to include data on
people with XDR tuberculosis.
The current report focused on eight countries: Es- Multidrug-resistant tuberculosis is resistant to at least rifampicin and isoniazid,
tonia, Latvia, Peru, the and accounts for 3·6%-4·8% of new tuberculosis cases worldwide.
Philippines, Russia, South
Africa, South Korea, and Thailand. Samples from pa- South Africa had the lowest rate of second-line treattients with MDR tuberculosis were obtained from ment (3%), while South Korea had the highest (54%).
large clinical centers in each country during 2005-2008.
The overall prevalence of resistance to any secondInclusion criteria were at least 30 days of treatment line drug was 43.7%, but the rate varied among the
with a second-line antituberculosis drug, with sputum countries, from 33% in Thailand to 62% in Latvia.
collection within 30 days before or after the initiation
Overall, 20% of isolates were resistant to at least
of therapy.
one second-line injectable drug, ranging from 2% in
Of 1,540 isolates tested, 1,278 (83%) were MDR. the Philippines to 47% in Latvia. The Philippines also
Most of those patients (94%) had a history of tubercu- had the lowest prevalence of resistance to all injectables
losis, and of those, 71% had experienced it at least (0.3%), while South Africa had the highest (26%).
once before the tested case.
The overall resistance rate to at least one secondOf the entire group, 93% had received first-line ther- line oral drug was 27%. Resistance to at least one oral
apy, but only 15% had received second-line drugs. drug ranged from 13% in Estonia to 38% in Latvia;
however, other countries also had a high prevalence,
including South Korea (36%), the Philippines (32%),
Russia (26%), and South Africa (22%).
A total of 6.7% of the isolates were XDR, with the
highest prevalence in South Korea (15%) and the lowest
in the Philippines (0.8%).
Prior treatment for MDR strains with the secondline drugs was the strongest risk factor for XDR tuberculosis, with a relative risk of 4.75 for injectables and 4
for oral medications.
Although countries with Green Light projects did
have more cases, the risks ratios for different resistance
types did not reflect the actual numbers, the authors
noted.
Resistance to fluoroquinolones and second-line injectable drugs – but not to other oral second-line drugs
– was significantly less prevalent in countries that had
Green Light Committee-approved projects. “This difference was due to the very low prevalence of resistance
to second-line drugs in the Philippines, which had the
largest Green Light Committee project,” the authors
said.
The individualized numbers should be useful to national disease management efforts, the researchers
added. “Our country-specific results can be extrapolated to guide in-country policy for laboratory capacity
and for designing effective treatment recommendations.”
PETTS data collection continues, they noted. “The
effect of the Green Light Committee initiative in combating acquired resistance to second-line drugs, the
timing of acquired resistance, and the role of specific
genetic mutations in different regions of the world are
also being assessed.”
The U.S. Agency for International Development,
the Centers for Disease Control and Prevention, the
National Institutes of Health, and the Korean Ministry
of Health and Welfare sponsored the study. The authors declared no financial conflicts.
© LISAFX / I S TOCKPHOTO . COM
Resistance to Second-Line TB Drugs Rises
PULMONARY MEDICINE
April 2013
7
LABA 사용 중지로 천식은 악화될 수 있어
BY MARY ANN MOON
IMNG Medical News
W
VITALS
ithdrawing long-acting betaagonist therapy worsened refractory asthma that had
been controlled with a combination of
LABAs and inhaled cortico-steroids, according to a meta-analysis.
The findings run counter to the Food
and Drug Administration’s black-box
warning that patients should reduce use
of LABAs such as salmeterol or formoterol once they achieve asthma control.
Stopping LABAs after achieving asthma control was associated with reduced
asthma control, increased symptom frequency, increased use of rescue bronchodilators, decreased asthma-related
quality of life, and similar rates of adverse
events and serious adverse events, com-
pared with continuing LABAs in combination therapy, according to the metaanalysis’ authors, who focused on the
only five randomized, controlled clinical
trials (RCTs) to examine this issue.
“Thus, in contrast to FDA recommendations of stepping off LABA therapy
[once] asthma is controlled, our analysis
supports the continued use of LABAs to
maintain asthma control,” Dr. Jan L.
Brozek of the department of clinical epidemiology and biostatistics and medicine, McMaster University, Hamilton,
Ont., and his associates wrote in
Archives of Internal Medicine (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2012.3250]).
However, they noted that this conclusion is based on the pooled results of
only five studies, all of which had substantial limitations.
The researchers undertook the meta-
주요 결과: ICS와 LABA 복합제로 잘 조절되고 있는 난치성 천식에서 LABA 사용을 중지하면 삶의
질 점수가 0.24점 낮아지고 무증상 일(symptom-free days)이 9.2% 감소되며, 증상완화제(rescue
bronchodilator) 사용빈도가 하루 평균 0.71회(0.71회/일) 증가한다.
출처: 청소년과 성인을 대상으로 한 다섯 개의 무작위배정 비교연구를 메타분석함 (천식이 조절된 후
계속 ICS와 LABA 복합제를 사용한 682명과 LABA를 중지하고 ICS를 단독으로 사용한 660명을 대
상으로 분석).
analysis because of the ongoing controversy over whether to withdraw or continue LABA therapy once asthma is adequately controlled, as the Food and
Drug Administration recommends in a
black-box warning for the drugs.
The five RCTs included in the metaanalysis were all sponsored by the manufacturers of the study drugs. Four were
published in peer-reviewed journals, and
one was a conference abstract. All the
RCTs involved adolescents or adults
with at least a 6-month history of mild
to moderate asthma, but four of the five
trials did not specify whether combined
therapy with inhaled corticosteroids and
LABAs had been required to control
symptoms at enrollment.
Compared with continued combination therapy, LABA step-down therapy
was associated with an average 0.24point drop in Asthma Quality of Life
Questionnaire scores for control of asthma, 9.2% fewer symptom-free days, and
an average of 0.71 more puffs/day from
a rescue bronchodilator.
Despite the meta-analysis results, the
investigators cautioned that the duration
of well-controlled asthma on combination therapy was shorter than the 3
SUMMARY
Stopping LABA Therapy May Worsen Controlled Asthma
FDA는 ICS와 LABA 복합제로 천식이 조절된
다면 LABA를 더 이상 사용하지 말 것을 권
고하고 있다. 그러나 이 권고에 따라 난치성
천식에서 LABA 투여를 중지할 경우 천식이
악화될 수 있음이 보고되었다. LABA stepdown 전략! 다시 고려해볼 때이다.
months that are recommended to adequately judge the treatment effect. None
of the RCTs reported emergency department visits, unscheduled office visits
for asthma, days missed from work or
school, costs, or complications associated
with the corticosteroids, the authors said.
All were of short duration, none provided information on treatment adherence,
and some had high dropout rates.
Nevertheless, “our findings likely represent the current best evidence about
stepping off LABA therapy in patients
with asthma,” the investigators asserted.
The pooled analysis showed “no statistically significant results for any of the
reported asthma outcomes of interest
showing a benefit from [the] LABA stepoff approach, compared with continued
use of the same dose of inhaled corticosteroids and LABA,” Dr. Brozek and his
associates said.
정위적방사선치료; 폐암 생존율 향상을 위한 새로운 치료전략
BY NEIL OSTERWEIL
IMNG Medical News
VITALS
BOSTON – Delivering stereotactic body radiation for
early-stage, inoperable non–small cell lung cancer doubled overall survival rates achieved in historical series
with conventional radiation, investigators reported at
the annual meeting of the American Society for Radiation Oncology.
The 3-year overall survival rate
reached 59.9% for 100 patients
whose stage IA non–small cell
lung cancer (NSCLC) was treated
with stereotactic body radiation
therapy (SBRT), said Dr. Yasushi
Nagata. He compared results of
the nonrandomized phase II trial
with 31%-39% in historical series
with conventional radiation.
The 5-year overall survival rate
was 40.8%, compared with 13%-22.2% historically,
added Dr. Nagata from Hiroshima University, Japan.
He described SBRT as well tolerated with only mild
toxicities, making it a suitable alternative to other therapies, particularly in older patients. “Patients with early
inoperable lung cancer should consider this treatment,”
Dr. Nagata advised in a briefing.
The investigators concluded that the treatment
should be the new standard, replacing conventional
radiotherapy in this population.
Similar in concept to stereotactic radiosurgery with
a cyberknife, SBRT is a technique for precise high주요 결과: IA병기 비소세포폐암을 정위적방사선치료를 할
경우 3년 생존률은 59%로 종래의 방사선치료에 의한 생존율
31%에 비하여 높았다.
