COPD: Pneumonia risk high after thoracic surgerycopd.readersone.com/contents/main/1402_copd.pdf ·...

Korean Edition VOL. 2 / NO. 4 / DECEMBER 2013

BY DOUG BRUNK

IMNG MEDICAL NEWS

SAN DIEGO – For thoracicsurgery patients, being onneoadjuvant chemotherapy,having chronic obstructivepulmonary disease, and aweight loss of greater than10% were all associated withpostoperative pneumonia, re-sults from a single-centerstudy showed.At the national conference

of the American College ofSurgeons/National SurgicalQuality Improvement Pro-gram, Dr. Elisabeth Dexternoted that after the firstACS/NSQIP data harvest atthe Roswell Park Cancer Insti-tute in Buffalo, N.Y., the riskof postoperative pneumoniawas 4.4%, compared with arate of 1.1% in all otherNSQIP hospitals. “The thoracic surgery ser-

vice had a high incidence of13.2%,” said Dr. Dexter, an at-tending surgeon in the depart-ment of thoracic surgery atthe cancer institute. “The highincidence of our postoperativepneumonia was likely [affect-ed] by our thoracic surgeryservice because our thoracicsurgery service had an in-creased percentage of the ab-stracted NSQIP data in our co-hort, from 12% to 14%,compared with other NSQIPhospitals of similar academicsize abstracting 2%. When wefound this high postoperativepneumonia rate, we decidedto query our NSQIP data and

our tumor registry betweenJuly 1, 2011, and Oct. 8, 2012,to ask the question: Is there anincreased incidence of postop-erative pneumonia in thoracicsurgery patients who receivedneoadjuvant chemotherapycompared with those who didnot?” She and her associates cross-

referenced ACS/NSQIP dataon 1,723 patients at the cancercenter with the tumor reg-istry. Of the 1,723 patients,1,645 had no postoperativepneumonia; 78 did. Comparedwith the non-pneumonia pa-tients, those who had pneu-monia were more likely to beolder (a mean of 67 vs. 60years, respectively; odds ratio,1.05; P less than .001); be male(59% vs. 37%; OR, 2.48; P lessthan .001); have chronic ob-structive pulmonary disease(35% vs. 9%; OR, 5.08; P lessthan .001); be smokers (36%vs. 24%; OR, 1.75; P = .021);have lost more than 10% ofbody weight (10% vs. 2.5%;OR, 4.47; P less than .001).On univariate analysis, post-

operative pneumonia was asso-ciated with being on neoadju-vant chemotherapy (4.2% vs.14%; OR, 3.75; P less than .001).

C O N T E N T S

See COPD · page 2

COPD는 흉부 수술 후폐렴 발생의 고위험인자COPD: Pneumonia riskhigh after thoracicsurgery

NEWSCOPD는 흉부 수술 후 폐렴 발생의 고위험인자미국예방진료 특별심의회(USPSTF)의 고찰 결과 CT를 이용한 폐암의 조기검진에 힘 실어주다정맥혈전색전증; 젊은 장기생존 암환자에서 3배 이상 발생Riociguat이 폐고혈압 환자의 운동능력을 향상대부분의 폐색전증 환자들은 외래 치료가 가능Quinolone계 항생제; 말초신경염 발생위험성에 대한 경고 강화FDA, 중환자 및 심폐우회수술 환자에 hydroxyethyl starch 용액을 더 이상 사용하지않도록 권고

PULMONARY MEDICINE술후 프로그램이 호흡기 합병증의 발생에 쐐기를 박다현재 흡연자는 과거 흡연자와는 달리 수술 후 위험이 높아져Afatinib; EGFR 돌연변이가 있는 전이성 비소세포폐암에 1차 치료제로 FDA가 승인약제 내성 폐렴이 의심될 때는 ceftaroline을 고려미국 폐 선별검사 연구 분석 결과: 저선량 CT 검사, 초기 폐암을 3배 이상 더 찾아내다

CARDIOVASCULAR DISEASE항구토제가 기도삽관이 된 뇌졸중 환자에서 폐렴의 발생을 감소시킨다심부전 환자를 호전시키는 5가지 치료법

CRITICAL CARE MEDICINE심부정맥혈전증 위험도 예측 공식인 IMPROVE의 유용성 재확인

CARDIOTHORACIC SURGERYACP, 중환자들의 혈당 140-200 mg/dL로 유지하도록 권고비소세포폐암의 쐐기 절제술: 15 mm은 최선의 절제연인가?

NEWS FROM THE COLLEGE심부전 치료 중 수분과 염분 제한, 과연 옳은 것인가?신체단련 수준으로 암 발생 위험을 예측할 수도

CASE FORUM

음악칼럼

Draft guidelines open for comment.

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BY SHARON WORC E S T E R

IMNG MEDICAL NEWS

Low-dose computed to-mography reduces lung

cancer mortality and all-causemortality when used as ascreening tool in asympto-matic adults at high risk forthe disease, according to the

results of a systematic reviewconducted for the U.S. Pre-ventive Services Task Force.

Review for USPSTF backs CT screening for lung cancer

미국예방진료 특별심의회(USPSTF)의고찰 결과 CT를 이용한 폐암의 조기검진에 힘 실어주다

CHEST PHYSICIANElsevier Korea LLC, 4FL, Chunwoo Bldg, 534 Itaewon-dong, Yongsan-gu, Seoul 140-861, S. Korea

See Screening · page 2

단일 기관에서 시행한 연구에서수술 전 항암약물치료를 받거나,COPD가 동반되어 있거나, 10%이상의 체중감소가 있을경우 수술후 폐렴 발생과 연관이 있는것으로 보고되었다.

SUM

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In 2004, the USPSTF deemed the ev-idence insufficient for recommendingfor or against low-dose computed to-mography (LDCT) for lung cancerscreening in asymptomatic individuals,but the findings of the current reviewsuggest screening has a definite benefitin most patients, Dr. Linda L.Humphrey, of Oregon Health and Sci-ence University and the Portland Vet-erans Affairs Medical Center, and hercolleagues reported.A draft recommendation based on

the findings, published online in Annalsof Internal Medicine (2013 July 29 [doi:10.7326/0003-4819-159-6-201309170-00690]), is available on the USPSTFwebsite for public comment.The researchers conducted a review

of the literature published between2000 and May 2013 and identified fourtrials that reported findings on the effi-cacy of LDCT screening in patientswith smoking exposure for both inter-vention and control groups. Threesmall trials showed varying degrees ofbenefit, but were underpowered; onelarge trial – the National Lung Screen-ing Trial (NLST) – showed a signifi-cant 20% reduction in lung cancermortality among those screened, aswell as a 6.7% reduction in all-causemortality.The randomized multicenter NLST

compared annual LDCT scans with an-nual single-view posterior-anteriorchest radiographs for 3 years in morethan 53,000 current or former smokersaged 55-74 years with at least a 30–

pack-year history of smoking (N. Engl.J. Med. 2013;368:1980-91). One cancerdeath was prevented for every 320 pa-tients who completed one screening,and one death from any cause was pre-vented for every 219 patients screenedin that study; the trial was stopped ear-ly after 6.5 years of follow-up based onthe findings.The benefits of LDCT for lung can-

cer screening in this population out-weighed the risks, Dr. Humphrey andher colleagues noted.Harms associated with LDCT, ac-

cording to findings from 7 trials and 13cohort studies that reported on suchoutcomes, included radiation exposure,overdiagnosis, and a high rate of false-positive findings that were resolved byfurther imaging in most cases. Falsenegatives were reported in six studies,and the rates ranged from 0% to 20%,but none of the studies evaluated theharm of false reassurance, the investi-gators noted. The benefits of screeningmust be weighed against these poten-tial harms.Lung cancer is the third most com-

mon cancer among men and womenin the United States, but is the leadingcause of cancer-related deaths, ac-counting for nearly 27%. The studies included in this review

were conducted in patients at high riskfor lung cancer based on current orformer smoking. However, patients atan increased risk for lung cancer, in-cluding older adults and those with afamily history of lung cancer, chronic

obstructive pulmonary disease, pul-monary fibrosis, and certain environ-mental and occupational exposures,may also benefit from screening.“Future research to identify methods

for focusing LDCT screening on per-sons at highest risk for disease, to im-prove discrimination between benignand malignant pulmonary nodules,and to find early indicators of aggres-sive disease is warranted,” the investi-gators noted. The review was funded by grants

from the Agency for Healthcare Re-search and Quality and the PortlandVeterans Affairs Medical Center. Dr.Humphrey is employed by the Depart-ment of Veterans Affairs, and she andher coauthors disclosed ties with Up-ToDate, the USPSTF, AHRQ, the De-partment of Veterans Affairs, theAmerican Lung Association, theChest/LUNGevity Foundation, theNational Lung Cancer Partnership,and/or the American College of ChestPhysicians.

2 NEWS D E C EMB E R 2 0 1 3 • C H E S T P H YS I C I A N

CHEST PHYSICIAN NEWS, Korean Edition is published by Elsevier Korea LLC, 4FL, Chunwoo Bldg, 534 Itaewon-dong, Yongsan-gu, Seoul 140-861, S. KoreaT: 82-2-6714-3000 F: 82-2-725-4698ⓒ Copyright 2013, by Elsevier Inc.

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 alsoprovides material exclusive to the members of the American College of Chest Physicians. Content for CHEST PHYSICIAN is provided byInternational Medical News Group, an Elsevier company. Content for NEWS FROM THE COLLEGE is provided by the AmericanCollege of Chest Physicians. No responsibility is assumed by Elsevier Korea LLC for any injury and/or damage to persons or propertyas a result of any actual or alleged libelous statements, infringement of intellectual property or privacy rights, or products liability,whether resulting from negligence or otherwise, or from any use or operation of any ideas, instructions, procedures, products ormethods contained in the material therein.The publication of an advertisement in the CHEST PHYSICIAN /Korean Edition does not constitute on the part of Elsevier Korea LLC aguarantee or endorsement of the quality or value of the advertised products or services described therein or of any of the representations or the claims made by the advertisers with respect to such products or services.

김덕겸 서울의대 보라매병원 호흡기내과김태형 한양의대 한양대구리병원 호흡기내과김영삼 연세의대 세브란스병원 호흡기내과박용범 한림의대 강동성심병원 호흡기내과

박주헌 아주의대 아주대학교병원 호흡기내과신경철 영남의대 영남대학교병원 호흡기내과윤형규 가톨릭의대 여의도성모병원 호흡기내과이상엽 고려의대 고대안암병원 호흡기내과

Editor-in-Chief유광하 건국의대 건국대병원 호흡기내과

Editors

Korean EditionCT benefits outweigh risksScreening from page 1

Lung cancer is the leading cause of cancer-related deaths, accounting for nearly27%.

©KUTAYTA

NIR/ISTOCKPHOTO.COM

C O M M E N T A R Y

Dr. W. Michael Alberts,FCCP, comments:폐암에 대한 조기검진으로 인한 잠재적인 이득은 초기에 발견하여 완치를 위한 수술이 가능하다는 것이다.하지만,조기검진의 실제적인 위험에 대해서는 명확하지 않았다. 암이 문제가 안되었을 수도 있고(과도한 진단), CT에서 발견된 것이 암이아닐 수도있고(위양성), 반복되는 방사선 촬영의 안전성에 대한 기술(방사선 노출)이필요할 수도 있다. 과거에는 위험/이득 계산이 알려지지 않았기 때

문에 ACCP(및 대부분의 다른 조직)에서 폐암조기검진으로 CT를 권고하지 않았다. 모든 사람들이 조기검진이 제대로 효과를 보기를 원하지만,2011년 국제폐암조기검진연구(NLST)결과가 나오기 전까지는 사망률에 대한 효과를 확신하지 못했다. 이번에보고된 미국예방진료 특별심의회에의한 체계적 문헌고찰 결과와 권고안이 공개적 논평의 시기를 거치고,

더 나아가 고위험군에 대한 최선의 진료 과정에적용되어, 생명을 구하는 과정에서 추후 보험이인정되기를 기대한다.

Certain surgical subspecialties at theinstitute had a high incidence of post-operative pneumonia: thoracic surgery(46%), GI surgery (21%), and gynecolo-gy (12%).When the researchers included the

entire cohort, those on neoadjuvanttherapy had an increased incidence ofpostoperative pneumonia, comparedwith those not on neoadjuvantchemotherapy (P = .001). When tho-racic surgery patients were excluded,non–thoracic surgery patients on

neoadjuvant chemotherapy had no in-creased incidence of postop pneumo-nia, compared with patients not onneoadjuvant chemotherapy (P =.681). On multivariate analysis, signif-icant variables associated with postoppneumonia were being on neoadju-vant chemotherapy (P= .001), havingchronic obstructive pulmonary dis-ease (P less than .0001), and havingweight loss of greater than 10% (P =.004).“Institutions with disproportionately

busy complex thoracic surgery pro-grams may have rates of postoperativepneumonia skewed higher than pre-dicted by NSQIP models,” Dr. Dexterconcluded.

[email protected]

High pneumonia riskCOPD from page 1

주요 결과: 다변수 분석에서 수술 후 폐렴의발생과 연관이 있는 변수는 수술 전 항암약물치료, COPD의 동반, 및 10% 이상의 체중감소 이었다.출처: 뉴욕 버펄로의 로즈웰 파크 암센터에서수술을 시행한 1,723명의 환자들을 대상으로연구가 진행되었다. 수술 후 폐렴은 46%가 흉부외과에서 발생하였다.

V I T A L S‘Our thoracicsurgery servicehad an increasedpercentage of theabstracted NSQIPdata in ourcohort.’