출처: 비무작위 2상 연구 자료.
dose targeting of tissues from multiple angles and
planes, allowing delivery of much larger doses by fraction than conformal 3-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy
sessions can often be compressed into as little as 4-6
fractions delivered over 2 to 2.5 weeks, compared with
8 to 9 weeks of daily fractions for other techniques.
The phase II Japanese Clinical Oncology Group trial,
JCOG-0403, is said to be the first to evaluate SBRT in
both operable and nonoperable
Stereotactic body NSCLC. At the 2010 ASTRO annual meeting, the investigators
radiation should
reported 3-year survival rates for
replace
64 patients with surgically reconventional
sectable NSCLC: overall survival
radiotherapy for
was 76%; progression-free surearly inoperable
vival, 54.5%; local progressionlung cancer.
free survival, 68.5%; and eventDR. NAGATA
free survival, 51.4%.
In the current study, 77 men
and 27 women with a median age of 78 years (range
59-90 years) were enrolled; four patients were later excluded from the study, three because they developed
a second primary cancer within 5 years of registration,
and one was “unexpectedly” treated with SBRT and
chemotherapy.
The median tumor size was 21 mm (range 9-30
mm). Fifty patients had adenocarcinomas, 40 had squamous cell carcinomas, and 14 had other tumor histologies. All patients had histologically or cytologically
proven NSCLC, clinical T1N0M0 disease, and were
determined by thoracic surgeons to be inoperable.
All patients completed the treatment protocol, consisting of a dose of 48 Gy at the isocenter divided into
4 fractions over 4-8 days.
The progression-free survival rate at 3 years was
49.8%; the local progression-free survival rate was
52.8%, and event-free survival, 46.8%.
SUMMARY
Stereotactic Radiation Boosts Lung Cancer Survival
초기폐암이지만 수술을 할 수 없는 경우 정위적방사선치료에
의한 생존율이 기존의 방사선치료결과보다 훨씬 높아 폐암치
료의 새로운 대안으로 부상하였다.
Grade 3 adverse events include dyspnea in 10 patients,
hypoxia in 8, pneumonitis in 7, chest pain in 2 and
cough in 1. There was one case each of grade 4 dyspnea
and hypoxia, but no treatment-related deaths.
8
PULMONARY MEDICINE
CHEST Physician • April 2013
환자가 느끼는 호흡곤란 정도가 COPD 결과에 영향을 미쳐
IMNG Medical News
VITALS
ATLANTA – The perception of dyspnea
among patients with chronic obstructive
pulmonary disorder plays a bigger role
in quality of life, functional status, and
depression than do objective measures
of disease severity, according to findings
from cross-sectional study involving 158
patients.
The findings suggest that assessing
and addressing dyspnea in COPD patients could play an important role in
improving quality of life outcomes, Dr.
Sandra Adams reported at the annual
meeting of the American College of
Chest Physicians.
주요 결과: 호흡곤란을 더 심하게 느끼는 환
자들이 삶의 질 지표, 기능적 상태 및 우울
증의 측면에서 더 나쁜 결과를 보였다.
출처: CASCADE trial에 포함된 158명의 환자
들에서 시행한 단면 연구 결과
The patients included in this analysis
are part of the CASCADE study, a 2year longitudinal observational study of
genes and depression in COPD. They
completed spirometry, the modified
Medical Research Council (mMRC) dyspnea scale, questions related to exacerbation risk within the last year, the
Chronic Respiratory Questionnaire
(CRQ), a nine-item depression interview,
the Personal Health Questionnaire
(PHQ-9), and a 6-minute walk test at
baseline.
Study participants had a mean age of
about 67 years, about 25% were women,
40% were on supplemental oxygen, and
the mean forced expiratory volume in 1
second (FEV1) percent predicted was
43%. Exacerbations were self-reported.
More than 60% had a self-reported
physician diagnosis of depression.
About 20% of the patients were found
to be grade A patients, based on the revised Global Initiative for Chronic Obstructive Lung Disease (GOLD) released
in December 2011, about 10% were
grade B patients, about 20% were grade
C patients, and about 50% were grade
D patients, said Dr. Adams of the University of Texas Health Science Center,
San Antonio.
Patients with grade A disease have
mild disease severity, airflow limitation,
and few exacerbations; those with grade
B disease are similar to those with grade
A, except they have more symptoms (in
this study, the grade B patients had no
exacerbations).
Those who have grade C disease experience minimal symptoms, severe airflow limitation, and/or two or more exacerbations each year; those with grade
D disease are similar to those with grade
C disease, except they have more symptoms.
“One thing we were actually really
surprised to find is that the group of A
and C with minimal symptoms may be
a lot more similar than we think, whereas
D and B with the severe symptoms –
even though they have significant differences in exacerbations and/or airflow
limitation, may be very similar,” she said.
Indeed, no differences on the various
measures used in this study were seen
between the A and C patients, and between the B and D patients. But when
the A and C patients were combined
and compared with the combined group
of B and D patients, significant differences emerged for every measure.
“Again, the big difference is symptoms; A and C have minimal symptoms
and B and D have severe symptoms,”
Dr. Adams said.
As it turned out, grades A and C patients had significantly higher CRQ
scores (higher scores are better) than
did grades B and D patients (mean of
105 and 98 for A and C vs. 80 and 84 for
B and D, respectively).
Grades A and C also had
COPD Severity Criteria
statistically and clinically
Grade
Patient Description
significantly greater 6minute walk test disMild disease severity, airflow
A
tances, Dr. Adams noted.
limitation, and few exacerbations.
On a physical function
B
Similar
to grade A, but with
measure of steps walked
more symptoms.
in a day, the A and C patients averaged 7,900, and
C
Minimal symptoms, severe airflow
the B and D patients avlimitation, and/or two or more
eraged only 4,800, she
exacerbations
each year.
added.
D
Similar to grade C, but with more
That’s 3,900 fewer steps
despite inclusion of Bsymptoms.
group patient (10% of the
Source: Global Initiative for Chronic Obstructive Lung
total study population) in
Disease
the B/D combined group,
Dr. Adams noted.
“Again … grade B had relatively nor- and/or the number of exacerbations,
mal lung function and no exacerbations, Dr. Adams said, explaining that it apbut yet they’re severely dyspneic,” she pears that the perception of dyspnea is
the main factor associated with these
noted.
As for depression, the history was sim- outcomes.
“And, in fact, those who report severe
ilar across all grades, although more
grade B and D patients than A and C pa- dyspnea may be even more limited than
tients had PHQ-9 scores of 10 or greater, those with frequent exacerbations,” she
which indicates significant depression. said.
What are the clinical implications of
On linear regression, an mMRC dyspnea
scale score of 2 or higher was associated the findings?
“We ask our patients, ‘How are you
with a significant increase in depression
doing? How is your shortness of breath?’
(odds ratio, 2.8).
“So the bottom line to this is grades A but actually getting an assessment and
and C have similar levels of depression, also trying to really address the dyspnea
quality of life, physical function, and in addition to the exacerbations is going
physical activity despite significant dif- to be really key in this population,” Dr.
ferences in FEV1 percent predicted and Adams concluded.
COMMENTARY
BY SHARON WORCESTER
Dr. Darcy D. Marciniuk, FCCP, comments:
COPD 환자에서 환자가 느끼는 호흡곤란 증상의 정도는 6분 보행검사
결과로 평가되는 활동성의 감소 및 PHQ-9 우울증 척도로 평가되는 우
울증의 증가와 관련을 보였다. 최근 개정된 GOLD Group A와 B에 속
하는, 폐기능이 FEV1 50%까지 감소된 환자들을 ‘상대적으로 정상 폐기
능을 가진’ 군으로 구분하는 것이 잘못된 용어 선택이라고 할지라도, 폐
기능 저하 한 가지만으로 COPD환자의 주관적 경험을 모두 설명할 수
없다는 것은 확실하다. 이 연구의 결과는 COPD 환자에서 다면적 평가
및 다양한 임상적 표현형의 중요성을 보여주고 있다.
IMNG M EDICAL M EDIA
Perceived Dyspnea May Affect COPD Outcomes
PULMONARY MEDICINE
April 2013
9
Crizotinib이 진행된 ALK 양성 비소세포폐암 치료를 바꾼다
VIENNA – Long-awaited data from the
phase III PROFILE 1007 confirm that
crizotinib provides superior progressionfree survival and responses, compared
with second-line chemotherapy in advanced anaplastic lymphoma kinase–
positive non–small cell lung cancer.
Median progression-free survival more
than doubled from 3.0 months with single-agent chemotherapy to 7.7 months
with crizotinib, according to an independent radiologic review (P value less
than .0001; hazard ratio, 0.49).