DR. DEXTER

미국예방진료 특별심의회의 체계적인 고찰 결과 무증상의 고위험군에서 저선량CT를 이용한 조기검진 방법이 폐암 사망률 및 전체 사망률을 줄이는 것으로 나타났다.SU

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C H E S T P H YS I C I A N NEWS 3

BY M I T CH E L L . Z O L E R

IMNG MEDICAL NEWS

AMSTERDAM – Children, adoles-cents, and young adults who surviveda diagnosis and treatment of cancerhad a greater than threefold higherrate of acute venous thromboem-bolism during roughly 10 years of fol-low-up compared with matched con-trols from the general population in astudy that included more than 30,000Canadians.The increased rate of VTE appeared

to be linked to the chemotherapy andradiation treatments that patients re-ceived, because patients who weremanaged only by surgery had a sub-stantially reduced rate of VTE duringfollow-up.“Our working hypothesis is that

VTE that develops during [initial]

treatment of childhoodcancers then places thesepatients at an increasedrisk” for a second VTElater in their life, Dr. Ke-tan P. Kulkar-ni said at the congress

of the International Soci-ety on Thrombosis andHaemostasis.If a first episode of VTE

during or soon after theinitial therapy that youngcancer patients receivecan be clearly establishedas a major risk factor fora subsequent episode ofVTE, the next stepwould be to test whether

improved prophylaxis during initialtherapy can prevent a first episode andthereby also cut patients’ risk for a sec-ond VTE severalmonths or yearslater. Clinicianswho manage chil-dren, adolescents,and young adultswith cancer needincreased aware-ness that VTE “isa major problem”during both initialtreatment and fol-low-up, Dr. Kulkarni said in an inter-view. “We think the VTEs during fol-low-up are recurrences of clots thatfirst formed during treatment.” He andhis associates have begun to review themedical records of each survivor tobetter determine how many of the

VTEs seen during follow-up were re-currences.Another major finding from this

analysis of people who survived atleast 5 years following cancer diagnosisat age 0-24 years was that the entirerange of cancers posed a VTE risk topatients, not just leukemia as some hadpreviously thought. The VTE rate dur-ing follow-up was similar regardless ofthe type of cancer, said Dr. Kulkarni, apediatric hematologist-oncologist atthe University of Alberta in Edmonton.The researchers used provincial

health insurance records from BritishColumbia during 1981-1999 to identify2,857 patients who were aged 0-24years at the time of their initial cancerdiagnosis and then lived for at least an-other 5 years. The survivors averagedabout 14 years old at the time of theirinitial cancer diagnosis. The investiga-

tors also assem-bled a controlgroup matched byage and sex fromthe general popu-lation, taking 10controls for eachcase for a total of28,570.During follow-

up that rangedfrom 5 to 21 years

and averaged nearly 10 years, theyfound that 43 survivors had an episodeof VTE, a 1.5% incidence rate, com-pared with a 0.5% rate among the con-trols. In a multivariate analysis thatcontrolled for sex, socioeconomic sta-tus, and region of residence, patients

who were cancer survivors had a statis-tically significant, 3.4-fold increasedrate of VTE compared with the con-trols, Dr. Kulkarni reported. Amongthe survivors the incidence of deepvein thrombosis was roughly 0.8%, theincidence of pulmonary embolism wasroughly 0.5%, and VTE in other loca-tions occurred in about 0.3% of thesurvivors. The incidence of VTEs washighest during the first 6 months fol-lowing cancer diagnosis.Cancer survivors who had been

treated by surgery alone had a statisti-cally significant, 81% lower rate of de-veloping a VTE compared with the pa-tients treated by chemotherapy alone,radiation alone, or both. Patients with relapses had a 2.5-fold

higher rate of VTE compared with sur-vivors who did not have a relapse. “Based on these compelling findings,

we should have a higher index of suspi-cion for VTE in pediatric cancer sur-vivors,” Dr. Burt Lesnick, FCCP, ofGeorgia Pediatric Pulmonary Associ-ates, remarked.Dr. Kulkarni had no disclosures.

BY MARY ANN MOON

IMNG MEDICAL NEWS

Riociguat, an agent from a new class of com-pounds known as soluble guanylate cyclase stim-

ulators, was found effective and safe for treating twodifferent types of pulmonary hypertension in sepa-rate industry-sponsored phase III clinical trials. Compared with placebo, daily oral riociguat signifi-

cantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonaryvascular resistance and World Health Organization(WHO) functional class. The results are from one in-ternational study involving 261 patients who hadchronic inoperable thromboembolic pulmonary hy-pertension and another study involving 443 patientswho had pulmonary arterial hypertension. The mag-nitude of the improvement was greater than that re-ported for existing medications such as endothelin-re-ceptor antagonists and prostanoids, both groups ofresearchers said. In early August, the FDA’s Cardiovascular and Re-

nal Drugs Advisory Committee voted unanimously

that riociguat should be approved for the two patientgroups.The pathogenesis of pulmonary hypertension in-

volves impairment of both nitric oxide synthesis andsignaling through the nitric oxide–soluble guanylatecyclase–cyclic guanosine monophosphate pathway.Riociguat directly stimulates soluble guanylate cy-clase independently of nitric oxide and also increasesthe enzyme’s sensitivity to nitric oxide. The drugalso raises levels of cyclic guanosine monophosphate,which induces vasorelaxation and has additional an-tiproliferative and antifibrotic effects.

The CHEST-1 trialIn the CHEST-1 (Chronic Thromboembolic Pul-monary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, thedrug was assessed in adults with chronic throm-boembolic pulmonary hypertension who were eitherineligible for the standard surgical treatment (pul-monary endarterectomy) or whose condition persist-ed or recurred after they underwent the surgery. It isestimated that 63% of patients with this disorder are

ineligible for endarterectomy, which is the only po-tentially curative treatment available, and thatthromboembolic pulmonary hypertension persists orrecurs in 35% of patients who do have the proce-dure. So an alternative approach is clearly needed,said Dr. Hossein-Ardeschir Ghofrani of UniversityHospital Giessen and Marburg, Germany, and his as-sociates.

VTE rate triples in young cancer survivors정맥혈전색전증; 젊은 장기생존 암환자에서 3배 이상 발생

New pulmonary drug ups walk distance Riociguat이 폐고혈압 환자의 운동능력을 향상

MITCHELL. ZOLER/IMNGMEDICALMEDIA

“We think the VTEs during follow-up are recurrencesof clots that first formed during treatment,” said Dr.Ketan P. Kulkarni.

‘We should havea higher index ofsuspicion for VTEin pediatriccancer survivors.’

DR. LESNICK

소아를 포함한 젊은 장기생존 암환자를10년 동안 관찰한 결과 일반인에 비하여정맥혈전색전증의 발생률이 3배 이상 높았으며, 암의 종류와 상관없이 진단 후초기에 항암치료와 방사선치료를 받은 환자에서 발생률이 높았다. 암 진단 후 첫6개월 이내 발생률이 가장 높았으며, 암치료 초기에 발병한 환자는 치료 후에도 2차로 발생하는 경우가 많아 암치료과정에서 임상의사들이 관심을 가져야할 중요분야이다.

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Riociguat은 수용성 gualylate cyclase 자극제로 알려진새로운 종류의 약물로서 독립적인 3상 임상시험에서 2가지다른 여건의 폐고혈압 치료 시 효과적이고 안전하다고 알려졌다. 이는 직접적으로 soluble guanylate cyclase를 자극하거나, nitic oxide에 독립적으로 작용하며, nitric ox-ide에 대한 enzyme sensitivity를 증가시킨다. 또한 c-GMP를 증가시켜 혈관 이완을 유발하는 이외에, 항섬유화및 항증식 효과가 있다. 위약과 비교할 경우, 매일 경구 ri-ociguat 처방은 6분보행검사로 측정되는 운동능력을 유의하게 호전시켰으며 또한 폐혈관 저항 및 WHO functionalclass를 향상시켰다.

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Continued on following page


The CHEST-1 study subjects, who were treatedand followed at 89 medical centers in 26 countries,were randomly assigned to receive either riociguat(173 patients) or matching placebo (88 patients) for16 weeks. The primary endpoint was change in 6-minute

walk distance. In the intention-to-treat analysis, thisincreased by a mean of 39 m in patients taking rio-ciguat, compared with a decrease of 6 m in those tak-ing placebo. The benefit was similar in a per-protocolanalysis, the investigators reported (N. Engl. J. Med.2013 July 25 [doi: 10.1056/NEJMoa1209657]). Riociguat improved 6-minute walk distance by 54

m in the patients who were ineligible for surgery andby 26 m in those who had persistent or recurrent dis-ease after surgery. The drug’s beneficial effect on ex-ercise capacity was consistent across several sub-groups of patients.

In addition, the active drug significantly reducedpulmonary vascular resistance; improved other he-modynamic factors, including mean pulmonaryartery pressure and cardiac output; improved WHOfunctional class, which is known to correlate withsurvival; and decreased levels of N-terminal pro-brainnatriuretic peptide (NT-proBNP). In exploratory analyses, riociguat also improved

scores on the Borg dyspnea index when comparedwith placebo, and nominally bettered scores on onemeasure of quality of life but not on a disease-specificQOL tool. Drug-related serious adverse effects included three

cases of syncope and one case each of gastritis, acuterenal failure, and hypotension with riociguat, andone case each of syncope and trauma with placebo.Three percent of the riociguat group and 2% of theplacebo group dropped out of the study owing to ad-

verse events, and another 2% of each group droppedout because of serious adverse events that were notconsidered to be related to the study drug. Therewere two deaths in the riociguat group and three inthe placebo group. A total of 237 of these study subjects elected to en-

roll in an extended study of the long-term safety andefficacy of riociguat (the CHEST-2 clinical trial). Anexploratory analysis of data from the first 12 weeksof that study showed further increases of 51-63 m inthe 6-minute walk distance, Dr. Ghofrani and his as-sociates said.

The PATENT-1 trialThe other phase III clinical trial reported in the NewEngland Journal of Medicine was the PATENT-1(Pulmonary Arterial Hypertension Soluble GuanylateCyclase-Stimulator) study. This trial also was fundedby Bayer HealthCare and headed by Dr. Ghofrani. In it, 443 patients who had symptomatic pul-

monary arterial hypertension were treated and fol-lowed up at 124 medical centers in 30 countries.These subjects had idiopathic or familial disease, orpulmonary arterial hypertension associated with con-nective-tissue disease, congenital heart disease, portalhypertension with liver cirrhosis, anorexigen use, oramphetamine use. A total of 44% of patients were already receiving

an endothelin-receptor antagonist (usually bosentan),and 6% were taking prostanoids (usually inhaled ilo-prost) for the disorder, and the other half of thestudy population was not receiving any other treat-ments. Concomitant therapy with oral anticoagu-lants, diuretics, and supplemental oxygen was per-mitted during the study.These study subjects were randomly assigned to

receive high-dose riociguat capped at 2.5 mg threetimes daily (254 patients), low-dose riociguat cappedat 1.5 mg three times daily (63 patients), or placebo(126 patients) for 12 weeks. The analysis of data fromthe low-dose group was considered exploratory andwas reported separately.The primary endpoint – change from baseline in 6-

minute walk distance – increased by a mean of 30 min the high-dose group but decreased by a mean of 6m in the placebo group in the intention-to-treatanalysis. The results were similar in the per-protocolanalysis, the investigators reported (N. Engl. J. Med.

2013 July 25 [doi: 10.1056/NEJMoa1209655]). This treatment benefit was consistent across sever-

al subgroups of patients. In addition, the active drugsignificantly decreased pulmonary vascular resis-tance, improved mean pulmonary artery pressureand cardiac output, lengthened the interval to clinicalworsening, improved NT-proBNP levels, improvedWHO functional class, and improved scores on theBorg dyspnea scale. Drug-related serious adverse events occurred in

1.4% of patients receiving high-dose riociguat and1% of those receiving placebo. A total of 3% of pa-tients in the riociguat group and 7% of those in theplacebo group discontinued the study drug becauseof adverse events.Serious or drug-related adverse events in both

groups included increased hepatic enzyme levels,acute renal failure, syncope, esophageal pain andswelling, supraventricular tachycardia, hypotension,generalized edema, hypoxemia, dyspnea, and wors-ening of pulmonary hypertension. There were twodeaths in the riociguat group and three in the place-bo group, none of which were considered to be relat-ed to the study drug.A total of 396 of the subjects in the PATENT-1

study elected to enroll in an extended study of thelong-term safety and efficacy of riociguat (thePATENT-2 clinical trial). An exploratory analysis ofdata from the first 12 weeks of that study showed afurther mean increase of 53 m in 6-minute walk dis-tance with high-dose riociguat.

Riociguat improved 6-minute walk distanceby 54 m in the patients who were ineligiblefor surgery and by 26 m in those who hadpersistent or recurrent disease aftersurgery.

Continued from previous page V I E W O N T H E N E W SRiociguat은 폐고혈압의 치료제로 FDA에서 검토 단계에 있으며, 이와 관련된 2개의 임상 시험인 CHEST-1 및 PATENT-1은 모두 Bayer Health Care에서 진행하였다.Riociguat이 운동능력에 있어 단지“약간의”효과만을 보였으나,수술이 불가능한 CTPH 환자들에게 있어 유효한 첫번째 경구치료제라고 Dr. Archer는 말한다.그러나 CHEST-1 연구는“riociguat이 우심실에 미치는 영향을 관찰하는 데 실패”하였다는 약점이 있고, PATENT-1은 효과의 크기가 작은 데 있어 제한점을 보이는데, 무엇보다도 중요한 점은50%의 환자들이 기타 폐동맥 고혈압 약물을 처방받지 않았으며,동시에 폐동맥 고혈압 처방을 받고 있던 환자들과 비교할 경우 ri-ociguat 치료에서 치료반응에 대한 속도가 대체로 더 빠르다고Dr. Archer는 말한다.

C H E S T P H YS I C I A N NEWS 5


IMNG MEDICAL NEWS

AMSTERDAM – Two-thirds of patients who present-ed to the emergency department of a U.S. tertiarycare hospital with an acute pulmonary embolism hadno acute deterioration and required no short-termhospital-based interventions, in an analysis of 298 pa-tients seen over a 2-year period.The finding “supports the assertion that outpatient

treatment of patients with pulmonary embolism [PE]is safe,” said Dr. Christopher Kabrhel at the 24thCongress of the International Society on Thrombosisand Haemostasis. “We want to identify patients forwhom nothing bad will happen. We showed thattwo-thirds of patients did well and didn’t need any-thing from the hospital and didn’t benefit from beingin the hospital. We need to identify some of these pa-tients,” soon after they present in the emergency de-partment, said Dr. Kabrhel, a surgeon and emer-gency-medicine physician at Massachusetts GeneralHospital and Harvard Medical School in Boston. Ifreliable risk markers can be found with further re-search, “perhaps we can identify half of the two-thirds–a third of all patients who come to the emer-gency department with a PE–who we know will besafe with outpatient treatment so we can send thosepatients home from the emergency department andnot admit them.”Most symptomatic U.S. patients who come to an

emergency department, and are diagnosed with a PEare immediately admitted to the hospital. In the cur-rent study, the hospitalization rate was 92% with amedian length of stay of 3 days. “We need a betterrule to decide whether a patient needs hospitaliza-tion. We need to find which patients benefit fromhospitalization,” Dr. Kabrhel said in an interview.He and his associates reviewed 298 adults 18 years

or older who presented to the Massachusetts GeneralHospital emergency department during October2009 through December 2011 with a radiographicallyproven PE diagnosed within 24 hours of arrival.They averaged 59 years old, half were women, andthe most common comorbidity was malignancy in107 patients (36%). The study’s primary outcome was any clinical de-

terioration or need for hospital-based interventionduring the 5 days following presentation at the emer-gency department, including the need for advancedcardiac life support, the development of a new car-diac dysrhythmia, the development of hypoxia or hy-potension, the need for thrombolysis or thrombecto-my, recurrent PE, or death. These events occurred in99 patients (33%); of these, 28 patients (9% of the to-tal group) had “severe” deterioration or required a“major” intervention. Twelve patients (4%) diedwithin 30 days of their initial emergency presenta-tion. The most common acute complication was theneed for respiratory support, in about 55 patients,followed by hypotension, in about 34.A multivariate analysis identified five baseline fac-

tors that significantly correlated with the primaryoutcome. Patients who had normal vital signs atbaseline had a 79% reduced rate of significant deteri-oration or need for hospital-based intervention. The other four factors were linked with increased

rates of deterioration and need for intervention:Right heart strain caused by the PE and identified byan echocardiogram boosted the risk of a bad out-come more than fourfold, coronary disease and cere-brovascular disease each were tied to a more thanthreefold increased rate, and residual deep veinthrombosis was linked with a more than doubledrate of bad outcomes.The subset of patients with the most severe out-

comes had only one direct correlation with bad out-comes, right heart strain on echo. This subset of pa-tients also showed a protective link against bad out-comes when their systolic blood pressure never fellbelow 90 mm Hg.In contrast to these factors linked to 5-day out-

comes, two different types of patient factors weresignificantly linked with 30-day mortality: having amalignancy and having chronic lung disease.“Previously validated clinical prediction rules that

looked at outcomes after PE were primarily validated

based on 30-day mortality or recurrent PE, and in-cluded factors like having cancer, heart failure, orchronic lung disease. But these scores are only ableto predict the outcomes we examined with 70% sen-sitivity,” Dr. Kabrhel said. He found this out by running the numbers he col-

lected through three validated scores for predictingPE outcome: the Geneva Prediction Score (Ann. In-tern. Med. 2006;144:165-71), the Severity Index(Am. J. Respir. Crit. Care Med. 2005; 172:1041-6),and the Simplified Pulmonary Embolism SeverityIndex (Arch. Intern. Med. 2010;170:1383-9). “Predic-tors of all-cause 30-day mortality are different thanpredictors of short-term outcomes” in PE patients,he said. “We found that echo is a very good predictor of

short-term outcomes, and also abnormal vital signs.The key point is we need to look at outcomes thatare relevant to the decisions made” in the emergencydepartment, Dr. Kabrhel said. “Looking at 30-daymortality in patients who are only hospitalized for 3days doesn’t really inform the decision on whoshould be in the hospital. I would suggest caution onusing [prediction] tools validated against 30-day mor-tality and recurrent PE to determine what to doacutely. We need better rules to decide which PE pa-tients need hospitalization.”Dr. Kabrhel said he has been a consultant to Diag-

nostica Stago, and is an officer for LitPulse.

[email protected]

Most pulmonary embolism patients can be sent home대부분의 폐색전증 환자들은 외래 치료가 가능

Most PE patients are immediately admitted, saidDr. Christopher Kabrhel.

MITCHELL. ZOLER/IMNGMEDICALMEDIA

‘We showed that two-thirds of patients didwell and didn’t need anything from thehospital and didn’t benefit from being inthe hospital.’

2009년 10월부터 2011년 12월까지 매사추세츠 종합병원응급실로 내원한 폐색전증 환자 298명을 조사하였다. 1차연구지표는 응급실 방문 후 5일 동안 심폐소생술, 부정맥,저산소증, 저혈압, 혈전용해술 또는 혈전제거수술, 폐색전증의 재발, 사망 등과 같은 병원 중재가 필요한 임상적 악화가 발생한 경우이다.99명(33%)의 환자가 병원 중재가 필요한 임상적 악화가발생하였고, 그 중 28명(9%)은 중증악화가 발생하였다. 다변량 분석 결과 내원 당시 정상 생체증후는 병원 중재의필요성을 79% 감소시켰다. 반면에 심장 초음파 검사상 우심기능저하는 4배, 관상동맥 질환과 뇌혈관 질환은 3배, 심부정맥혈전증은 2배 이상 임상적 악화 위험을 증가시켰다.중증악화는 우심기능 저하와 유의한 관련성을 보였다. 악성종양과 만성 호흡기 질환은 30일 사망률과 유의한 관련성을 보였다.결론적으로 환자의 2/3는 입원치료에서 받는 잇점이 없었고폐색전증 환자가 외래치료를 받는 것은 안전하다. 어떤 환자에서 입원치료가 필요한 지에 대한 신뢰성 있는 위험 지표를 찾기 위해서는 더 많은 연구가 필요하다.

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BY A L I C I A AU LT

IMNG MEDICAL NEWS

The Food and Drug Administra-tion is requiring a strongerwarning about the potential for

peripheral neuropathy with fluoro-quinolone antibiotics that are takenorally or by injection.The warning does not apply to topi-

cal formulations, which have not beenassociated with neuropathy. Drug la-bels and patient medication guidesmust be updated, said the agency.The potential for neuropathy was

first added to the labels of all drugs inthe class in 2004. The new warningwas necessary because “the potentialrapid onset and risk of permanencewere not adequately described” in the2004 label iteration, the FDA noted.Before requiring new warnings, the

FDA reviewed its Adverse Event Re-porting System (FAERS, formerlyknown as AERS) database. The agency found that cases of fluo-

roquinolone-associated peripheral neu-ropathy with an outcome of “disabili-ty” had been reported to the AERSdatabase between January 2003 andAugust 2012, although the FDA didnot say how many cases it found. Thereports indicated a rapid onset of pe-ripheral neuropathy, often within a

few days of starting the quinolone.Some cases reported neuropathy thatcontinued for a year, even though themedication had been stopped.The database was not able to show

whether neuropathy was permanent,however, because it is designed to col-lect spontaneous reports.The FDA said it had not been able to

identify any risk factors for the devel-

opment of peripheral neuropathy. Butthe onset of the condition seemed tohave no correlation with the patient’sage or how long they took the antibi-otic.The updated warnings apply to all

approved fluoroquinolones: lev-ofloxacin (Levaquin), ciprofloxacin(Cipro), moxifloxacin (Avelox), nor-floxacin (Noroxin), ofloxacin (Floxin),and gemifloxacin (Factive). According to the FDA, 23 million

outpatients were prescribed an oralquinolone in 2011. A total of 70% re-ceived ciprofloxacin; 28% were pre-scribed levofloxacin; and 9% were giv-en moxifloxacin. Gemifloxacin,ofloxacin, and norfloxacin each ac-counted for less than 1% of those pa-tients in 2011.There were 3.8 million inpatients

who received an injectable quinolonein 2011. The most-prescribed was lev-ofloxacin, accounting for 63% of pre-scriptions, followed by ciprofloxacin(28%) and moxifloxacin (13%). The agency recommended that pa-

tients who develop neuropathy symp-toms stop taking the quinolone and be

treated with a different antibiotic, un-less the benefit outweighs the risk.Patients taking the medications who

develop symptoms are urged to telltheir physician immediately.

[email protected]

BY E L I Z A B E TH MECHCAT I E

IMNG MEDICAL NEWS

The Food and Drug Administra-tion is warning that hydroxy-ethyl starch solutions should

no longer be used in the treatment ofcritically ill adult patients – includingpatients with sepsis and those admittedto an intensive care unit – after com-pleting an analysis of data that foundan increase in the risk of death and re-nal injury in these groups. In a statement, the agency also rec-

ommended that the use of hydroxy-ethyl starch (HES) solutions, used asplasma volume expanders, be avoidedin patients who are having open heartsurgery with cardiopulmonary bypass(CPB), because of an increased risk ofexcessive bleeding. The FDA is making these recom-

mendations after completing an analy-sis of data from randomized con-trolled trials, meta-analyses, andobservational studies in thousands ofcritically ill patients, and from a meta-analysis of 18 randomized controlledtrials of almost 1,000 patients under-going open heart surgery with car-diopulmonary bypass. The data on critically ill adults in-

cluded three double-blind, multicenter,randomized controlled studies pub-lished in 2012, which compared HESwith saline solution or Ringer’s ac-etate, in patients with severe sepsis(two studies), or patients in the ICUwho had sepsis, had undergone elec-tive surgery, and had an APACHE IIscore of at least 25. In these studies,which monitored patients for 90 days,HES was associated with increasedmortality and/or renal injury requiringRRT, the FDA statements said. The re-sults of meta-analyses and observation-al studies in similar populations lendadditional support to these findings,the statement added. In the meta-analysis of studies of pa-

tients undergoing open heart surgerywith cardiopulmonary bypass, the “useof different HES products, irrespectiveof molecular weight or degree of mo-lar substitution, was associated with in-creased bleeding,” according to thestatement. The meta-analysis was pub-lished in 2012 (J. Thoracic Cardiovasc.Surg. 2012:144;223-30). A boxed warning about the risk in

ICU and septic patients is being addedto the labels of HES products, and theinformation about the excessive bleed-ing risk in open heart surgery patients

is being added to the warnings and pre-cautions section. There are four FDA-approved HES

products for treating and preventinghypovolemia: HESPAN (6% HES450/0.7a in sodium chloride injection);Hetastarch (6% in 0.9% sodium chlo-ride injection), a generic equivalent ofHespan; Hextend (6% HES 450/0.7 inphysiologic solution); and Voluven(6% HES 130/0.4 in normal saline). The advisory is available at fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm. Adverse events related toHES solutions should be reported to the

FDA’s MedWatch program atfda.gov/Safety/MedWatch/HowToRe-port/default.htm or 800-332-1088.

[email protected]

Neuropathy warning strengthened for fluoroquinolonesQuinolone계 항생제; 말초신경염 발생위험성에 대한 경고 강화

FDA: No starch solutions for critically ill, CPB patients

FDA, 중환자 및 심폐우회수술 환자에 hydroxyethyl starch용액을 더 이상 사용하지 않도록 권고

Onset seen within days of starting drug. V I E W O N T H E N E W SDr. Marcos I. Restrepo, FCCP,comments:FDA는 quinolone에 의한 말초신경염 발생에 대하여경고를 강화하였는데 이는 보건학적으로 매우 중요한문제이다. 임상의사들은 quinolone을처방하기 전 이 약제의 효과와 위험성을 반드시 고려하여야 하고, 환자에게 미리 알려 복용 후 말초신경염 증상이 발생하면 의사에게 즉시 보고하도록 권고하여야한다. Quinolone은 임상현장에서 많이 사용되는 항생제이기에 이 약제에 의한 말초신경염 발생의 위험요소와 예후에 대하여 우선적으로 이해하여야한다.

Some cases reportedneuropathy that continued for a year, even though themedication had been stopped.

미국의 FDA에서 hydroxyethyl starch(HES) 용액을 중환자실에 입원하는 패혈증환자와 심폐우회수술을 이용하여 심장수술을 하는 환자에서 더 이상 사용하지 않을것을 권고하였다. 기존의 연구결과를 분석한 결과 패혈증 환자에서 신부전과 사망의위험성을 높이고, 심장수술 환자에서는출혈의 위험성이 증가하였기 때문이다.

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C H E S T P H YS I C I A N PULMONARY MEDICINE 7

술후 프로그램이 호흡기 합병증의 발생에 쐐기를 박다Postop program puts dent in pulmonary complications

BY MARY ANN MOON

IMNG MEDICAL NEWS

Amultidisciplinary postoperativecare program of patient andstaff education, early patient

mobilization, and pulmonary interven-tions has begun to reduce the excessiverate of postsurgical pulmonary compli-cations at a large urban safety-net hos-pital, according to a report in JAMASurgery.“We are eager to monitor our out-

comes over a longer period, and weare stimulated by the possibility thatpostoperative complications may be di-minished by adherence to simple, inex-pensive, easily performed patient carestrategies,” said Dr. Michael R. Cassidyof the department of surgery, BostonUniversity Medical Center, and his as-sociates.

When data collected in the NationalSurgical Quality Improvement Pro-gram revealed that their center “was ahigh outlier for all measured postopera-tive pulmonary complications,” the in-vestigators formed a multidisciplinarygroup to address the problem. “It wasdisturbing to discover that our hospitalwas a high outlier in all NSQIP-definedadverse pulmonary outcomes, but weregarded this as an opportunity to im-prove care,” they said.BUMC is the largest safety-net fa-

cility in New England. The annualincome of more than half of its pa-tients is below $20,420, approximate-ly 25% of its patients do not speakEnglish, and 70% belong to racial orethnic minorities, the investigatorsnoted. The committee included representa-

tives from the hospital’s departmentsof surgery, nursing, and quality im-provement, as well as from the unitson respiratory therapy, preoperativeassessment, infection control, andphysical therapy. To devise a programto reduce the incidence of adverse pul-monary complications, these membersreviewed the sparse literature regard-ing prevention of postoperative pneu-monia and audited postsurgical pul-monary practices at their medicalcenter. The audit found that patients re-

ceived no formal preoperative educa-tion about the importance of lung ex-pansion, mobility, and other strategiesto prevent pulmonary complications,and that families usually weren’t in-cluded in whatever minimal educationdid take place. In addition, physicians’

orders for nurses regarding postopera-tive pulmonary care “were irregular orabsent.”The program that was then devel-

oped was given the acronym “ICOUGH” to help physicians, nurses,patients, and families remember its keyprinciples: Incentive spirometry,Coughing and deep breathing, Oralcare, Understanding, Getting out ofbed frequently, and Head-of-the-bed el-evation. It was intended for all patientson the general surgery and vascularsurgery services.I COUGH included brochures, a

video, and posters to educate pa-tients, families, nurses, and physi-cians about the importance of pul-monary care. Proper use of incentivespirometry was demonstrated, theuse of mouthwash and toothbrushingwas recommended at least twice aday, and elevation of the head of thebed to at least 30 degrees was advo-cated. All this information was rein-forced at preoperative clinic visitsand in the preoperative holding areajust before surgery. Nursing staff alsoreiterated the information after theprocedures, as did surgeons, attend-ing physicians, and house staff duringrounds. The effort also included standardized

electronic physician order sets with“specific and detailed orders for all ele-ments of the I COUGH program.”These included instructions for pa-tients to perform deep breathing andcoughing every 2 hours; for patients toperform incentive spirometry 10 timesevery hour while awake; for nurses todocument incentive spirometry vol-ume every 4 hours and to ensure thatthe head of the patient’s bed was ele-vated to at least 30 degrees; for pa-tients to walk at least once on the dayof operation unless contraindicated;and for patients to get out of bed andsit in a chair for a while at least 3 timesper day.Dr. Cassidy and his associates then

compared data collected during theyear before I COUGH was implement-ed to that collected during the year af-terward. Before I COUGH, 80% of 250 pa-

tients were in bed at the time of theaudit, with only 19.6% seated in a chairor walking. After I COUGH, 69.1% of250 patients were out of bed. Before ICOUGH, only 52.8% of patients hadan incentive spirometer within reachand an unknown number were using itappropriately, whereas afterward77.2% of patients had the device withinreach and were using it appropriately.Both findings were statistically signifi-cant. The incidence of postoperative

pneumonia was 2.6% before ICOUGH, which dropped to 1.6% inthe year afterward (P = .09). Similarly,the incidence of unplanned intuba-tions was 2.0% before I COUGH,which decreased to 1.2% afterward,

the authors reported (JAMA Surg.2013 June 5 [doi: 10.1001/jama-surg.2013.358]).