Crizotinib (Xalkori) remained superior
regardless of whether chemotherapy
contained docetaxel (Taxotere) (7.7 vs.
2.6 months; P less than .0001) or pemetrexed (Alimta) (7.7 vs. 4.2; P = .0004),
an agent previously shown to be effective against ALK-positive NSCLC.
The overall response rate was 65.3%
for crizotinib and 19.5% for chemotherapy in the intent-to-treat population of
347 patients (overall response rate ratio
3.4; P less than .0001).
Crizotinib changed the natural history of
the disease, Dr. Jean-Charles Soria said.
Crizotinib was also associated with
significantly greater improvement in
lung cancer symptoms and quality of
life, Dr. Alice Shaw reported during a
presidential symposium at the European
Society for Medical Oncology Congress.
“Taken together, these results establish crizotinib as the standard of care for
patients with advanced, previously treated ALK-positive non–small cell lung cancer,” she said.
ALK rearrangements are present in
about 5% of lung cancers, typically in
younger, never smokers.
Overall survival in the study was 22.8
months for chemotherapy and 20.3
months for crizotinib (P = .5394; HR,
1.02). The interim survival analysis was
immature with just 40% of expected
deaths reported and likely confounded
by the high number (87%) of chemotherapy patients who crossed over to crizotinib after progression, she noted. After
adjustment for crossover, the hazard ratio suggests a survival advantage with
crizotinib (HR, 0.83).
Discussant Dr. Jean-Charles Soria of
Institut Gustave Roussy, Villejuif,
France, agreed and said the survival
주요 결과: 중간 무진행 생존기간이 항암요
법을 사용한 경우 3개월이었으나 crizotinib을
사용한 경우 7.7개월이었다. (P<.0001, 위험률
0.49)
출처: 318명의 진행된 ALK 양성 비소세포폐
암 환자를 대상으로 한 3상시험 결과.
times in either arm were impressive, observing that just 2 years ago survival in
second-line ALK-positive NSCLC was
just 9 months.
“This is really changing the natural
history of the disease,” he said.
Crizotinib, an oral, first in class ALK
inhibitor, was given accelerated approval
in 2011 in the United States to treat advanced ALK-positive NSCLC but is not
approved in Europe, where regulatory
agencies have required data from the
randomized trial.
“While the U.S. treats, Europe randomizes,” Dr. Soria lamented to a loud
round of laughter.
He observed that worldwide use of
crizotinib will require that several financial and practical issues surrounding implementation of molecular testing in daily practice be addressed including the
optimal technique, type of sample, and
tissue availability. Testing for epidermal
growth factor receptor, another molecular alteration that directs targeted therapy in lung cancer, “should not compete
with ALK,” he said, adding that multiplexing test strategies “are key.”
Investigators at 105 sites across 21
countries in Europe, the Americas, and
Asia-Pacific randomized 173 patients to
crizotinib 250 mg twice daily in a 21-day
cycle and 174 patients to chemotherapy
containing pemetrexed 500 mg/m2 or
docetaxel 75 mg/m2 given intravenously
on day 1 of a 21-day cycle.
Treatment duration varied significantly, with patients receiving a median of
11 cycles of crizotinib vs. 4 cycles of
chemotherapy. This may have influenced the higher number of all-cause
deaths among crizotinib patients (25
deaths vs. 7 deaths), said Dr. Shaw, a
thoracic oncologist at Massachusetts
General Hospital Cancer Center in
Boston.
Crizotinib patients were more likely
than were chemotherapy patients to experience the now well-known side effect
of visual disturbances (any grade 60%
vs. 9%), as well as diarrhea, nausea, elevated transaminases (16% grade 3/4 ),
edema, upper respiratory infection, dysgeusia, and dizziness. In contrast, fatigue,
alopecia, dyspnea, and rash were more
common in those receiving chemotherapy.
Despite the fact that patients on crizotinib experienced more nausea and vomiting, antiemetic use was significantly
higher in the chemotherapy arm (67%
vs. 20%), observed Dr. Shaw, who said
the majority of adverse events were
grades 1/2, generally manageable and
tolerable.
This was reflected in patient-reported
lung cancer symptoms and quality of
life. Based on the EORTC Quality of
Life Questionnaire (QLQ C-30) and
QLQ-LC 13, crizotinib patients had
greater improvement from baseline in
cough, dyspnea, fatigue, alopecia, insomnia, and pain as well as global quality
of life (both P less than .0001).
“This is a compound with very mild
toxicity,” commented Dr. Soria. He said
clinicians need to be aware of crizotinib’s
distinct side-effect profile, including other rare events such as renal cysts, pneumonitis, asymptomatic bradycardia, and
low testosterone, “although we don’t
really know if it impacts sexual life.”
The topic of hypogonadism was raised
in a separate session on second-generation ALK inhibitors at the meeting and
in a recent report of rapid-onset hypogonadism secondary to crizotinib use in
19 men with metastatic NSCLC (Cancer
2012 [doi:10.1002/cncr.27450]).
Dr. Shaw said in an interview that the
study was small and “requires a lot more
validation.” Although testosterone levels
were not checked in PROFILE 1007, it
is being done for the next generation of
ALK inhibitors, she added.
Dr. Soria said resistance to crizotinib
will become a problem with increasing
worldwide use, and that strategies to
counter this may include the secondgeneration ALK inhibitors, increased
crizotinib dosing, and crizotinib plus ablative therapy given the poor penetration of crizotinib in the brain.
Brain metastases were present in 35%
Data now support crizotinib as the
standard of care, said Dr. Alice Shaw.
of patients in both arms. Three-fourths
of patients were never smokers, roughly
95% had adenocarcinoma, and their median age was about 50 years.
SUMMARY
IMNG Medical News
VITALS
B Y PAT R I C E W E N D L I N G
P HOTOS PATRICE W ENDLING /IMNG M EDICAL M EDIA
Crizotinib Changes Advanced ALK-Positive NSCLC Tx
3상 임상연구인 PROFILE 1007 결과에 따
르면 crizotinib이 ALK 양성 진행된 비소세
포폐암 치료에서 2차 항암제인 docetaxol이
나 pemetrexed를 포함한 항암요법에 비해
월등하게 우수한 중간 무진행 생존기간과 반
응률을 보임이 확인되었다.
10
PULMONARY MEDICINE
CHEST Physician • April 2013
Tiotropium 추가요법이 조절되지 않는 천식환자의 악화 감소에 도움
BY MARY ANN MOON
IMNG Medical News
A
dding tiotropium to standard combination therapy may help reduce exacerbations in some
adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting
beta-agonists, according to two randomized, controlled
trials published in the New England Journal of Medicine.
However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthmarelated quality of life scores.
Compared with placebo, tiotropium administered
once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided
“modest” bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A.M. Kerstjens
of the University of Groningen (the Netherlands) and
the Groningen Research Institute for Asthma and
COPD, and his associates (N. Engl. J. Med. 2012 Sept.
3 [doi:10.1056/NEJMoa1208606]).
However, the improvements in forced expiratory
volume in 1 second (FEV1) were “relatively small (less
than 10%),” and the number of symptom-free days did
not differ between patients who received tiotropium
and those who received placebo.
Moreover, the use of rescue medications was the
same between the two groups, and patient ratings of
asthma-related quality of life also were the same on
two measures, the researchers noted.
Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for
the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.
Dr. Kerstjens and his colleagues assessed the drug’s
effects in two 48-week randomized, controlled trials
conducted in 15 countries, both of which were funded
by Boehringer Ingelheim and Pfizer. They presented
their findings at the annual meeting of the European
Respiratory Society simultaneously with publication.
The studies included 912 adults aged 18-75 years
who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use
of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either
tiotropium (237 patients in study 1 and 219 patients in
study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.
Patients were allowed to continue the use of stable
doses of sustained-release theophylline, leukotriene
modifiers, anti-immunoglobulin E antibody, or oral
glucocorticoids, and were given open-label inhalers of
salbutamol or albuterol for use as rescue medication.
The first two lung-function end points of both studies
were the peak FEV1 response and the trough FEV1 response at week 24, expressed as the change from baseline FEV1. Tiotropium topped placebo in peak FEV1
response by an average of 86 mL in trial 1 and 154 mL
in trial 2, differences that were significant.
The average difference in trough FEV1 response between tiotropium and placebo groups was 88 mL in
trial 1 and 111 mL in trial 2. Those differences were
“relatively small” but also statistically significant.
“It should be noted that [these differences occurred]
in patients who were already receiving a long-acting
bronchodilator and had fixed airflow limitation,” the
investigators noted. The results also should be considered “in the context of the need for additional treatments for this patient population and the limitations
of current alternatives,” they added.