These successes are due in part tothe involvement of the multidiscipli-nary team at all stages of developmentof the I COUGH program, the investi-gators said.“We have not imposed a standard of

care by mandate, but instead have in-volved nursing leadership and practic-ing ward and ICU nurses in the processof redefining the culture.“We found that involvement of rep-

resentatives of each discipline signifi-cantly increased acceptance of the ICOUGH program, and instilled asense of commitment and pride thatcould not have been achieved by sim-ply instituting and enforcing a policywithout input from all parties in-volved,” Dr. Cassidy and his col-leagues added.While the study had several limita-

tions, including variations in data-gath-ering techniques and NSQIP reportingprotocols, the investigators pointed to“substantial differences in nursing prac-tice documented between the auditsbefore and after I COUGH implemen-tation.” “We believe that a favorable change

in practice occurred as a result of ourprogram,” they wrote.

V I E W O N T H E N E W SStevenQ. Simpson,FCCP, comments:이 논문은 질 향상과환자의 경과에 대한몇 가지 중요한 점을열거하고 있다. 첫째, 이는 전문가간의 팀워크를 필요

로 한다. 둘째, 이러한 변화가 한낱 변화일 뿐인지 혹은 더 나은 것을 위한 변화인지를 평가하는 이외에도 우리가 시행하는 치료가 우리가 생각한 것만큼 효과적이지 않다는 것을평가하고 수용할 것을 필요로 한다. 저자들이했던 종류의 노력들은 크거나 작은 어느 병원에서나 또는 어떠한 임상적인 문제들에도 실행할 수 있다. 이는 우리 모두를 위한 뛰어난일례라고 할 수 있다.

Before I COUGH, 80% of 250patients were in bed at the timeof the audit, with only 19.6%seated in a chair or walking.After I COUGH, 69.1% of 250patients were out of bed.

‘We found that involvement ofrepresentatives of eachdiscipline significantlyincreased acceptance of the ICOUGH program, and instilled asense of commitment and pride.’

주요 결과: I COUGH 이전에는 환자들의 52.8%만이 incentive spirometer에 접근할 수 있었으며, 미상의 환자들만이 적절하게 사용하고 있었다. I COUGH 이후에는 77.2%가 기구에 대한 접근성이 있었으며 적절하게 사용하였다.출처: I COUGH 이전과 이후 각각 250명의환자들에서 술후 합병증의 발생을 비교하였다.

V I T A L S

JAMA Surgery에 의하면, 다각적 술후 처치프로그램과 스태프 교육, 환자의 조기 동원및 호흡기 중재 치료가 술후 호흡기 합병증을 감소시킴이 외과, 간호팀, QI 팀의 대표를 비롯하여, 호흡기 치료, 수술전 평가, 감염관리와 물리치료 팀을 모두 망라한 BostonUniversity Medical center의 다학제팀의활동에서 증명되었다.“I COUGH”라고 명명된 프로그램은 의사, 간호사, 환자 및 가족들이 가장 중요한 원칙을 기억하도록 권고하였다.

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8 PULMONARY MEDICINE D E C EMB E R 2 0 1 3 • C H E S T P H YS I C I A N

현재 흡연자는 과거 흡연자와는 달리 수술 후 위험이 높아져Current but not past smokers at postoperative risk

TBY MARY ANN MOON

IMNG MEDICAL NEWS

Current smoking is associatedwith an increased risk of mor-tality and other adverse out-

comes following major surgery, butpast smoking is not, according to a re-port in JAMA Surgery. Current smoking correlates with

these adverse outcomes even in pa-tients who don’t have obvious smok-ing-related disease such cardiovasculardisease, chronic pulmonary disorders,or cancer, which suggests that smokingmay exert its deleterious effectsthrough acute or subclinical chronicvascular and respiratory pathologicmechanisms, said Dr. Khaled M. Musal-lam of the American University ofBeirut (Lebanon) Medical Center andhis associates. Since smoking cessation has clear

benefits on morbidity and mortality inthe surgical setting, “surgical teamsshould be more involved in the ongo-ing efforts to optimize measures forsmoking control,” they wrote.“Surgery provides a teachable envi-

ronment for smoking cessation. Unlikethe long-term consequences of smok-ing, the acute consequences of smokingon patients’ postoperative outcomescan provide a strong motive for quit-

ting,” the investigators said.Dr. Musallam and his colleagues ex-

amined the effect of smoking on surgi-cal outcomes using data from theAmerican College of Surgeons NationalSurgical Quality Improvement Pro-gram (NSQIP), which includes a reg-istry that provides feedback to partici-pating hospitals regarding 30-dayrisk-adjusted surgical morbidity andmortality.For this study, they analyzed data on

607,558 patients undergoing majorsurgery at more than 200 participatinghospitals during a 2-year period in theUnited States, Canada, Lebanon, andthe United Arab Emirates. The meanage of the patients was 56 years (range,16-90 years); 43% were men and 57%were women.A total of 125,192 patients (21%)

were current smokers and 78,763 (13%)were past smokers who had quit atleast 1 year before surgery. The re-maining patients had never smoked.Only current smokers showed an in-

creased likelihood of 30-day mortality.They also were at greater risk for ad-verse arterial events such as MI orstroke, as well as for adverse respira-tory events such as pneumonia, needfor intubation, and need for a ventila-tor, within 30 days of surgery, the in-

vestigators said (JAMA Surg. 2013June 19[doi:10.1001/jamasurg.2013.2360]).The higher risk of these adverse out-

comes occurred with smokers across allage groups but was particularly notableamong those older than age 40 years. Itwas seen in both sexes, among thoseundergoing inpatient as well as outpa-tient procedures, in patients who hadgeneral as well as other types of anes-thesia, across a variety of surgical sub-specialties, and in both elective andemergency surgery cases.The association between current

smoking and adverse outcomes alsoremained robust in a sensitivity analy-sis, Dr. Musallam and his associatessaid.There was a dose-response effect in

an analysis of patients’ smoking history,with the likelihood of adverse arterialand respiratory events increasing intandem with increasing pack-years ofsmoking, but even current “light”smokers who had fewer than 10 pack-years of smoking history were at in-creased risk for postoperative mortalityand morbidity.“These findings encourage ongoing

efforts to implement smoking cessationprograms,” Dr. Musallam and his asso-ciates said.“Early intervention in heavy smokers

is warranted, especially because the ef-fect of smoking on postoperative arteri-al and respiratory morbidity seems tobe dose dependent. However, because

smokers with a cigarette smoking his-tory of less than 10 pack-years arealso at risk of postoperative death, re-cent and light smokers should also betargeted,” they suggested.Dr. Musallam and his associates

no financial conflicts of interest.

Surgery teams should take advantage of their‘teachable environment’ to help patients quit.

대수술을 받은 60만명 이상의 환자를대상으로 한 National Surgical QualityImprovement Program(NSQIP)의 자료를 분석한 결과 현재 담배를 피우고있는 환자는 수술 후 30일 내 사망률과 심근경색이나 뇌경색, 호흡기 합병증의 발생 위험이 비흡연자나 과거 흡연자에 비해 높았다. 흡연량이 많을수록 합병증 발생이 더 많이 생겼지만 10갑년 이하의 흡연량이 적은 현재 흡연자도 수술 후 사망률과 질병 이환의 위험이 높아졌다.

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V I E W O N T H E N E W SDr. MarcosI. Restrepo,FCCP, comments:이 기사는 대수술을 받는 환자에게 흡연의 해로운 영향을 보여주는 또 다른메시지이다. 대수술을 받아야 하는 것은 금연을 할 수있는 완벽한 기회이다. 이 기회를 놓치지맙시다!

BY M . A L E X AND E R O T T O

IMNG MEDICAL NEWS

The tyrosine kinase inhibitor afatinib receivedFood and Drug Administration approval in July

for the first-line treatment of metastatic non–smallcell lung cancers that express epidermal growth fac-tor exon 19 deletions or exon 21 L858R substitutiongene mutations. Its brand name is Gilotrif, and it willbe marketed by Boehringer Ingelheim.The agency also approved a kit to detect those mu-

tations, Qiagen’s therascreen EGFR RGQ PCR Kit;they occur in most of the 10% of NSCLC tumors thathave epidermal growth factor receptor mutations. Genentech’s erlotinib (Tarceva), was approved for the

same indication in May, along with its ownmutationscreening tool, Roche’s cobas EGFRMutation Test.In the study that won approval for afatinib, 230

NSCLC patients with the mutations were random-ized to afatinib 40 mg orally; 115 others were ran-domized to up to six cycles of pemetrexed and cis-platin. Median progression-free survival was 11.1months in the afatinib group and 6.9 months in thechemotherapy group. There was no significant differ-ence in overall survival. The therascreen kit was vali-dated in that trial. Gilotrif’s side effects include diarrhea, which can

lead to kidney failure and severe dehydration; livertoxicity; lung inflammation; and severe rashes. Lessserious side effects include acnelike skin eruptions,

dry skin, pruritus, mouth inflammation, paronychia,and decreased appetite.In a phase II Japanese study, afatinib 50 mg/day

showed “modest but noteworthy efficacy” in NSCLCpatients who progressed after being on erlotinib orgefitinib, or both, for 12 or more weeks. Of 62 treat-ed patients, 45 (72.6%) were EGFR mutation positivein their primary tumor; 51 (82.3%) patients had de-veloped resistance to erlotinib or gefitinib. Medianvalues for progression-free and overall survival were4.4 and 19.0 months (J. Clin. Oncol. 2013 July 1 [doi:10.1200/JCO.2012.45.0981]).

[email protected]

Afatinib approved for tumors with growth factor mutations

Afatinib; EGFR 돌연변이가 있는 전이성 비소세포폐암에1차 치료제로 FDA가 승인

새로운 tyrosine kinase 억제제인 afatinib이 EGFR 돌연변이가 있는 stage IV 비소세포폐암에 1차 치료제로 승인받았다. 그러나, 이 신약은 이전에 사용되었던 erlotinib과gefitinib에 내성을 보였던 환자들에게 2차 약제로 사용하였을 때 8% 반응률을 보였으며, 약간의 추가적인 효과를보고하였다. 단지 예비결과의 발표이지만 매우 흥미로운 점은전이성 비소세폐암 환자에게 afatinib과 cutuximab(Erbitux,EGFR 수용체에 결합하는 단일 항체) 병합요법을 하였을때 30% 반응률을 보고하였다

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C H E S T P H YS I C I A N PULMONARY MEDICINE 9

Think ceftaroline in suspected drug-resistant CAP약제 내성 폐렴이 의심될 때는 ceftaroline을 고려

BY BRUC E J ANC I N

IMNG MEDICAL NEWS

ESTES PARK, COLO. – Ceftaroline ishands-down the most exciting and im-portant of the four systemic antibacter-ial agents to reach the U.S. marketsince the great 7-year drought in ap-provals ended in 2008, an infectiousdisease expert says.

Ceftaroline is a novel cephalosporinwith unique binding to penicillin-bind-ing proteins, including the altered ver-sions that confer resistance in methi-cillin-resistant Staphylococcus aureus(MRSA) and penicillin- andcephalosporin-resistant Streptococcuspneumoniae. Thus, ceftaroline is a po-tent and effective drug in the increas-ingly common situation of beta-lac-tam-resistant community-acquiredpneumonia (CAP) or complicated skinand soft tissue infections, noted Dr.Mary T. Bessesen, chief of the infec-tious diseases section at Denver V.A.

Medical Center. She reports having no financial rela-

tionship with the maker of ceftaroline.In the pivotal FOCUS 1 and FOCUS

2 trials conducted in patients with CAPnot due to MRSA, ceftaroline provednoninferior overall to ceftriaxone (Ro-cephin). Of note, in the 14% of FOCUSparticipants with CAP due to S. aureus,ceftaroline proved to be significantlymore effective than ceftriaxone. Impor-tantly, the same was true among theone-third of FOCUS participants inwhom S. pneumoniae was isolated(Clin. Infect. Dis. 2010;51:1395-405).“I think if you’re going to impact

mortality in CAP, pneumococcus hasto be the primary target. Ceftaroline isa good alternative when penicillin-re-sistant S. pneumoniae is suspected orproven,” Dr. Bessesen said at a confer-ence on internal medicine sponsoredby the University of Colorado.Other common pathogens in CAP

that are sensitive to ceftaroline are He-mophilus influenza and Moraxella ca-tarrhalis. The Gram-negativepathogens E. coli, Klebsiella pneumoniae,and Enterobacter cloacae are also ceftaro-line sensitive, with activity similar toceftriaxone and ceftazidime. Not only is MRSA sensitive to cef-

taroline, so are methicillin-sensitive S.aureus, vancomycin-intermediate S. au-reus, vancomycin-resistant S. aureus,linezolid (Zyvox)–resistant S. aureus,and daptomycin (Cubicin)–nonsuscep-tible S. aureus. Ceftaroline does not cover the atypi-

cal pneumonia pathogens Mycoplasmapneumoniae, Chlamydia pneumoniae,and Legionella pneumoniae, nor does itcover Pseudomonas aeruginosa or ex-tended-spectrum beta-lactamase-pro-ducing Enterobacteriaceae, stressed Dr.Bessesen.

The current CAP guidelines don’t in-clude recommendations for ceftaroline,because the drug received Food andDrug Administration approval fortreatment of CAP and complicatedskin and soft tissue infections after theguidelines were issued.