A third lung-function end point was the time until at
least 25% of patients had their first severe exacerbation
of asthma. That interval was 56 days longer with
tiotropium (282 days), compared with placebo (226
days).
The number of severe exacerbations was a secondary
end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly
fewer than the 0.66 per patient-year with placebo.
In addition, 27% of patients in both tiotropium
groups had at least one severe exacerbation, which
was significantly less than the 33% rate in both placebo
groups.
However, asthma-related quality of life did not differ
significantly between tiotropium and placebo groups
SUMARRY
Tiotropium Cut Asthma Exacerbations
2개의 무작위 대조군 연구에서 기존의 치료에도 조절되지 않
는 천식 환자에서 지속성 흡입 항콜린제의 병용요법은 추가
적인 이득과 안전성을 보였다. ICS/LABA의 사용에도 지속적
인 기도폐쇄가 있는 천식환자에서 하루 한번 tiotropium 1년
간 사용은 폐기능의 개선과 악화까지의 기간 연장을 보였으
며, 부작용의 차이는 없었다.
in either trial. The minimal clinically important difference between the two groups was not achieved when
measured by both the Asthma Control Questionnaire
7 and the 32-item Asthma Quality of Life Questionnaire.
Similarly, daily symptom diaries showed “small or
nonsignificant” differences between the active drug
and the placebo groups in symptom-free days. And the
use of rescue medications also was similar.
Adverse events occurred in 73.5% of the tiotropium
group and 80.3% of the placebo group, and allergic
rhinitis was the only one that occurred more often in
the tiotropium group. Adverse events were judged to
be treatment related in 5.7% of the tiotropium group
and 4.6% of the placebo group.
Serious adverse events occurred in 8.1% of the
tiotropium group and 8.8% of the placebo group.
Three of those events – two asthma exacerbations and
one cerebral infarction – occurred in the tiotropium
group and were considered life threatening.
Cardiac events occurred in less than 2% of both
study groups; they were considered drug related in
0.4% of patients in the tiotropium group and 0.2% of
those in the placebo group. Adverse changes in blood
pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study
groups.
Less than 2% of all patients experienced dry mouth
– a typical adverse event with anticholinergic agents –
but it was reported more frequently in the tiotropium
group (eight patients vs. three patients), Dr. Kerstjens
and his associates said.
Dr. Kerstjens reported additional associations with
Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.
PEDIATRIC CHEST MEDICINE
소아에서 Budesonide 사용이 성인신장을 감소시킴
Budesonide for Kids Reduces Adult Height
IMNG Medical News
L
ong-term use of inhaled budesonide is associated not only with
slowed growth in prepubertal
children, but with reduced final adult
height as well.
An 8-year observational study found
that children who had used budesonide
during an asthma treatment trial were
more than 1 cm shorter than those who
used nedocromil or placebo. The findings suggest that glucocorticoid-related
growth impairment has a lasting effect
on potential adult height, H. William
Kelly, Pharm.D., and his colleagues
wrote in the the New England Journal
of Medicine (N. Engl. J. Med.
2012;367:904-12 [doi: 10.1056/NEJMoa1203229]).
The prospective study followed 943
children who had participated in the
Childhood Asthma Management Program (CAMP) trial. CAMP randomized
children with asthma aged 5-13 years to
placebo, 400 mcg/day budesonide, or
16 mg/day nedocromil.
Initial follow-up averaged 4.3 years,
with height measured once or twice a
year for the subsequent 8 years. Final
height was measured at a mean age of
25 years.
The mean adult height in the budesonide group was 171.1 cm – significantly
shorter than the 172.3 cm in the placebo
group. Mean adult height in the nedocromil group was almost the same as
in the placebo group (172.1 cm).
Women in the budesonide group were
particularly affected; they were a mean
of 1.8 cm shorter than women in the
Continued on following page
©C OMSTOCK /T HINKSTOCKPHOTOS . COM
BY MICHELE G. SULLIVAN
Glucocorticoid-related growth impairment has a lasting effect on potential adult
height, study findings suggest.
Continued from previous page
COMMENTARY
Final height was related to daily
dosage during the randomized trial, with
placebo group. Men who took budes- a decrement of 0.1 cm for each microonide were a mean of 0.8 cm shorter gram per kilogram of budesonide. Sevthan men who took placebo as children. eral baseline characteristics were also
During the first 2 years of the CAMP significantly related to lower adult
trial, rates of growth had already slowed, height, including Hispanic ethnicity and
showing a 1.3-cm difference between being female, or having a higher Tanner
the budesonide and placebo groups. At stage, greater body mass index, longer
the end of that trial, the difference was duration of asthma, and low vitamin D
1.2 cm, a deficit that did not change as levels.
Since the CAMP trial concluded, rethe patients entered young adulthood.
search has shown
that 200 mcg/day
budesonide in a
Dr. Susan Millard, FCCP, comments:
dry-powder inNEJM 에 발표된 이 논문은 소아환자를 진
haler is sufficient
료하는 모든 의사들에게 중요한 정보를 준
to control mild to
다. 하지만 모든 의사들과 부모들에게 남겨
moderate asthma
지는 최종 질문은 ‘기도의 구조변화, 결근과
and prevent exac결석으로 인한 경제적, 교육적 부담, 천식의
erbations in chil악화로 인한 사망의 위험성과 성인 신장 1.2
dren.
cm의 감소를 어떻게 받아들여야 하는 것인
“Even at this
가?’ 이다.
lower dose, there
was a reported mean reduction of 1.0
cm in height during the first 2 years of
therapy,” the investigators noted.
“Although the systemic effects of inhaled glucocorticoids are dose dependent, they are also dependent on the
therapeutic index of the specific inhaled
glucocorticoid and the delivery device
used. Thus, it seems prudent to select
inhaled glucocorticoids and devices with
higher therapeutic indexes, and to use
them in the lowest effective doses in
children with persistent asthma.”
Ultimately, they concluded, parents
and physicians must work together to
decide the risk-benefit ratio that is most
appropriate and acceptable for each individual patient.
“In the information about inhaled glucocorticoids and their side effects that is
provided to parents, the potential effect
on adult height must be balanced against
the large and well-established benefits
of these drugs in controlling persistent
VITALS
PEDIATRIC CHEST MEDICINE
April 2013
11
주요 결과: 소아 때부터 budesonide를 400
mcg 흡입해온 성인들은 nedocromil 혹은
위약을 사용한 성인들보다 신장이 1 cm가 작
았다.
출처: 이 연구는 8년간의 관찰연구로 소아기
천식관리 프로그램연구에 참여한 943명의
환자들을 포함하였다.
asthma,” concluded Dr. Kelly of the University of New Mexico, Albuquerque,
and his coauthors.
The CAMP trial and its observational
study were funded by the National
Heart, Lung, and Blood Institute and
the National Center for Research Resources.
Dr. Kelly serves on steering committees for and has received consulting fees
from AstraZeneca, GlaxoSmith-Kline,
and other companies. His coauthors reported that they have multiple financial
relationships with pharmaceutical companies.
PULMONARY PERSPECTIVES
COPD에서 성별에 따른 차이점: 아직도 문제가 되는가?
An ongoing concern has been whether women
with COPD are less frequently diagnosed.
C
OPD is currently the third leading
cause of mortality in the United
States (Heron M. National vital statistics
reports; vol 60(6). Hyattsville, MD: National Center for Health Statistics 2012,
http://www.cdc.gov/nchs/data/nvsr/
nvsr60/nvsr60_06.pdf), but this burden
is disproportionately shared by women.
COPD-related deaths in the United
States among women now outnumber
those of men (Han et al. Am J Respir
Crit Care Med. 2007;176[12]:1179).
While it is tempting to presume that
this is completely attributable to a relative increase in
tobacco
use
among women,
there are epidemiologic and
biological data
supporting the
idea that COPD
disease presentation and progression may
DR. CARLOS
differ in women,
MARTINEZ
revealing significant opportunities to improve clinical care and consider new avenues for research.
Diagnosis
An ongoing concern has been whether
women with COPD are less frequently
diagnosed. Two studies with similar design have attempted to answer that question. In the first, when a clinical vignette
suggestive of a diagnosis of COPD was
presented to physicians, the diagnosis of
COPD was less frequent when the subject was a woman (Chapman et al.
Chest. 2001;119[6]:1691). In the second
study, published 5 years later, the gender
discrepancy in diagnosis disappeared
when physicians were presented with
spirometry (Miravitlles et al. Arch Bronconeumol. 2006;42[1]:3). These data underscore the importance of obtaining
spirometry data to counter the risk of
physician gender bias in diagnosis of the
disease. Furthermore, the implications
for diagnosis in women may be even
more important for women than men.