Clinical trials investigating ceftaro-line in CAP caused by MRSA would bewelcome, Dr. Bessesen noted, becausethe current CAP guidelines don’t in-clude any recommendations for CAPpneumonia. “It really leaves us wondering in

high-risk cases what’s best to do,” shesaid. “There’s been some controversyabout vancomycin versus linezolidwhen you suspect MRSA pneumonia.Ceftaroline would be a nice way to getaround all of that.” Ceftaroline is administered intra-

venously twice daily, with dose adjust-ment for renal function. The drug’spharmacokinetics are favorable for in-tramuscular injection, but there arelimited clinical data for this route, andit is not FDA approved. Ceftaroline costs about $84 per day,

or four times more than ceftriaxone,Dr. Bessesen said. As a result, formula-ry committees are reluctant to put cef-taroline on the list. That makes Dr. Bessesen see red. “I’ve never been on a drug company

speakers bureau. I’ve never had any re-

search money from drug companies. Ispeak only as someone who’s interest-ed in us being able to continue to treatbacterial infections when I say we’vegot to change our attitude. We have tobe willing to pay something for theseantibiotics,” she asserted. With regard to the other three sys-

temic antibiotics approved by theFDA in the 5 years since the 7-yeardrought ended, bedaquiline (Sirturo)is the most important globally, be-cause it is indicated for multidrug-re-sistant tuberculosis. Fidaxomicin isan effective drug for Clostridium diffi-cile diarrhea; it’s eight times more po-tent than vancomycin against C. diffi-cile, has minimal systemic absorption,and offers the major advantage ofproducing little negative impact onfavorable gut flora. Telavancin is aonce-daily agent for hospital-acquiredand ventilator-associated bacterialpneumonia. Dr. Bessesen reported having no

conflicts of interest.

[email protected]

Cost barrier:Ceftaroline costs about $84 per day, or four timesmore thanceftriaxone.

DR. BESSESEN

V I E W O N T H E N E W SDr. VeraDePalo, FCCP, comments:검증된 효과를 보이는 새로운 항균제는 항균제 내성을 다룰 때 추가적인 선택을 가능하게 해준다. 새로운 cephalosporin계약물인 ceftaroline은 약제 내성을 보이는S. aureus 치료 시 또 다른 선택이 될 수있다.

‘If you’re going to impact mortalityin CAP, pneumococcus has to bethe primary target. Ceftaroline is agood alternative when penicillin-resistant S. pneumoniae issuspected or proven.’

Ceftaroline은 새로운 cephalosporin제제로 beta-lactam계 내성 지역사회 폐렴혹은 복합 피부 및 연부조직 감염증에있어 강력하고도 효과적인 약물이다.MRSA가 원인이 아닌 CAP에서 ceftri-axone에 비해 열등하지 않으며, S.pneu-moniae 혹은 S. aureus 감염의 경우ceftriaxone 보다 더 효과적으로, MSSA,MRSA,VISA,VRSA 및 Linezoline-re-sistant 혹은 daptomycin-nonsuscep-tible infection에서도 유효하다. Penicillin내성 pneumococcal pneumonia 혹은MRSA pneumonia의 경우 치료제로 고려할 수 있으나, ceftriaxone의 4배에 달하는 비용은 처방 시 중요한 문제가 될수 있다.

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10 PULMONARY MEDICINE D E C EMB E R 2 0 1 3 • C H E S T P H YS I C I A N

미국 폐 선별검사 연구 분석 결과: 저선량 CT 검사, 초기 폐암을 3배 이상 더 찾아내다

BY MARY ANN MOON

IMNG MEDICAL NEWS

Low-dose CT screening of adultsat high risk for lung cancer wasthree times better than radiogra-

phy at detecting early, more treatablemalignancies in the National Lung

Screening Trial, according to a reportpublished in the New England Journalof Medicine.The initial findings from the NLST

showed that low-dose CT (LDCT) lungscreening reduced lung-cancer mortali-ty by 20%, relative to radiographicscreening. The investigators now re-

port more detailed findings from thefirst two rounds of screening, whichshow that this decrease in lung cancermortality “was coupled with a shift todetection of earlier-stage non-small-celllung cancers,” which are potentiallycurable, said Dr. Denise R. Aberle ofthe department of radiological sciences,

University of California, Los Angeles,and her associates. In the NLST, 53,454 adults at high

risk for lung cancer were randomlyassigned to undergo three annualscreenings using either LDCT or radi-ography at 33 medical centers acrossthe country. The screening tookplace between August 2002 and Sep-tember 2007.At the first round of screening, the

sensitivity of LDCT was 94.4%, thespecificity was 72.6%, the positivepredictive value was 2.4%, and thenegative predictive value was 99.9%.In comparison, the sensitivity of radi-ography was 59.6%, the specificitywas 94.1%, the positive predictivevalue was 4.4%, and the negative pre-dictive value was 99.8%.At the second round of screening,

LDCT’s sensitivity was 93%, specifici-ty was 83.9%, positive predictive val-ue was 5.2%, and negative predictivevalue was 99.9%. In comparison, radi-ography’s sensitivity was 63.9%,specificity was 95.3%, positive predic-tive value was 6.7%, and negativepredictive value was 99.8%. During the first round of screening,

nearly half (47.5%) of the staged can-cers detected on LDCT were stageIA, compared with only 23.5% ofthose detected on radiography. Incontrast, only 31.1% of the stagedcancers detected on LDCT were ad-vanced stage III or IV cancers, com-pared with 59.1% of those detectedon radiography.This discrepancy in the distribution

of early- vs. late-stage cancers persist-ed during the second round ofscreening, Dr. Aberle and her associ-ates reported (N. Engl. J. Med. 2013Sept. 4 [doi:10.1056/NEJMoa1208962]). In the future, “the performance

characteristics of LDCT may be en-hanced by determining the most ap-propriate risk cohort, refining bothalgorithms for interpreting the re-sults of screening and definitions ofpositive findings, and determiningthe appropriate duration and timingof screening,” they added. The NLST was funded by the Na-

tional Cancer Institute. Dr. Aberle re-ported no potential financial conflictsof interest; one of her associates re-ported ties to Endocyte, Frontier Sci-ence, and other companies.

NLST details: LDCT detects threefold more early lung cancers

미국 폐 선별검사 연구 결과 폐암 고위험군을 대상으로 저선량 CT를 이용하여 선별검사를 하면 흉부 방사선 검사에 비하여 보다 치료 가능한 초기 폐암을 3배 이상 더 발견할 수 있었다. 첫번째 선별검사에서 저선량 CT에서 발견된 폐암 중 stage 1A 폐암은 87건(47.5%)였지만 흉부 단순 방사선 검사에서는 31건(23.5%)에 지나지 않았다

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C H E S T P H YS I C I A N CARDIOVASCULAR DISEASE 11

Antiemetic cuts pneumonia in intubated stroke patients

항구토제가 기도삽관이 된 뇌졸중 환자에서 폐렴의 발생을 감소시킨다

BY SARA F R E EMAN

IMNG MEDICAL NEWS

LONDON – Metoclopramide signifi-cantly reduced the incidence of pneu-monia in intubated stroke patientsand was associated with improvedmortality in a single-center, random-ized controlled study. A total of 34 of 60 (57%) patients in

the trial developed pneumonia, ofwhom the majority (87%) received aplacebo, while only 8 (27%) cases oc-curred in patients who received theantiemetic therapy.A third of the cohort died by 30

days, but of these 20 deaths, 12 oc-curred in the placebo group versus 8in the metoclopramide arm.Neurological improvement also

was seen in the patients given meto-clopramide, Dr. Anushka Warusevi-tane of University Hospital of NorthStaffordshire in Stoke-on-Trent, Eng-land, reported at the annual Euro-pean Stroke Conference.For the whole group, National In-

stitutes of Health Stroke Scale(NIHSS) scores were 19.3 at baseline,indicating moderate to severe stroke,16.8 at 1 week, 17.4 at 2 weeks, and19.6 at 3 weeks post stroke.In the trial, adult patients admitted

to the acute stroke unit within 7 daysof having a stroke and who needed anasogastric tube fitted for more than24 hours were randomized to receivemetoclopramide 10 mg three times aday or the same volume of a similar-looking placebo for a maximum of 3weeks. All patients received standardstroke care.The average age of the 60 patients

finally recruited was 78 years, 63%were female, and 93% had cerebralinfarcts. Pneumonia was diagnosed accord-

ing to four criteria outlined by theBritish Thoracic Society: acute lowerrespiratory tract infection symptoms;new focal chest signs; fever (morethan 38° C), chills and rigors, elevat-ed white cell count, or increased in-flammatory markers; and new radio-logical shadowing.Dr. Warusevitane reported that all

of the episodes of pneumonia oc-curred within 10 days of the initiationof nasogastric feeds. The averagetime for pneumonia to develop wassignificantly longer in the metoclo-pramide group (4 days versus 2 daysfor placebo). Significantly shorter pe-riods of antibiotic use were noted inthe active versus placebo arm, at amean of 2 days and 8 days, respec-tively. Only 1 patient given metoclo-

pramide had an episode of aspiration,which was witnessed by a health careprofessional, compared with 14 pa-tients given placebo. There was evi-

dence that once the nasogastric tubewas removed, the actively treated pa-tients had a better swallowing re-sponse.“I’m convinced enough to change

practice locally,” senior study authorDr. Christine Roffe said in an inter-

view. Dr. Roffe, professor of medicineat Keele University, England, concededthat a single-center study of just 60 pa-tients might not convince the widerstroke community. Dr. Warusevitane and Dr. Roffe re-

ported having no disclosures.

단일 기관에서 시행한 무작위 대조군 연구에서 metoclopramide가 기도삽관이 된뇌졸중 환자에서 폐렴의 발생 빈도를 감소시키고 사망률의 감소와 연관이 있는것으로 보고되었다SU

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ARY

Heart failure: Five interventions that improve care심부전 환자를 호전시키는 5가지 치료법

T B Y BRUC E J ANC I N

IMNG MEDICAL NEWS

ESTES PARK, COLO. – Introducingfive evidence-based interventions in pa-tients with heart failure with reducedejection fraction would dramaticallycut admissions for heart failure, ac-cording to Dr. JoAnn Lindenfeld, vicepresident of the Heart Failure Societyof America. Here are the five interventions: rec-

ognizing when to switch fromfurosemide to another oral loop diuret-ic; up-titrating beta-blocker therapy tothe maximum recommended dose asquickly as possible; adding a low-dosealdosterone antagonist to the treat-ment regimen; identifying and treatingiron deficiency; and prescribing digoxinin symptomatic patients with a lowejection fraction, Dr. Lindenfeld said ata conference on internal medicinesponsored by the University of Col-orado.

Loop diureticsFurosemide, everybody’s favorite low-cost loop diuretic, turns out to have anenormously variable oral bioavailabili-ty, ranging from 10% to 90% from pa-tient to patient. It also varies substan-tially from day to day within the sameindividual. In contrast, torsemide (De-madex) and bumetanide (Bumex) havea consistently high oral bioavailabilityof roughly 90%. They are useful alter-natives in poorly compensated heartfailure patients. “When your patient says they’re not

diuresing and you’re pretty surethey’re taking their drugs, or if they’vehad more than one recent admissionfor heart failure and they’re havingtrouble with congestion and fluid re-tention, think about switching tobumetanide or torsemide,” said Dr.Lindenfeld, professor of medicine andmedical director of the heart transplantprogram at the university“In my own practice, when I have a

patient admitted for acute decompen-sated heart failure with congestion andI don’t find another reversible cause, Iwill usually switch them,” noted Dr.

Lindenfeld, who also is codirector ofits Center for Women’s Health Re-search.In a classic study, 234 patients hospi-

talized for acute decompensated heartfailure were randomized at dischargeto torsemide or furosemide in equiva-lent doses. The torsemide group subse-quently had a 52% lower rate of heartfailure hospitalization (Am. J. Med.2001;111:513-21). Bumetanide is now a pretty inexpen-

sive drug, Dr. Lindenfeld noted. Inmaking the switch, remember that 40mg of furosemide is equivalent to 1mg of bumetanide or 20 mg oftorsemide.

Beta-blockerup-titrationBeta-blocker andangiotensin- converting en-zyme (ACE) in-hibitor therapyboth have a classIA recommenda-tion in heart fail-ure. But what’s the best way to jugglethe timing of dual dose increases? “None of the guidelines says how to

manage up-titration, but I strongly be-lieve that once you have somebodyon a reasonable dose of an ACE in-hibitor – say, 5 mg of lisinopril or theequivalent – then you should go tothe beta-blocker and up-titrate it to itsmaximum,” she said. “Then later,come back to the ACE inhibitor andget the patient on the maximum doseof that.”The rationale for this approach is

based on a comparison of the out-comes of the landmark beta-blockertrials versus ATLAS, a 3,104-patient tri-al conducted in the pre-beta- blockerera in which patients were randomizedto low-dose lisinopril at 2.5-5 mg/dayor high-dose therapy at 32.5-35mg/day to determine which was bet-ter. After 4 years of follow-up, thehigh-dose group showed a 24% reduc-tion in the risk of heart failure hospital-izations, but no significant advantagein terms of all-cause mortality (Circula-

tion 1999;100:2312-8). Contrast those results with the out-

comes of the major clinical trials forcarvedilol, metoprolol, and bisoprolol,each of which featured up-titration tothe target dose within 8 weeks when-ever possible. All three studies werehalted within less than a year becauseof a roughly 35% reduction in mortali-ty, compared with placebo. And thatmortality benefit became apparent at 3months. “These are huge reductions in mor-

tality,” Dr. Lindenfeld noted. “Youdon’t want to have a patient comeback every 4 weeks to up-titrate their

ACE inhibitor for5 months andmiss the opportu-nity to get the pa-tient on an effec-tive dose of abeta-blocker,when the lifesav-ing benefit beginsso early.”The recom-

mended maxi-mum doses in heart failure patients arecarvedilol (Coreg) at 25 mg twice dai-ly, or 50 mg twice daily for patientsweighing more than 85 kg; 200mg/day for extended-release metopro-lol (Toprol XL); and 10 mg/day forbisoprolol (Zebeta). The three beta-blockers are similar in their efficacy fortreating heart failure, she said. Howev-er, bisoprolol has the fewest pul-monary effects and is thus the bestchoice in patients with chronic ob-structive pulmonary disease (COPD),even though it lacks a specific Foodand Drug Administration–approved in-dication for heart failure, she said.

Aldosterone antagonistsIn terms of mortality benefit, the randomized trial data show that the al-dosterone antagonists are nearly asgood as beta-blockers. Yet they remainwidely underutilized in the UnitedStates, according to Dr. Lindenfeld. Indeed, three major randomized tri-

als showed roughly a 25% reduction intotal mortality, compared with place-bo, in patients on standard back-ground therapy including a beta-block-er and ACE inhibitor, along with a20% decrease in risk of sudden cardiacdeath. The doses used were spirono-lactone at 12.5-25 mg/day oreplerenone (Inspra) at 25-50 mg/day. An intriguing retrospective analysis

conducted in close to 7,000 patientswith heart failure following an acutemyocardial infarction concluded thatgetting the aldosterone antagonist on-board early in that situation is key. Pa-tients who started on the drug lessthan 7 days post MI had a 29% reduc-tion in total mortality and a 47% de-crease in sudden cardiac death, com-pared with those started on day 7 orlater (Eur. J. Heart Fail. 2009;11:1099-105). That benefit is believed to

be the result of early left ventricular re-modeling. A definitive European prospective,

randomized trial looking at the impactof starting an aldosterone antagonistwithin 7 days after acute MI is due tobe presented later this year. The insideword is the results are favorable, shenoted. Hyperkalemia is a legitimate con-

cern when prescribing an aldosteroneantagonist. These agents should beavoided in a patient who has a creati-nine level above 2.5 mg/dL or an esti-mated glomerular filtration rate below30 mL/min per 1.73 m2, or if otherpotassium-sparing drugs are onboard.Potassium levels should be checked af-ter the first 3-7 days of therapy, againat 1 month, and then every 3 months,as well as anytime a patient becomesdehydrated.

Iron replacementA new European study is illuminatingon this issue: Among a cohort of 1,506patients with chronic heart failure, ful-ly 50% were determined to have irondeficiency, as defined by a ferritin levelless than 100 mcg/L, or a ferritin levelof 100-299 mcg/L with a transferringsaturation lower than 20%. In a multi-variate regression analysis, iron defi-ciency was a strong independent pre-dictor for mortality, associated with a42% increased risk (Am. Heart J.2013;165:575-82). “I think if you restricted the study to

hospitalized heart failure patients, theiron deficiency rate would be evenhigher. It’s just appalling how manypeople we send home iron deficientwithout iron replacement therapy,”

In poorlycompensatedheart failure,torsemide andbumetanide areuseful alternativesto furosemide.

DR. LINDENFELD

심박출률이 저하된 심부전 환자들에서 5가지의 치료법이 입원율을 낮추는 것으로보고되었다. 1) 이뇨제를 furosemide에서다른 종류의 loop diuretic으로 바꿀 것,2) 베타 차단제를 권고되는 최대한의 용량을 쓸 것, 3) 저용량의 aldosteroneantagonists를 추가할 것, 4) 철 결핍성빈혈을 치료할 것, 5) 증상이 있고 심박출률이 저하된 환자에서 digoxin을 처방할 것을 Lindenfeld 박사가 권고하였다.

SUM

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12 CARDIOVASCULAR DISEASE D E C EMB E R 2 0 1 3 • C H E S T P H YS I C I A N

V I E W O N T H E N E W S

Dr. Jun Chiong, FCCP, comments:심부전은 미국 등 선진국에서 가장 흔한 입원의 원인이 되는 질환이다. 이 환자들의 치료를위한 진료비는 급격히 증가되어 왔다. Lin-denfeld 박사가 권고한 5가지 치료법은 입원율을 낮출 수 있는 단순하고 효과적인 방법이다. 심부전의 관리에 있어 여러의료적, 사회적인 요소들을 고려해야 하지만 사회적 요소에대한 것들이 아직잘 다루어지지 않고있다.

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Iron deficiency among chonic heart failure patients

‘I think if yourestricted

the study tohospitalizedheart failurepatients, the

iron deficiencyrate would beeven higher.’

Note: Based on data for 1,506 patients.

Source: Am. Heart J. 2013;165:575-82 IMNG Medical Media

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C H E S T P H YS I C I A N CARDIOVASCULAR DISEASE 13

Dr. Lindenfeld asserted. She noted that in the European

FAIR-HF trial involving 459 hospital-ized iron-deficient heart failure patientsrandomized at discharge to intra-venous iron corrective and mainte-nance therapy or to a matching place-bo, the iron replacement groupdemonstrated significant improvementin quality of life and exercise capacity.The benefits were seen regardless ofwhether a patient’s baseline hemoglo-bin was high or low. In addition, the rate of the combined

endpoint of first hospitalization forworsening heart failure or death was7.5% in the iron recipients, comparedwith 13.9% in placebo-treated controls– a difference that didn’t achieve statis-tical significance because the study wasunderpowered to evaluate that end-point (N. Engl. J. Med. 2009;36:2436-48). “Iron replacement is a distinct ad-

vantage for these patients, so youshould be looking for iron deficiency.You probably don’t need to use IV

iron, but if your patient is in the hospi-tal anyway, IV iron is pretty benignand will get him iron-repleted almostimmediately,” Dr. Lindenfeld noted. Before sending iron-deficient pa-

tients home on oral iron, make surethey can absorb it. Many older individ-uals can’t. Indeed, among patients hos-pitalized at the University of Coloradoheart failure service, only 13% can ac-tually absorb oral iron, she said.A simple way to tell is to draw a

serum iron level, give the patient aniron tablet, and check the serum ironlevel again in 1-3 hours. It shouldroughly double, Dr. Lindenfeld said.

DigoxinIn the classic digoxin trial involvingclose to 7,000 patients, heart failurehospitalization was a prospectively de-fined endpoint. In patients who had aleft ventricular ejection fraction of25%-45%, hospital admission for heartfailure was reduced by 26% in patientsassigned to digoxin. In patients whoseLVEF was less than 25%, the reductionin hospitalization was 39%. “So don’t forget that digoxin is still a

good drug in patients with low ejec-tion fraction or who have substantialsymptoms,” Dr. Lindenfeld said. “If we had a drug approved today

that didn’t change mortality but re-duced hospital admissions by 39%,

we’d all be giving it.”She reported consulting for

Medtronic, St. Jude, Boston Scientific,Gambro, and ResMed.

[email protected]

Continued from previous page

Avoidable deaths from cardiovascular disease

Note: Based on data from the National Vital Statistics System.

Source: MMWR 2013 Sept. 3 (early release);62 IMNG Medical Media

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D A T A W A T C H

심부정맥혈전증 위험도 예측 공식인 IMPROVE의 유용성 재확인


IMNG MEDICAL NEWS

AMSTERDAM – A simple formula forcalculating the risk faced by acutely ill,hospitalized patients for venous throm-boembolism was validated in a case-control study with more than 400 pa-tients.This VTE risk-calculator formula “is

the first [risk-assessment model (RAM)]to be validated on a large scale in hos-

pitalized medical patients,” Charles E.Mahan, Pharm.D., said at the congressof the International Society on Throm-bosis and Haemostasis. “Applying this RAM could spare

20%-30% of these patients from get-ting unnecessary prophylaxis” withan anticoagulant, said Dr. Mahan, di-rector of outcomes research at theNew Mexico Heart Institute, Albu-querque.He cautioned that the new evidence

he presented still needs to be pub-lished, and a prospective test of the riskformula should also be done, but thenew findings give this risk-scoringmethod a leg up over the several otherrisk-assessment methods that are outthere.“This gives us some information

that we can comfortably use,” saidDr. Mahan in an interview. Otherformulas for estimating VTE risk inpatients hospitalized for medical rea-sons include the Padua PredictionScore (J. Thromb. Haemost.2010;8:2450-7), but the RAM testedby Dr. Mahan now “has the best evi-dence base for hospitalized, acutelyill patients.”The validation used the risk for-

mula developed by the IMPROVE(International Medical PreventionRegistry in Venous Thromboem-bolism) study, which included over15,000 medical patients at 52 hospi-

tals in 12 countries (Chest2011;140:705-14). The IMPROVE RAM includes seven

risk factors that each score from 1 to 3points (see box). A history of VTEscores 3 points; immobilization for aweek or more, ICU stay, and age over60 each score 1 point; and three otherfactors each score 2 points.The valida-tion cohort came from the more th an130,000 patients aged 18 years or olderwho were hospitalized for at least 3days during 2005-2011 at a McMasterUniversity–affiliated hospital in Hamil-ton, Ont. After excluding pregnant pa-tients, patients with recent surgery,and patients with VTE at admission,

the researchers identified 139 patientswho developed VTE within 90 days ofhospital admission and matched themwith 278 patients who did not developa VTE as controls. Matching was bygender, hospital, and date of admis-

캐나다 보건의료자료에서 417명의 환자군과대조군을 추출하여 시행한 후향적 환자-대조군 연구결과에 의하면, 심부정맥혈전증위험도 예측 공식인 IMPROVE가 민감도와특이도가 우수하며 이를 적용하여 불필요하게 항응고요법을 시행하는 환자를 20 -30% 줄일 수 있었다.

SUM

MAR

Y

V I E W O N T H E N E W SDr. Steven Q. Simpson, FCCP,comments:심부정맥혈전증은 병원에 입원하는 환자에서 일어나서는 안 되는 질환이기때문에 대부분의 병원에서 모든 고위험환자를대상으로 예방요법을 시행한다. 이런 이유로비교적 위험도가 낮은 환자에서 불필요하게예방요법을 시행하는 경우가 있다. 이 연구의목적은 이런 불필요한 예방 요법을 시행 받는환자의 수를 줄이는데 있다. 우리의목표는 예방요법에필요한 대상자를찾아 치료를 하고,필요가 없는 환자에게는 시행하지 않는 것이다. 그럼에도 불구하고아직도 예방치료의대상자를 많이 찾아 치료하는데 더 관심을가지고 있다.

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Bar chart labelThe IMPROVE risk-assessment model

Note: In 2011, the authors of IMPROVE set a total score of 0 or 1 as low risk and not needinganticoagulant prophylaxis and a score of 2 or more as appropriate for prophylaxis.

Source: Chest 2011;140:705-14 IMNG Medical Media

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Risk factor

Prior venous thromboembolism

Diagnosed thrombophilia

Current lower-limb paralysis

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Stay in the ICU or coronary care unit

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CRITICAL CARE MEDICINE


Embolism risk-prediction formula gains validation

14 CRITICAL CARE MEDICINE D E C EMB E R 2 0 1 3 • C H E S T P H YS I C I A N

BY M . A L E X AND E R O T T O

IMNG MEDICAL NEWS

Blood glucose levels should be targeted to 140-200 mg/dL in surgical or medical ICU patientson insulin therapy, according to advice the

American College of Physicians published in theAmerican Journal of Medical Quality. Also, “clinicians should avoid targets less than …

140 mg/dL because harms are likely to increase withlower blood glucose targets,” the group said (Am. J.Med. Qual. 2013 [doi:10.1177/1062860613489339]).The advice isn’t new, but instead a restatement of

ACP’s 2011 inpatient glycemic control guidelinesreissued as part of its “Best Practice Advice” cam-paign, said Paul G. Shekelle, Ph.D., senior author ofboth the advice paper and guidelines (Ann. Intern.Med. 2011;154:260-7). “This is based on the prior guidelines, so there’s

nothing new here in that sense. The Best PracticeAdvice series sometimes runs in parallel to the guide-

lines, sometimes it is something completely differentthan any ACP guidelines, and sometimes, like thiscase, it runs asynchronous to the guidelines. Ideally,these will be more synchronous in the future,” Dr.Shekelle, director of the RAND Corporation’s South-ern California Evidence-Based Practice Center, saidin an interview.ACP’s advice is largely in keeping with glucose

control recommendations from other groups,which have tended toward liberalization in recentyears amid evidence that aggressive, euglycemiccontrol in hospitalized patients, even if they havediabetes, doesn’t improve outcomes and carries toohigh a risk of hypoglycemia and its attendant prob-lems.“Nobody is advocating tight glycemic control any-

more in the hospital. It isn’t necessary and may beharmful,” said Dr. Etie S. Moghissi, the lead authoron a 2009 inpatient glycemic control consensus state-ment issued by the American Association of ClinicalEndocrinologists and American Diabetes Association(Diabetes Care 2009;32:1119-31).The consensus statement recommended an upper

limit of 180 mg/dL based on the pivotal NICE-SUG-AR study, instead of 200 mg/dL, which Dr. Shekellesaid ACP chose because it was the upper target limitin several of the additional studies upon which thegroup based its 2011 guidelines (N. Engl. J. Med.2009;360:1283-97). But Dr. Moghissi, who is with the department of

medicine at the University of California, Los Angeles,said she’s concerned that 200 mg/dL might be toohigh.“We know that when we set targets, people do not

achieve them. So when we set a higher target, mostof the time people go above that. The concern” isthat a target of 200 mg/dL “may be perceived [asmeaning that] a little bit over 200 mg/dL is okay,”but “above 200 mg/dL, usually there are issues withincreased risk of infection, poor wound healing, vol-ume depletion,” and other problems, she said in aninterview. Dr. Shekelle and Dr. Moghissi said they have no

relevant disclosures.

[email protected]

ACP, 중환자들의 혈당 140-200 mg/dL로 유지하도록 권고ACP restates 140- to 200-mg/dL blood glucose target

sion.The IMPROVE RAM showed

“good” discrimination in the validationcohort, Dr. Mahan said. The incidenceof VTE during the 90 days after hospi-talization in the validation cohort was0.20% in patients with low scores, 0 or1; 1.04% in patients with moderatescores, 2 or 3; and 4.15% in those withhigh scores, 4 or greater. By compari-son, in the first IMPROVE cohort the

VTE rates were 0.45% in patients withlow scores, 1.30% in those with mod-erate scores, and 4.74% in those withhigh scores.Analysis showed that in the new co-

hort, the IMPROVE formula could ac-count for about 77% of the variabilityin VTE incidence, performance thatwas also similar to that of the deriva-tion cohort. But the formula failed topredict a VTE in several patients: 26

patients (19%) who had a VTE duringfollow-up had an IMPROVE score of 0or 1 at the time of their hospitaliza-tion.The data showed that a score cut-

point of 2 had a sensitivity of 81% anda specificity of 60%, whereas a cut-point of 3 had a sensitivity of 63% anda specificity of 78%.

[email protected]


CARDIOTHORACIC SURGERY

주요 결과:심부정맥혈전증 위험도 예측 공식인IMPROVE의 타당도 검증을 위한 연구를 통해,이 예측식의 민감도와 특이도가 우수하다는사실을 재확인하였다.출처: 캐나다 보건의료자료에서 417명의 환자군과 대조군을 추출하여 시행한 후향적 환자-대조군 연구결과

V I T A L S

C H E S T P H YS I C I A N CARDIOTHORACIC SURGERY 15

비소세포폐암의 쐐기 절제술: 15 mm은 최선의 절제연인가?Wedge resection in NSCLC: Is 15 mm the magic margin?

BY PATR I C E WEND L I N G

IMNG MEDICAL NEWS

MINNEAPOLIS – Increasing the sur-gical margin length up to 15 mm dur-ing wedge resection of small lungcancer tumors significantly loweredthe risk of local recurrence among474 consecutive patients.