A meta-analysis of 11 longitudinal studies
concluded that for the same amount of
tobacco smoked, women experienced a
greater rate of lung function decline
(Gan et al. Respir Res. 2006;7:52). The
Lung Health Study also demonstrated
more rapid lung
function decline
in women who
continued to
smoke but, importantly, an
even greater potential to recover lung function
after smoking
cessation comDR. MEILAN HAN
pared with men
(Bjornson et al.
Am J Public
Health. 1995;85[2]:223). Unfortunately,
multiple studies have also concluded
that smoking cessation is actually more
difficult for women to achieve and maintain (Han et al. Am J Respir Crit Care
Med. 2007;176[12]:1179).
Biological Basis
There may be a biological basis to differences in tobacco susceptibility. Each
cigarette smoked may represent a relatively higher “dose,” given that women
are, on average, smaller than men. Clinical studies suggest that the plasma clearance of nicotine is also lower in women
than men; women may have lower capacity for DNA repair than men and are
more prone to oxidative damage (Rivera
et al. Clin Chest Med. 2004;25[2]:391).
Adipokines have also recently gained interest as potential mediators in the deregulated pro- and anti-inflammatory balance responsible for the development of
COPD, with both systemic and
bronchial leptin levels being associated
with the disease and with more severe
local inflammation (Assad et al.
Biochimie. 2012 Mar 14 [epub ahead of
print]). New evidence points toward a
stronger association between leptin levels and other inflammatory markers in
women with COPD than men (Breyer
et al. Respir Med. 2011;105[7]:1046).
Mortality Rates
Conflicting data exist regarding differences in mortality rates between men
and women with COPD. A recent analysis of the TORCH study demonstrated
that women, in general, had lower allcause mortality, which is consistent with
population-based data. However, after
‘EACH CIGARETTE SMOKED MAY
REPRESENT A RELATIVELY
HIGHER “DOSE,” GIVEN THAT
WOMEN ARE, ON AVERAGE,
SMALLER THAN MEN.’
adjusting for baseline variables, including
FEV1, BMI, geographic region, and history of myocardial infarction, the difference was no longer statistically significant (Celli et al. Am J Respir Crit Care
Med. 2011;183[3]317). While respiratory-related deaths were the most frequent
cause of death, overall, the causes of
death appeared to be similarly distributed between men and women.
Symptom Differences
One of the most interesting and ubiquitous findings in women with COPD is a
SUMMARY
Gender Differences in COPD: Do They Still Matter?
여성에서는 COPD의 임상양상과 병의 진행
이 다를 수 있다는 여러 가지 역학적, 생물학
적인 연구 결과들이 있으며, 따라서 앞으로
COPD 환자 개개인에 대한 맞춤 치료를 개
발하기 위해서는 성별에 따른 차이점을 탐구
하고 이해하는 것이 중요하다.
lower frequency of phlegm production
(de Torres et al. Chest. 2005;128(4):2012),
even when the frequency of cough is
similar or higher and the reported dyspnea more severe (Celli et al. Am J Respir
Crit Care Med. 2011;183[3]: 317).
Women are also under-represented
among patients with a chronic bronchitic
COPD phenotype (Kim et al. Chest.
2011;140[3]: 626). The differences in
phlegm and bronchitic symptoms, in
general, are intriguing, as among advanced COPD subjects in the National
Emphysema Treatment Trial (NETT),
women exhibited less radiologic emphysema and smaller airway lumen area
with thicker bronchial walls as compared
with men (Martinez et al. Am J Respir
Crit Care Med. 2007;176[3]:243). Studies
also suggest women report more severe
dyspnea during exercise as compared
with men with similar lung function (de
Torres et al. Respir Res. 2007;8:18), but
the reasons for this are still not well understood.
Quality of Life
Gender differences are also evident in
personal experiences from COPD. In
mild to moderate COPD, quality of life
(QOL) is significantly worse among
women (Celli et al. Am J Respir Crit
Care Med. 2011;183[3]:317), and the factors related to poorer QOL in women
are also not well understood. In trying
to understand factors that predict QOL,
a combination of dyspnea, exercise capacity, and comorbidities were significantly associated with QOL in men with
Continued on following page
12
PULMONARY PERSPECTIVES
Continued from previous page
COPD. In women, however, only dyspnea and oxygenation were significant
predictors of QOL (de Torres et al.
Health Qual Life Outcomes. 2006;4:72).
Evidence from other chronic diseases
(Ng et al. Womens Health Issues.
2010;20[5]:316) suggests that a patient’s
experience with the medical system and
their relationship with their health-care
provider may also contribute to gender
differences in a patient’s experience of
the disease. Differences in comorbidities
may also contribute to variation in QOL
(Ninot et al. Heart Lung. 2006;35[2]:130).
In general, women with COPD report
more anxiety, depression, obesity, and
CHEST Physician • April 2013
physician-diagnosed osteoporosis than
men (Almagro et al. Respir Med.
2010;104[2]:253). Another factor that
may also contribute to gender discrepancies in QOL is the finding that women
report more frequent exacerbations. This
has been documented in several large
clinical trials, including TORCH (Celli
et al. Am J Respir Crit Care Med.
2011;183[3]:317), UPLIFT (Tashkin et al.
Respir Med. 2010;104[10]:1495) and the
NIH-sponsored azithromycin in COPD
trial (Albert et al. N Engl J Med.
2011;365[8]:689). Whether this is due to
a difference in reporting threshold or
disease biology is unknown, but it is a
topic worthy of further investigation.
Medications
Importantly, these trials did not demonstrate significant differences in the efficacy of the therapies being studied, including tiotropium, fluticasone/salmeterol,
and azithromycin, respectively. However, it is only recently that gender differences in therapeutics have even been
examined. It was 1994 when the US National Institutes of Health issued a guideline that gender differences in clinical
trials must be evaluated to ensure the
safety and efficacy of the drug in all of
the patients who might be receiving
that drug (Federal Register of March
28, 1994; FR 59 14508-14513). Prior to
1994, women had been largely excluded
from drug studies due to safety con-
cerns. Even if data up to this point suggest that existing pharmacotherapies for
COPD are equally efficacious in men
and women, it is important that we continue to examine the efficacy of all future medications developed for COPD
in both men and women. In our quest
to define personalized medicine for
COPD, gender-related differences can
be exploited to help us better understand
the disease and must remain an important consideration in our future approach to diagnosis, prognosis, therapy,
and research.
Dr. Carlos Martinez; and
Dr. MeiLan Han
University of Michigan
Ann Arbor, Michigan
CRITICAL CARE
급성호흡곤란: 생리학적 접근을 시도해야..
Acute Dyspnea: Try Physiologic Approach
BY SHERRY BOSCHERT
IMNG Medical News
DENVER – If you presume that a patient who comes
to the emergency department with acute dyspnea primarily has a pulmonary cause, you’ll almost always
be right. Those few other cases, though, take a bit of
detective work.
In the approximately 5% of cases in which dyspnea
is not easily referable to the lungs, the culprit may be
a cardiac problem (usually in a very young child) or,
rarely, other problems – hemoglobinopathies, diseases
that cause metabolic acidosis, or neurologic disorders,
Dr. Jeffrey Sankoff said at the annual meeting of the
American College of Emergency Physicians.
Take a physiologic approach that can guide you
through the differential diagnosis, he suggested. “As
somebody who trained in critical care, everything
boils down to physiology,” said Dr. Sankoff of the
University of Colorado, Denver, and director of quality
and patient safety at Denver Health Medical Center.
To begin, think of diseases that cause hypoxemia,
hypercapnia, or metabolic acidosis, which lead to dyspnea.
Hypoxemia
The most common cause of hypoxemia is ventilationperfusion (V-Q) mismatch, in which blood flows in
the lungs but areas are not getting oxygen. Diffusion
abnormalities, in which oxygen gets into alveoli but
oxygen transit to the bloodstream is impaired, also
cause hypoxemia. These occur in primary pulmonary
disease.
Extrapulmonary disease processes create four causes
of hypoxemia: a shunt, low mixed venous oxygen saturation (Mvo2), decreased fraction of inspired oxygen
(Fio2), and alveolar hypoventilation.
A V-Q mismatch at its most extreme is a shunt, in
which blood bypasses the lungs altogether, he said.
Disease processes that cause blood to go directly from
the right to the left side of circulation result in hypoxemia. A shunt is almost always intracardiac, rarely intrapulmonary.
In children, shunts are seen at characteristic times
for the development of cyanotic congenital heart disease, most commonly patent ductus arteriosus in an
infant. Look for a shunt by its hallmark – oxygen saturation will not improve when you give the patient
oxygen. “This is the test for any young child under
the age of 6 weeks who comes to the emergency department hypoxemic,” Dr. Sankoff said.
Adults with shunts will have a murmur as well as
dyspnea. “Adults don’t develop shunts de novo. This
is going to be happening as part of some acute process,”
he said. The chest x-rays in adults with shunts often
are normal.
The second cause of hypoxemia – low Mvo2 –
occurs mainly when blood flows too slowly through
the capillary bed, allowing excess oxygen extraction,
and blood returns to the heart in a deoxygenated
state. Focus on right ventricular impairment to identify
the etiology. Left ventricular impairment will show
up on x-ray as pulmonary edema. A right-sided infarction or cor pulmonale from pulmonary embolism will
impair right ventricular function. Cardiac tamponade
from infectious, inflammatory, or neoplastic processes
also can cause low Mvo2 and dyspnea, though nobody
really understands why, he added.
The third cause of hypoxemia – decreased Fio2 –
usually is a problem relegated to people at high altitudes or industrial workers in enclosed spaces, where
hypoxemia (low partial pressure of oxygen in blood)
causes hypoxia (low oxygen levels in tissues). Dr.
Sankoff uses this category to remind himself to look
for diseases that are not associated with lower Fio2
and hypoxemia but still are associated with hypoxia –
primarily hemoglobinopathies.
“If a patient has 100% oxygen saturation yet is hypoxic, they have a problem with hemoglobin,” Dr.
Sankoff said. It may be a severe or acute gardenvariety anemia causing the dyspnea, or occasionally a
hereditary hemoglobinopathy such as thalassemia or
sickle cell disease. To diagnose these, have a high
index of suspicion. You’ll see no patient improvement
on oxygen therapy, and some diseases create a characteristic appearance of the blood.
Alveolar hypoventilation may be the most insidious
cause of hypoxemia, and dyspnea and may be a flag
for impending respiratory compromise if there is
peripheral weakness. The most common acquired
causes of peripheral neuromuscular weakness are Guillain-Barré syndrome, amyotrophic lateral sclerosis,
and Colorado tick paralysis. Make the diagnosis in
context with other findings, he said. Expect an abnormal motor exam. Check the negative inspiratory force;
if it isn’t at least –20 cm H2O, it’s abnormal and the
patient likely will need respiratory support.
Hypercapnia
Diseases that cause hypercapnia can cause dyspnea.
Three things cause carbon dioxide levels in the blood
to rise: increased metabolic rate (more likely in the
ICU than in the emergency department), decreased
minute ventilation, and increased pulmonary dead
space. All can be diagnosed by checking arterial blood
gases.
Metabolic Acidosis
Acidosis, usually due to high levels of lactate, stimulates
respiratory drive to try to balance pH. Sepsis is the
most important cause of acidosis. When sepsis is developing, dyspnea frequently is a subtle sign. Have a
high index of suspicion for sepsis, and be wary of a
normal oxygen saturation level in a patient with dyspnea, he said. Other causes of metabolic acidosis that
lead to dyspnea include diabetic or alcoholic ketoacidosis.
Putting this physiologic approach to dyspnea into
context, consider three scenarios, Dr. Sankoff suggested. A patient with dyspnea who responds to oxy-
IT TAKES A BIT OF DETECTIVE WORK TO
FIND THE CAUSE IN THE FEW CASES OF
DYSPNEA THAT ARE NOT EASILY
REFERABLE TO THE LUNGS.
gen therapy and has an abnormal chest x-ray has a primary pulmonary problem. A patient who responds to
oxygen but has a normal chest x-ray may have sepsis,
another cause of acidosis, or alveolar hypoventilation;
their response to oxygen may be transient. They will
respond to oxygen but continue to be tachypneic.
The third scenario – normal x-ray, but the patient
does not respond to oxygen therapy – raises a broad
differential diagnosis including sepsis, other causes of
acidosis, hypercapnia, cardiac causes, and hemoglobinopathies. Narrow the differential by recalling the
history and physical findings and getting arterial blood
gas tests.
Dr. Sankoff reported having no relevant financial
disclosures.
CRITICAL CARE
April 2013
13
새로 개정된 패혈증 치료 지침
BY BRUCE JANCIN
IMNG Medical News
DENVER – Look for some big changes
ahead in the forthcoming update of the
Surviving Sepsis Campaign international
guidelines.
In the 4 years since the last version of
the guidelines came out, major studies
have been released that resolved hot debates regarding sepsis management and
in some cases overturned established
dogma. At the annual American College
of Emergency Physicians (ACEP) meeting, emergency physicians deeply involved in crafting the Surviving Sepsis
Campaign 2012 guidelines provided a
preview of what’s to come.
Among the areas that will see key
new recommendations are antibiotic
therapy, fluid resuscitation, vasopressors,
and lactate monitoring.
‘At this time,
we’re thinking
stay away from
low-molecularweight starches
for resuscitation.’
DR. OSBORN
SUMMARY
▶ Antibiotics ASAP. The critical importance of getting empiric antibiotics
on board within 6 hours after recognizing that a patient has sepsis has been effectively hammered home over the
years. But how fast is fast enough? Several recent small studies have reached
conflicting conclusions. Now, however,
an 800-lb gorilla of a study has provided
a definitive answer.
This study, now in press, involved
14,895 patients enrolled in the Surviving
Sepsis Campaign’s worldwide database.
All had severe sepsis or septic shock,
and all received antibiotics within the
first 6 hours, explained Dr. Tiffany M.
Osborn, a coauthor of the study and of
the forthcoming guidelines.
“This was a big question for us. The
results strengthen the importance of getting antibiotics started as soon as possible
– within the first hour if possible. We
found there’s about a 4% increase in
mortality for every hour delay. And it’s
cumulative: it’s 4% after the first hour,
8% after the second, 12% after the third,
2012년에 새로 개정된 패혈증 치료 지침에
의하면, 패혈증이 진단되면 항생제는 가능한
1시간 이내에 투여해야 한다. 패혈성 쇼크 초
기에는 crystalloid 수액제제와 albumin을 투
여하고, 저분자량 콜로이드용액이나 starche
용액의 사용은 피해야 한다. 충분히 수액을
공급했는데도 불구하고 평균 혈압을 65
mmHg 이상 유지할 수 없을 때는 dopamin
보다는 norepinephrine을 사용할 것을 권고
하였다.
and so on,” according to Dr. Osborn of
Washington University at St. Louis.
A similar time-dependent increase in
mortality was observed in patients with
severe sepsis as well as in those in septic
shock, she added.
▶ Fluid resuscitation. The initial fluid
of choice for resuscitation in severe sepsis
and septic shock remains crystalloids, as
before. That’s a grade 1A recommendation. What’s brand new is a recommendation to consider adding albumin in
the initial fluid resuscitation (grade 2B).
This guidance was heavily influenced
by a meta-analysis of 17 studies involving
close to 2,000 patients that demonstrated
a significant protective effect for the use
of albumin as an initial resuscitation fluid
(Crit. Care Med. 2011;39:386-91).
At this late date, Dr. Osborn said, the
guideline panel is strongly leaning toward a recommendation against the use
of low-molecular-weight colloids or
starches such as hydroxyethyl starch
130/0.42. That would be ground shaking, as synthetic colloids or starches, particularly those of low molecular weight,
are a very popular resuscitation fluid
both in the United States and abroad.
However, recent studies implicate these
fluids in increased risks of 90-day mortality and renal failure, compared with
the use of Ringer’s lactate.
“Having said this, there are two other
trials currently pending. Any month now
the results will come out, and we’ll see
‘By far and
away, I’m going
to choose
norepinephrine as
the initial
vasopressor
agent.’
DR. WINTERS
where we are at that point. But at this
time, we’re thinking stay away from
low-molecular-weight starches for resuscitation,” Dr. Osborn said.
One of the main reasons the Surviving
Sepsis Campaign 2012 guidelines won’t
actually be published before January
2013 is the guideline panel’s eagerness
to see the results of those two studies,
she added.
▶ Vasopressor therapy. The initial target remains, as before, a mean arterial
pressure of at least 65 mm Hg. But while
the 2008 guidelines recommended either
norepinephrine or dopamine as the firstchoice vasopressor to correct hypotension in patients not sufficiently responsive to fluid resuscitation, the new
guidelines will state that norepinephrine
is the preferred agent (grade 1B). That’s
a major change. Dopamine has been essentially kicked to the curb in response
to multiple studies in the last 4 years implicating it in an increased incidence of
arrhythmias and, in some studies, higher
mortality.
The final nail in dopamine’s
coffin for use in patients with
severe sepsis or septic shock
was a recent meta-analysis involving five observational and
six interventional studies totaling nearly 2,800 patients (Crit.