No additionalbenefit was ob-served, howev-er, beyond 15mm, said Dr.Kamran Mohi-uddin, a surgicalresearch fellowat Brigham andWomen’s Hos-pital, Boston. Compared

with a margin length of 5 mm, theadjusted risk of local recurrence wasestimated to be 45% lower with amargin length of 10 mm (hazard ra-tio, 0.55), 59% lower with a 15-mmmargin (HR, 0.41), and 54% lowerwith a 20-mm margin (HR, 0.46).“The downward trend flattens out,

indicating diminished benefit of in-creasing the margin length,” he saidat the annual meeting of the Ameri-can Association for ThoracicSurgery.Currently, the data are unclear re-

garding the optimal margin length forwedge resection of small non–smallcell lung cancer (NSCLC) tumors ofless than 2 cm. Wedge resections areassociated with margins less than 1cm and a high risk for locoregionalrecurrence (Ann. Surg. Oncol.2007;14:2400-5), with a multicenter,prospective study suggesting that theoptimal margin length should be larg-er than the maximum tumor diame-ter (Ann. Thorac. Surg. 2004;77:415-20).When asked during a discussion of

the analysis whether a more aggres-sive resection or segmentectomywould be performed if margins arefound in the operating room to be in-adequate based on the current re-sults, senior author Dr. Scott J. Swan-son, director of minimally invasivethoracic surgery at the hospital, saidthey are taking the results forwardinto practice, but that it’s unclearwhether 15 mm is the optimal num-ber to target.“Is 15 mm the correct margin? I am

not sure we know the answer in allcases, but it is a useful number tokeep in the surgeon’s head when weare doing resections for tumors thatare 2 cm or less,” he said in an inter-view. “A 15-mm margin seems to bea better target to aim for than marginlength to tumor diameter ratio ofgreater than 1, as suggested by otherinvestigators.”The current analysis included data

from all patients, aged 21-85 years,who underwent wedge resection for

NSCLC 2 cm or less at their institutionbetween January 2001 and August2011. Margin length, defined as the dis-tance from the tumor to the closest sta-pled resection margin, was 0.1-0.5 cmin 36%, 0.6-1.0 cm in 25.5%, 1.1-2.0 cmin 28.5%, and greater than 2 cm in10%.The mean tumor size was 1.33 cm,

the location of the tumor was the rightupper lobe in the majority (36%), andvideo-assisted thoracic surgery (VATS)was used in 57.5%. The patients’ meanforced expiratory volume in 1 second(FEV1) was 79.8%, and the mean agewas 68.5 years.Perioperative death occurred in 1 pa-

tient and at least one major complica-tion in 41 patients, Dr. Mohiuddin said.The local recurrence rate was 5.8%

at 1 year, 11.3% at 2 years, and 16.8%at 3 years. Median follow-up was 3.9years.In multivariate regression analysis,

increased margin length was signifi-cantly associated with a lower risk oflocal recurrence, with evidence of di-minished additional benefit beyond alength of 15 mm (P = .031), he said.The analysis adjusted for FEV1, chronicobstructive pulmonary disease, smok-ing, diabetes, tumor size, tumor lobe

location, location within the hemotho-rax, surgeon, whether VATS or opensurgery was used, and whether or notnodes were sampled.Dr. Mohiuddin and his coauthors re-

ported having no financial disclosures.

[email protected]

DR. MOHIUDDIN

V I E W O N T H E N E W SDr. Lary Robinson, FCCP,comments: 연구자들은 절제연의 길이가(종양으로부터 가장 가까운 스테이플 절제선까지의 거리) 15mm까지는 절제연의 길이가 클수록 재발율이 감소하지만 15 mm 이상 부터는 재발률은 안정상태를 유지하는 것을 관찰하였다. 즉, 작은 주변부 종양에 대해 15 mm이상의 절제연으로 쐐기절제술을시행하는 것은 국소 재발률을 더 이상 감소시키지는 못하였다.

이 연구 코호트의 474명 환자들의전체 3년 국소 재발률은 16.8%였다.아직까지는 IA병기의 비소세포폐암의 표준 수술방법은 폐엽절제술이다. 그러나 폐기능이 제한되어 있거나, 하나 이상의 폐엽에 다발성 작은 종양이 있어서 소절제술(lesserresection)이 필요한 경우 또는 아엽절제술이 계획된 경우에는 이 연

구 분석 결과가 의사들에게 쐐기 절제술을 계획하는데 도움을 줄 수 있을 것이다.

16 NEWS FROM THE COLLEGE D E C EMB E R 2 0 1 3 • C H E S T P H YS I C I A N

심부전 치료 중 수분과 염분 제한, 과연 옳은 것인가?Fluid, sodium restriction during heart failure questioned

BY DR . J U N CH I ONG ,

F C C P ; A N D KY L E T R I N I D A D

Acute decompensated heart fail-ure (ADHF) is traditionallymanaged by restricting fluid and

sodium intake. However, the benefit ofthis intervention is unclear and has not

been tested scientifically but has servedas a necessary procedure for patientshospitalized. Aliti and colleagues (JAMA

2013;173:1058) tested this hypothesis.The investigators randomly assignedthe subjects into a control group [CG](n = 37) that maintained a typical hos-

pital diet with liberal fluid and sodiumintake and an intervention group [IG](n = 38) that restricted fluid intake to800 mL per day and sodium intake to800 mg per day. Seventy-five patientswere observed during hospitalization;all of them had systolic dysfunctionwith a mean ejection fraction of 27%

and were similar in their baselinecharacteristics.Throughout their stay, the clinical

congestion score (CCS), bodyweight, B-type natriuretic peptide(BNP), and perceived thirst of eachpatient were measured and record-ed; IV drugs, including diuretics, va-sodilators, and inotropes, were alsorecorded. After hospitalization, pa-tients were followed up within 30days. There were no significant dif-ferences in weight loss in the CG(means of 82.4 kg +/– 12.8 kg) andIG (means of 78 kg +/– 12.6 kg) andclinical stability (CCS). In addition,as a secondary end point, perceivedthirst was more detrimental in theIG (5.1) compared with the CG(3.44), based on scores determinedby a visual analog scale; more pa-tients also had BNP levels over 700pg/mL in the IG. Furthermore, dur-ing follow-up, patients demonstrateda higher mean CCS (7.9) in the IGthan in the CG (6.0). No significantchanges in IV drugs were observedbetween the two groups. As a result,the authors concluded that fluid andsodium intake restrictions are notnecessary.

This study ex-plains that thereverse of thetraditional viewon sodium in-take is actuallytrue: an increasein sodium intakebenefits a pa-tient with HF.With the in-

crease of sodium in the intravascularlumen, osmosis diffuses extravascularfluid into the lumen, increasing thefluid volume and allowing for ade-quate diuresis. All in all, restriction offluid and sodium intake reveals aweak correlation with body weightloss and clinical stability.

Dr. Chiong is CEO, Hospital to HomeMedical Specialists, Inc.; and AssociateClinical Professor of Medicine, Pharmacyand Outcomes, Loma Linda University,Loma Linda, CA. Mr. Trinidad is a re-search assistant at Hospital to HomeMedical Specialists, Inc. The authors re-ported having no conflicts related to thematerial presented in this article.

급성 심부전은 전통적으로 수분과 염분 섭취를 제한하며 치료하였다. 하지만 급성심부전 환자를 대상으로 한 최근 연구에의하면 수분과 염분을 제한한 환자나 제한하지 않은 환자나 입원 30일 후 clinicalcongestion score, 체중, 주사 약물사용에 차이가 없었으며, B-type natriureticpeptide와 갈증 정도는 오히려 수분과 염분을 제한한 군에서 더 높았다. 이 결과는전통적인 관점을 뒤집는 것으로 혈관 내염분이 높아지면 혈관 밖의 수분을 혈관내로 끌어들이고 이로 인해 충분한 이뇨작용이 일어나기 때문인 것으로 보인다.

SUM

MAR

Y

DR. CHIONG

C H E S T P H YS I C I A N NEWS FROM THE COLLEGE 17

BY PAT R I C E WEND L I N G

IMNG MEDICAL NEWS

Measured levels of cardiorespi-ratory fitness appear to be aspredictive of cancer risk and

survival as they are of heart diseaserisk and survival, according to a 20-year, prospective study of more than17,000 men.The risks of lung and colo-rectal can-

cer were reduced 68% and 38%, respec-tively, in men with the highest level ofcardiorespiratory fitness, comparedwith those who were the least fit.Cardiorespiratory fitness did not sig-

nificantly reduce prostate cancer risk,but the risk of dying was significantlylower among men with prostate, lung,or colorectal cancer if they were morefit in middle age(P <.001). Prior studies

have shown thatbeing physicallyactive is protec-tive against can-cer, but this studyis unique becauseit looked at avery specificmarker – car-diorespiratory fitness as measured bymaximal exercise tolerance testing, Dr.Susan G. Lakoski said during a briefinghighlighting research at the upcomingAmerican Society of Clinical Oncologymeeting.“Fitness as formal measurement is

known to prevent cardiovascular dis-ease, and it’s also known that it helps interms of survival risk; but what hasn’tbeen known is, Does it prevent inci-dent cancer and mortality after cancerdiagnosis? That’s what’s elucidated inthe current study,” said Dr. Lakoski, di-rector of the cardiovascular prevention

program for cancer patients at the Uni-versity of Vermont, Burlington.She noted that several organizations,

including the President’s Council onFitness, Sports & Nutrition, are tryingto measure fitness formally and that theAmerican Heart Association has issuedpolicy statements that fitness should bemeasured and normative values devel-oped to determine cardiovascular risk. “Fitness is a formal measurement: It’s

sort of like measuring your LDL choles-terol; you get a very specific number totarget,” Dr. Lakoski said. “When youask someone about their physical activi-ty, you don’t get that information.”The 17,049 men in the study under-

went exercise tolerance testing with atreadmill or bicycle and risk factor as-sessment at an average age of 50 years

as part of theCooper CenterLongitudinalStudy in Dallas.Metabolic equiva-lents (METs)were used torecord the men’scardiorespiratoryfitness (CRF) andto place theminto five CRF

quintiles. Lung, colorectal, andprostate cancers were assessed usingMedicare claims data at Medicare age,and cause-specific mortality was deter-mined after cancer diagnosis.Over the 20 years of follow-up, 2,885

men were diagnosed with prostate,lung, or colorectal cancer, and 769 ofthem died.Compared with men in the lowest

CRF quintile, hazard ratios (HR) for in-cident lung, colorectal, and prostatecancer among men in the highest quin-tile were 0.32 (P < .001), 0.62 (P = .05),and 1.13 (P = .14), after researchers ad-

justed for such risk factors as smoking,body mass index, and age, Dr. Lakoskireported. In men who developed cancer, both

cancer-specific mortality and cardiovas-cular-specific mortality declined acrossincreasing CRF quintiles (P < .0001).Even a single MET increase reduced

the risk of dying from cancer and car-diovascular disease by 14% and 23%,respectively (HR, 0.86; HR, 0.77; P <.001 for both measures), Dr. Lakoskisaid.Another striking finding is that even

if men aren’t obese, they still have anincreased risk of cancer if they aren’tfit, “which suggests that everyone canbenefit from improving their fitness,”Dr. Sandra Swain, ASCO president andmedical director of the Washington

(D.C.) Cancer Institute, told reporters.“The findings make clear that pa-

tients should be advised that they needto achieve a certain fitness level, andnot just be told that they need to exer-cise,” Dr. Swain noted in a statement.“Fitness is a key risk factor for sur-

vival, and based on this study, an im-portant factor to measure to assess fu-ture cancer risk and prognosis in men,”Dr. Lakoski said in an interview.The study did not evaluate whether a

particular type of exercise contributedmore consistently to cardiovascular fit-ness, but in general, activities per-formed at high intensity, regardless oftype, are the best way to improve fit-ness, she said.More research is needed to deter-

mine fitness and cancer risk in women,and fitness and risk of all major site-spe-cific cancers, Dr. Lakoski observed. She reported having no relevant fi-

nancial disclosures.

[email protected]

심폐단련 운동수준이 암 발생 위험이나 사망률을 예측할 수 있는 것으로 나타났으며,최고 수준의 심폐단련이 된 남성에서는 신체단련이 가장 저조한 남성에 비해서 폐암은

68%, 대장직장암은 38% 감소하였다. 폐암, 대장직장암, 전립선암이 있는 남성이 중년에 신체단련이 잘 되어 있으면 사망위험을 감소시키는 것으로 나타났다.SU

MM

ARY

COURTESYCOOPERCLINIC

The risk of lung cancer was reduced 68% in men with the highest level ofcardiorespiratory fitness, a large study suggests.

Fitness levels may predict cancer risk신체단련 수준으로 암 발생 위험을 예측할 수도

A single METincrease reducedthe risk of dyingfrom cancer by14% in the studyof more than17,000 men.

DR. LAKOSKI

V I E W O N T H E N E W SDr. Darcy D. Marciniuk, FCCP,comments: 20년간의 추적 관찰 연구를통해 남성에서 높은 수준의 체력단련으로 폐암에 대한 보정 위험도를 68% 감소시켰으며,대장직장암의 발병률도 38% 감소시켰다. 특히,두가지 암에서 일관되게 사망률을 감소시킨 결과는 매우 인상적이다. 만일 이런 결과가 공식적으로 기술된 심폐운동검사로 실험하여 얻어졌다면,기사 1면을 장식하였을 것이다. 모든의사들은열심히 체력단련을 하고,능동적으로 환자들에게 똑같이 할 수 있도록 해야 한다. 다 같이 생명을구해봅시다!(Let’savesome lives!)