Care Med. 2012;40:725-30).
“Dopamine has actually fallen by the wayside. By far and
away, I’m going to choose norepinephrine as the initial vasopressor agent,” declared Dr.
Michael E. Winters of the University of Maryland, Baltimore.
The new guidelines will suggest that be reserved for highly
selected patients: those at very
low arrhythmia risk and with a
low cardiac output and/or low
heart rate (grade 2C), he noted.
Another change in the new
guidelines will be a recommen- Fluid: ‘‘We want to give patients what they need
dation that epinephrine be but not more,” Dr. Tiffany M. Osborn said.
added when an additional agent
is needed in order to maintain adequate the bundle plus lactate clearance, morblood pressure (grade 2B).
tality further fell to about 22% (J. In▶ Don’t overdo the fluids. “We want tensive Care Med. 2012 [doi:10.1177/
to give patients what they need but not 0885066612453025]).
more,” Dr. Osborn explained. The 2012
Thus, the coming Surviving Sepsis
guidelines will recommend that physi- Campaign 2012 guidelines will suggest
cians use some sort of fluid challenge that in patients with elevated lactate levtest while administering fluid boluses. els as a marker of hypoperfusion, resusThe goal is to keep giving fluid only so citation should be targeted at normalizlong as hemodynamic improvement is ing lactate as rapidly as possible (grade
seen in response. This can be achieved 2C). Having said that, however, a norin a variety of ways, including monitor- mal lactate doesn’t indicate absence of
ing change in pulse pressure, stroke vol- shock. Other factors, such as the patient’s
ume variation, heart rate, or arterial central venous oxygen saturation level,
pressure.
need to be considered as well, the physi▶ Lactate clearance. Serum lactate is cians emphasized.
recognized as an indicator of global orThe Surviving Sepsis Campaign guidegan hypoperfusion and shock. But in- lines are sponsored by 27 medical orgacorporating lactate clearance as one of nizations. Among them are the Society
the goals of early sepsis therapy has been of Critical Care Medicine, ACEP, the
“a very hot topic,” Dr. Winters observed. Society of Hospital Medicine, the AmerImproved clarity was provided by a ican College of Chest Physicians, the
prospective 556-patient quality improve- American Thoracic Society, the Infecment study by investigators in the Asian tious Diseases Society of America, the
Network to Regulate Sepsis Care. Pa- Surgical Infection Society, the Pediatric
tients who got the primary severe sepsis Acute Lung Injury and Sepsis Investigamanagement bundle of care as recom- tors, and a host of international groups.
mended in the 2008 Surviving Sepsis
Dr. Osborn and Dr. Winter reported
Campaign guidelines had an unadjusted having no financial conflicts.
mortality of 43.6%. This bundle includes
early antibiotic administration, hemodynamic monitoring and support, and
Dr. Vera De Palo, FCCP, comments:
achievement of a central venous oxygen
패혈증 환자에게 적절한 시기에 최적의 치
saturation level greater than 70% by 6
료를 하면 치료성적을 향상시킬 수 있다는
hours. However, patients who got the
것이 임상연구를 통해 증명되었다. 시간이
bundle plus lactate clearance had a 20.5%
지나면서 새로
mortality rate (Crit. Care 2011;15:R229
운 연구결과가
[doi:10.1186/cc10469]).
누적되면 최근
The importance of lactate clearance
에 시행한 임
was further underscored by the findings
상시험의 결과
in the GENESIS Project (Generalized
를 근거로 하
Early Sepsis Intervention Strategies).
여, 이전에 만
This quality improvement initiative,
든 지침을 재
conducted at five U.S. community hos분석하고 새로
pitals and six tertiary centers, showed
운 지식을 반
a 42.8% mortality in 1,554 historical
영하여 치료지침을 개정하는 것이 중요하
controls treated for sepsis before im다. 이런 과정을 통해 중증 패혈증과 패혈
plementation of the Surviving Sepsis
성쇼크 환자를 치료하는 protocol의 내용
Campaign resuscitation bundle. In an을 발전시키고 임상에 잘 적용함으로써 사
other 4,801 patients who got the bun망률이 높은 이 질환의 생존율을 향상시킬
dle, mortality was significantly lower
수 있기를 기대한다.
at 28.8%. And, in those who received
COMMENTARY
새로운 지침에 따르면, dopamine의 사용은 피하고,
진단 후 1시간 이내에는 반드시 항생제를 투여해야 한다.
© SUPOJPP / FOTOLIA . COM
Update Ahead for Surviving Sepsis Guidelines
CRITICAL CARE
14
CHEST Physician • April 2013
말기 암 환자에서 임종에 대비한 상의를 일찍 하는 것은
공격적인 치료를 줄인다
Early End-of-Life Discussions Cut Aggressive Care
IMNG Medical News
P
VITALS
atients with stage IV lung cancer
who had end-of-life discussions
with caregivers before the last 30
days of life were less likely to receive aggressive care in their final days and more
likely to get hospice care and to enter
hospice earlier, a study of 1,231 patients
found.
Nearly half received aggressive care
in their last 30 days (47%), including
chemotherapy in the last 14 days (16%),
ICU care in the last 30 days (6%), and/or
acute hospital-based care in the last 30
days of life (40%), Dr. Jennifer W. Mack
and her associates reported.
Guidelines advise starting end-of-life
care planning for patients with incurable
cancer early in the course of the disease
while patients are relatively stable, not
when they are acutely deteriorating.
Many physicians in the study postponed the discussion until the final
month of life, and many patients didn’t
remember or didn’t recognize the endof-life discussions. Discussions that were
documented in charts were not associated with less-aggressive care or greater
hospice use, if patients or their surrogates
said no end-of-life discussions took place.
In the study, 88% of patients had endof-life discussions. Among the 794 patients with end-of-life discussions documented in medical records, 39% took
place in the last 30 days of life and 63%
happened in the inpatient setting. Fiftyeight percent of patients entered hospice
care, reported Dr. Mack, a pediatric oncologist at the Dana-Farber Cancer Institute and Harvard Medical School,
Boston, who studies patient-related communications issues.
The study was published the Journal
of Clinical Oncology (doi:10.1200/
JCO.2012.43.6055).
Chemotherapy in the last 2 weeks of
life was 59% less likely, acute care in the
last 30 days was 57% less likely, and ICU
care in the last 30 days was 23% less
likely when patients or surrogates reported having end-of-life discussions.
Patients whose first end-of-life discussion happened while they were hospitalized were more than twice as likely
to get any kind of aggressive care at the
end of life and three times more likely
to get acute care or ICU care in the last
30 days and to have hospice care start
within the last week before death.
Having a medical oncologist present
주요 결과: 환자 또는 보호자들이 임종에 대비한 상의를 받은 경우, 임종 전 마지막 2주내에 항암약
물치료는 59%, 마지막 30일내에 급성 치료는 57%, 마지막 30일 내에 중환자실 치료는 23% 감소하
였다.
출처: 미국 5개 주의 HMO 또는 재향군인병원에서 제 4병기 폐암 또는 대장암 환자 1,231명을 대상
으로 한 종단적 연구
at the first end-of-life discussion increased
the odds of having chemotherapy in the
last 2 weeks of life by 48%, decreased
the odds of ICU care in the last 30 days
by 56%, increased the likelihood of hospice care by 43%, and doubled the
chance of hospice care starting in the
last 7 days of life. All of these odds ratios
were significant after controlling for other factors.
Data came from a larger cohort of
2,155 patients with stage IV lung or colorectal cancer receiving care in HMOs
or Veterans Affairs medical centers in
five states. All were followed for 15
months after diagnosis in the Cancer
Care Outcomes Research and Surveillance Consortium.
An earlier analysis by the same investigators showed that 87% of the 1,470
patients who died and 41% of the 685
still alive by the end of follow-up had
end-of-life care discussions. Oncologists
documented end-of-life discussions with
27% of their patients, suggesting that
most discussions were with non-oncologists. (Ann. Intern. Med. 2012;156:20410).
The current study analyzed data for
1,231 of the patients who died but who
lived at least 1 month after diagnosis,
in order to assess whether the timing
of discussions influenced end-of-life
care.
Patients were significantly less likely
to say they’d had an end-of-life discussion
if they were unmarried, black or nonwhite Hispanic, or not in an HMO.
When discussions don’t begin until
the last 30 days of life, the end-of-life period usually is already underway, the investigators noted. Physicians should consider moving end-of-life care discussions
closer to diagnosis, they suggested, while
patients are relatively well and have time
to plan for what’s ahead.
“It’s something that any physician can
do,” but some previous studies report
that physicians are reluctant to start endof-life discussions early because these
are emotionally difficult conversations,
they worry about taking away hope, and
they are concerned about the psycho-
logical impact on patients – though there
is no clear evidence that it does have
psychological consequences for patients,
Dr. Mack said.
“It’s a compassionate instinct,” she
said. “Being in the room with a family
when I deliver this kind of news, that
emotional impact is right in front of me.
I believe there are bigger consequences”
from not discussing end-of-life care, such
as perpetuating false hopes and asking
people to make decisions about what’s
ahead without a clear picture of the situation, she added.
The conversation should take place
more than once because patient preferences may change over time and patients
need time to process the information
and their thoughts about it, Dr. Mack
said.
Further work is needed on why some
documented end-of-life discussions were
not reported by patients/surrogates.
“Every physician can relate to this – that
sometimes we have conversations but
they’re not heard or understood by patients,” she said. “It reminds me that I
need to ask patients what they’re taking
away from these conversations and use
that to guide me going forward.”
That finding echoes two recent large,
population-based studies that found
many patients with terminal cancer mistakenly think that palliative chemotherapy or radiation will cure their disease.
Some previous studies suggest that
patients dying of cancer increasingly are
receiving aggressive care at the end of
life and that this trend may be modifiable.
Other studies have reported an association between having end-of-life discussions and reduced intensity in care.
The current study was longitudinal and
is one of the first to look at the effects of
the timing of these discussions.
Most patients who realize that they
are dying do not want aggressive care.
Also, studies report that less-aggressive
91823
end-of-life care is easier on family members and less expensive.
Dr. Mack and her associates reported
having no financial disclosures.
When Patients or Surrogates Had End-of-Life Discussions ...
ICU care in the
last 30 days was
23%
Chemotherapy
in the last
2 weeks was
59%
Acute care
in the last
30 days was
57%
less likely
less likely
Note: Based on a study of 1,231 patients.
Source: J. Clin. Oncol. 2012 (doi:10.1200/JCO.2012.43.6055)
less likely
63% of discussions
occurred in the
inpatient setting.
IMNG M EDICAL M EDIA
BY SHERRY BOSCHERT
음악칼럼
April 2013
15
지오반니 페르골레시 <성모 애가>
Giovanni Battista Pergolesi <Stabat Mater>
오 재 원 교수
한양대학교구리병원
소아청소년과
*** 생의 마지막 순간 좀먹어 들어가는 폐를 웅크려 잡고 피를 토
하듯 써 내려간 페르골레시의 신앙고백
‘스타바트 마테르’란 라틴어로 '어머니가 서 계시다'는 뜻으로 ‘예수
그리스도 달리신 십자가 곁에 비통하게 우시며 성모님이 서 계시
네’라는 말로 시작되는 곡이어서 이런 제목이 붙었다. 우리말로는 '
슬픔의 성모', 또는 ‘성모애가’라고 번역된다. 13세기 이탈리아 시인
이었던 야코포네 디 토디가 쓴 시에 프란체스코 수도회 수사가 곡을
붙인 것이 최초의 <스타바트 마테르>였고, 그 후 많은 작곡가들이
같은 시에 곡을 붙였다. 비발디, 로시니, 구노 등이 작곡한 <스타바
트 마테르>도 사순절 기간에 자주 연주된다. 트리엔트 공의회 이후
가톨릭 전례에서 제외되었던 <스타바트 마테르>는 1727년 다시 정식
으로 전례서에 채택되었고, 이 무렵 이탈리아에서는 도메니코 스카
를라티의 <스타바트 마테르>가 사순절 및 성모의 고통을 묵상하는
축일마다 연주되고 있었다. 나폴리의 산타마리아 성당에서는 스카
를라티 곡의 오랜 반복에 식상하여 당시 오페라 작곡가로 명성을
떨치기 시작한 신진 작곡가 페르골레시에게 새로운 <스타바트 마
테르>작곡을 의뢰하게 된다. 이 곡은 성모의 고통을 노래하며 깊은
공감을 표현하는 작품으로 십자가위에서 죽음을 맞이하는 아들을
지켜보는 어머니의 참혹한 고통이 오히려 우리가 세상에서 겪는
고통에 따뜻한 위로가 됨을 느낄 수 있게 한다.
이탈리아 작곡가 페르골레시는 ‘소규모 음악’의 효과에 능숙한
작곡가였다. 이 곡은 소규모 앙상블과 소프라노 및 알토 두 성악가
만이 연주하는 작은 작품이지만, 그 평온하고 고요한 음악 안에 담긴
슬픔의 폭발력은 가히 대단하다. 어릴 때부터 소아마비로 다리가
불편했고 늘 병약했던 페르골레시는 오로지 음악에만 빠져 살다가
열세 살에 나폴리 음악원에 입학했다. 교회음악뿐만 아니라 단막극
오페라 '마님이 된 하녀'의 대성공으로 그는 유럽 음악계에서 대단
한 명성을 얻었다. 그러나 불과 스물여섯 살이었던 1736년 폐결핵이
악화된 페르골레시는 프란체스코 수도원에 몸을 의탁했다. 삶이 곧
끝난다는 것을 알고 있었던 그는 재산을 모두 다른 사람들에게 넘
겨주었고 남은 것은 그 무렵 작곡 중이던 <스타바트 마테르> 뿐이
었다. 병고 속에서도 천국을 염원하며 그는 이 최후 작품에 혼신의
힘을 기울였다. 수도원에 보존된 자료에 따르면 그는 이 작품을 2
년에 걸쳐 꼼꼼히 다듬고 손질한 것으로 보인다. 페르골레시는
천재성을 다 풀어헤치지도 못하고 미처 사랑 같은 것은 해볼 겨를도
없이 생의 종말을 맞아야 했다. 생의 마지막 순간에 좀먹어 들어
가는 폐를 웅크려 잡고 피를 토하듯 써 내려간 <스타바트 마테르>가
더욱 페르골레시의 아픈 초상을 떠올리게 한다.
제1곡 비탄에 잠긴 어머니 서 계셨네 슬픈 선율로 시작하면서
소프라노와 알토가 번갈아 노래를 한다. 제2곡 탄식하는 어머니의
마음 호소력 강한 소프라노 솔로 곡이다. 제3곡 오! 그토록 고통
하며 소프라노와 알토가 함께 부르는 비교적 간결한 곡이다. 제4
곡 근심하며 비탄에 잠겨 알토 솔로와 대조적으로 아주 밝은 곡으로
독백하는 느낌이다. 제5곡 울지 않을 사람이 있을까 느린 곡으로
소프라노가 부르고 그 후 알토가 받아 부른 후 듀엣으로 부른다. 제
6곡 슬퍼지지 않을 사람이 있을까 간단한 3부 형식으로 바로크 특
유의 지속음이 연출되고 경쾌하게 끝난다. 제7곡 자기 백성의 죄
들을 위하여 소프라노 솔로 곡으로 슬픈 선율은 마치 모차르트 <레
퀴엠> ‘라크리모사’를 연상케 한다. 제8곡 사랑하는 아들을 보았네
알토솔로의 담백한 곡이다. 제9곡 아 어머니, 사랑의 샘이여 이중
창으로 폭풍과 같이 빠른 템포로 대위법적 조화를 이룬다. 제10곡
나의 심장을 타오르게 하소서 평화로운 바로크적 전원풍 음악
이다. 제11곡 거룩하신 어머니 알토 솔로로서 명상적이고 아름답다.
제12곡 상처 입은 당신의 아드님 밝고 화려한 분위기이다. 제13곡
당신과 함께 울게 하소서 ‘paradisi gloria’라고 노래 부르며 절망적
상황에서 천국을 그리고 있다. 제14곡 십자가 가까이 당신과 함께
제15곡 처녀들 중 빛나는 처녀시여 제16곡 그리스도의 죽음을 제
17곡 그분의 상처들에 제18곡 처녀여, 당신에 의해 제19곡 십자가
로 내가 보호 받게 하시고 제20곡 이 몸이 죽을 때에 마지막 ‘아
멘’ 부분은 영화 <아마데우스>에서 어린 살리에리가 성당에서 기
도할 때 그의 아버지가 식사도중 죽는 장면에서 드라마틱하게 나
온다.
들을만한 음반
마가렛 마살(소프라노), 루치아 발렌티니-테라니(메조소프라노),
클라우디오 아바도(지휘), 런던 심포니오케스트라[DG, 1985]
엠마 커크비(소프라노), 제임스 보우먼(알토), 크리스토퍼
호그우드(지휘), 고음악 아카데미 챔버 오케스트라[Decca 1988]
준 앤더슨(소프라노), 세실리아 바르톨리(메조소프라노),
샤를 뒤투아(지휘), 몬트리올 신포니에타[Decca, 1991]