18 CASE FORUM D E C EMB E R 2 0 1 3 • C H E S T P H YS I C I A N

COPD 환자에서 DAXAS 투여 증례

김덕겸 교수서울대학교보라매병원 호흡기내과

증례74세 남자 환자로 30대 중반에 폐결핵으로 치료 받은 병력이있는 15갑년의 흡연력이 있는 과거 흡연자이다. 체중은 59 kg,키는 160 cm였다. 환자는 50대 초반부터 경도의 호흡곤란이발생하였고(mMRC 1), 상기도 감염 후 증상 악화로 외부 병원에서 천식으로 진단 후 치료를 간헐적으로 해오고 있었다.동반질환으로는 20년 전부터 진단된 당뇨가 있었으며, 경구혈당 강하제를 복용하고 있었다. 그림 1의 흉부 사진상 좌상부에 경도의 과거 결핵 반흔이 관찰되며, CT상 폐기종은 저명하지 않은 상태이다.2년 전 본원 내원 당시 속효성기관지확장제 사용 후 시행한

시행한 폐기능 검사(그림 2A) 상에서 FEV1/FVC 0.50%, FEV10.72 L 정상예측치의 32%, FVC 1.45L, 정상예측치의 44%이며,기관지확장제 반응없는 폐쇄성과 제한성 환기장애가 혼합된 형태로 나타났으나, 폐용적 검사에서 잔기용량(RV) 306%로 증가되어있고, 흡기용량(IC)이 16%로 감소되어 있고, 전폐용적(TLC)는161%로 제한성 장애보다는 심한 폐쇄성 환기 장애로 인해 air-trapping으로 인한 폐의 과팽창(hyperinflation)소견이 확인되었다. 당시 호흡곤란 정도는 mMRC 3 정도였다.환자는 지속성 기관지확장제인 tiotropium 1puff qd과 흡입형

스테로이드/지속성 베타항진제 복합제인 fluticasone/sameterol500ug 1 puff bid 로 치료를 시작하였고, 교육을 통하여 약제순응도를 증가시켜서 꾸준한 흡입제 사용을 하고 있었다. 1년전 시행한 폐기능 검사 소견(그림 2B)에서 FEV1/FVC 0.47%,FEV1 1.04 L 정상예측치의 47%, FVC 2.35 L, 정상예측치의72%이고, RV 104%으로 이전의 과팽창 소견은 호전되었으나폐기능이 정상까지 회복되지 못하는 소견을 나타냈었다. 호흡곤란정도는 mMRC 2 정도로 호전되었으나 만성적인 객담과 함께환자는 1년에 1회 입원 및 2회의 중증 급성 악화로 외래를 방문하여 전신 스테로이드를 처방 받았으며, 체중은 65 kg까지 증가되었고, 당 조절도 불량하여 인슐린 치료를 시작하였다(그림 3

임상 경과요약 참조).기존 약제 치료로도 해결되지 않는 지속적인 호흡곤란 및 잦은

급성 악화로 인하여 2013년 3월부터 roflumilast 500ug qd를투여하였으며, 이 시점에서 인슐린 치료 중이었으며, HbA1c8.5%, 체중 64 kg였으며, 지방간 및 지질 이상증도 동반되었다.Roflumilast 투여 후 환자는 체중 감소 이외의 특이 부작용 없

이 규칙적으로 흡입제 치료와 함께 약물 복용하였다. 2013년 3월 이후로 현재까지 급성 악화없이 외래 추적 중이며, 가장 최근시행한 폐기능 검사 결과(그림2C)에서 관찰하듯이, FEV1/FVC 43%,FEV1 1.15L 53%, FVC 2.65, 82%로 호전된 상황이며, 체중은57kg까지 감량되었으며, 주관적인 호흡곤란 감소 증상은 폐기능검사 소견보다 더 두드러져 mMRC 1으로 회복되었으며, HbA1c6.5%까지 호전되어 경구 혈당 강하제로 변경하여 유지 중이다.

고찰본 증례는 기존의 기관지확장제 및 흡입형 스테로이드로 적극적인 치료에도 불구하고 중증 급성악화가 자주 발생하여 심각하게 삶의 질이 저하된 만성 폐쇄성 폐질환(COPD) 환자이다.호흡곤란과 더불어 만성적인 기침 및 객담이 동반된 만성 기관지염의 임상 양상을 나타냈으며, phosphodiesterase4 (PDE4)억제제인 Daxas(roflumilast)를 사용하여 임상적인 호전을 나

타내었던 사례로 동반질환으로 당뇨, 과체중, 지질이상증등이 있었다.COPD 치료의 근간인 기관

지확장제와 항염증치료제 중에서 항염증 치료 효과를 기대할 수 있는 약물은 스테로이드 제제로 흡입스테로이제와 전신스테로이제가 있으며,장기적인 위험요소 (급성악화나 폐기능 저하)를 줄이기 위해서 사용하는 경향이 있다.COPD의 병태생리적인 면에서 접근하면 만성적인 기도내염증이주된 요인이므로 장기적으로 항염증작용 약물이 효과를 보일 것으로 기대하나,

현재까지의 약물들은 아직도임상의사들이 기대하는 치료효과에 미치지 못하는 현실이다. Daxas(roflumilast)는 선택

적인 PDE4 억제제로서 항염증 효과를 작용기전으로 하는새로운 약제이다. 새로운 항염증제제로서 장기적인 효과인 급성악화 빈도의 감소를기대하는 약물이지만, 초기임상연구에서 폐기능 개선 효과도 보고되었고, 최근에는삶의 질 개선 효과도 밝혀졌다. 급성악화빈도의 감소측면에서 중증(FEV1 정상예측치의50% 미만) COPD 중 특히,지속적인 기침과 가래를 주증상으로 하는 만성기관지염 임상

형에서 도움을 줄 수 있는 것으로 알려져 있다. 본 증례의 경우도 내원 당시 mMRC 호흡곤란지수(Modified

Medical Research Council Dyspnea Scale)가 2점으로 평지에서는 걷는데 무리가 없으나 언덕이나 비탈길에서는 호흡곤란으로 고생하였고, 호흡곤란 외에도 객담 및 기침이 만성적으로지속되는 만성기관지염 임상상을 갖는 환자였다. 지난 1년간 입원이나 응급실 방문을 필요로 한 중증 급성 악화 1회를 포함하여급성 악화가 3회 있었던 고위험군으로 GOLD의 새분류 D군이며,국내 치료 지침 다군에 속한다(국내 COPD 진료지침 앱 참조).흉부단층촬영 소견에서 폐기종의 증거가 뚜렷하지 않은 상황에서폐기능 저하 소견이 관찰되며, 이로 인한 잦은 급성 악화를 경험하였으나, PDE4 억제제 투여 후 급성 악화 빈도가 감소하여투약 이후 급성 악화 병력이 없이 지내고 있으며, 객담양도 유의하게 호전된 예이다. COPD 환자는 폐기능 저하로 인한 호흡곤란 등 호흡기 증상

이외에도 다양한 복합질환을 동반하는 특성이 있다. COPD가만성 전신성 질환으로 간주되는 근거 중의 하나로 심혈관계, 내분비계, 근골격계, 혈액학적 질환 등 다양한 질환이 병발 또는호발하여 환자 평가 시에 유의하여야 한다. 본 증례도 복합질환으로 당뇨가 있었으며, 과체중으로 호흡곤란 증상이 더 악화되었던 예였다. Roflumilast가 작용하는 PDE4 수용체는 호흡기계 뿐만 아니라 소화기계 및 신경계에도 분포하여 다양한 이상반응을 초래하기도 한다. 그 중 대표적인 증상의 하나가 체중감소이며, 임상시험 환자군에서는 8.4~12.0%에서 발생하였다.평균 약 2kg 내외의 감량이 일어나나, BMI가 클수록 더 두드러지며, 제지방체중(fat free mass)는 비교적 유지되는 특징이있으나 중증의 저체중 환자에서도 발생할 수 있어 주의를 요한다.본 증례의 경우도 치료 시작 후 지속적인 체중 감소가 있었으나 정점에 이른 뒤 더 이상의 감소는 없이 유지되고 있다. 체중감소에 따른 BMI 감소는 일부 환자, 특히, 비만이나 과체중이동반되거나 당뇨가 있는 본 증례와 같은 경우에는 환자에 바람직한 결과로 나타날 수 있다. 또한, 최근에는 COPD가 없는 제2형 당뇨병 환자에서 daxas를 투여한 무작위 대조군 연구에서위약군에 비하여 HbA1c를 평균 0.45% 감소시키는 효과를 나타내었다. 본 증례의 경우 초기 내원 당시 당뇨 조절 정도는 매우불량하여 HbA1c 8.5~9.6 %이었으나 COPD 악화 조절을 위한roflumilast 투여 후 부수적으로 당조절도 잘 되어 HbA1c

그림 1. Chest X-ray/chest CT

그림 3. 임상 경과 요약

그림 2. 폐기능 검사 소견


C H E S T P H YS I C I A N CASE FORUM 19

6.5~7.5%로 감소되어 인슐린 치료를 중단할 수 있게 되는 이득을얻었다. 중증 COPD환자에서 급성 악화를 줄여 이에 따른 위험성을

줄이고, 삶의 질을 개선하는 목적으로 새로운 경구 항염증치료제인 roflumilast를 투여해 볼 수 있으며, 특히 본 증례와 같이만성기관지염이 주증상인 경우가 주 대상이지만, roflumilast의다양한 부수효과, 특히, 체지방 감소나 당대사에 미치는 영향 등을고려할 때, 일부 COPD와 동반질환으로 과체중이나 당뇨 등의질환이 있는 경우에 roflumilast 치료를 적극적으로 고려해 볼

수 있을 것이다.

참고문헌1. 대한결핵 및 호흡기학회 COPD진료지침개정위원회, COPD 진료지침 2012

개정. 2012;29-372. Global Initiative for Chronic Obstructive Pulmonary Disease

(GOLD). Global Strategy for The Diagnosis, Management andPrevent of Chronic Obstructive Pulmonary Disease (Revised 2011)[Internet]. (accessed 22 Feb 2012) Available from:http://www.gold-copd.org.

3. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM,Martinez FJ; M2-124 and M2-125 study groups. Roflumilast insymptomatic chronic obstructive pulmonary disease: two ran-

domised clinical trials. Lancet. 2009 Aug 29;374(9691):685-94.4. Rennard SI, Calverley PM, Goehring UM, Bredenbroker D,

Marinez FJ. Reduction of exacerbations by the PDE4 inhibitorroflumilast - the importance of defining different subsets of pa-tients with COPD Respiratory Research 2011,12:18

5. Wouters EFM, Brendenbroker D, Teichmann P, Brose M, RabeKF, Fabbri LM, Goke B. Effect of the phosphodiesterase 4inhibitor roflumilast on glucose metabolism in patients withtreatment-naïve, newly diagnosed type 2 diabetes mellitus. JClin Endocrinol Metab 2012. 9799):E1720-E1725.

6. Vollert S, Kaessner N, Heuser A, Hanauer G, Dieckmann A,Knaack D, Kley HP, Beume R, Weiss-Haljiti C. The glucose-low-ering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice. Diabetologia. 2012 Oct;55(10):2779-88.

차이코프스키 <현을 위한 세레나데> C장조, 작품번호 48Pyotr Ilich Tchaikovsky <Serenade for Strings> C major, Op.48

오재원 교수한양대학교구리병원 소아청소년과

차이코프스키는 젊은 시절 자주 서구 유럽을 방문하면서 바로크의 모음곡 양식과 고전주의 음악의 간결하고 명쾌한 음악기법에 심취하기도 하였다. 특히 이 작품을 쓸 무렵 모차르트에대해 애정과 존경심을 가지고 있었다. 그에 대한 애착으로 모차르트의 세레나데 <아이네 클라이네 뮤직>을 모델로 하여 세레나데를 피아노곡으로 작곡하였으나 얼마 지나지 않아 현악 합주용으로 좀 더 풍성하고 다양한 색채로 편곡하였다. 당시 향토색이짙은 다른 러시아 작곡가와 달리 차이코프스키만의 서유럽악풍과 슬래브적인 분위기가 잘 섞인 뛰어난 작곡기법으로 다양한정서를 살렸고 형식과 하모니가 훌륭하게 구축된 고전미 넘친작품을 남기게 된다. <현을 위한 세레나데>는 서정적이고 우아한 선율이 담긴 전형

적인 세레나데 곡으로 차이코프스키의 은인이자 모스크바 음악원장인 니콜라이 루빈스타인도 완성도 높은 작품이라고 극찬하

였다. 이 작품에서는 일반적으로 가벼운 세레나데와는 달리 전4악장으로 진중한 선율과 깊은 서정적인 분위기는 차이코프스키의 성격을 잘 표현하고 있다. 성격상 그의 음악에는 항상 깊은애수와 어두운 면이 감돌고 있다. 때로는 몽상적이고 서정적인정열을 겸해 극히 세련되었고 비교적 러시아적 체취가 적어작곡가의 서구적 일면을 대표하는 곡이기도 하다.

이탈리아어로 저녁을 뜻하는 ‘sera’와 옥외에서란 뜻의 ‘alsereno’에 그 어원을 둔 ‘세레나데’는 기악과 성악 모두에 적용되는 음악양식이다. 이런 배경으로 ‘세레나데’는 원래 어둠이 깔리고 난 후 연인의 창가에서 부드럽고 감미롭게 불렀던 로맨틱한 연가이었다. 시간이 흐르면서 가사가 없는 관현악 작품의 제목에도 사용되었는데, 서정적이면서 우아한 선율들을 포함하고있는 것이 공통점이라 할 수 있을 것이다. ‘현을 위한 세레나데’는 차이코프스키 외에도 모차르트, 엘가, 드보르작, 등 여러 작곡가의 작품이 있다. 1880년 겨울에 완성한 <현을 위한 세레나데>에서 각 악장마다

차이코프스키의 특징들을 고스란히 간직하고 있다. 전 4악장 구성이며 유명한 제2악장의 왈츠, 차이코프스키다운 우수를 느끼게 하는 제3악장의 엘레지, <러시아 주제에 의한 변주곡> 의 제4악장이 여기에 포함되어 있다. 이 작품은 현악 4중주곡에 콘트라베이스를 첨가한 현악 5성부의 작품이다. 평소 자신의 작품들에 대해 확신을 가지지 못했던 차이코프스키가 그의 절대적인 후원자인 폰 메크 부인에게 보낸 편지에서 “내 마음속에 자리 잡고 있는 확신이 일러주는 대로 ‘세레나데’를 작곡했습니다.

이 작품은 나의 진심에서 우러나온 진솔한 감성들을 모두 담고있으며, 음악적으로도 매우 뛰어난 완성도를 갖추고 있다고 감히 말하고 싶습니다.”라며 확신을 가지고 작곡했다는 강한 표현을 쓸 정도로 그 스스로 마음에 흡족해 했던 작품이다. 제1악장 Pezzo in forma di Sonatina - Andante non troppo- Allegro moderato 아주 소박하면서도 기품 넘치는 선율을현의 유니즌으로 시작하는데, 이 주제가 점점 발전되면서 드라마틱한 변화들을 일구어내고 있다. 차이코프스키만의 극적인 멜로디, 선명하고 정제된 현의 향연, 지극히 서정적이고 우아함의극치를 달린다.제2악장 Waltz: Moderato, tempo di valse 우아한 백조처럼왈츠를 추는 발레리나의 모습이 연상된다. 발레보다 더 역동적인리듬과 아름다운 왈츠풍의 리듬이 감미롭고 흥겨워진다.제3악장 Elegie: Larghetto elegiaco 슬래브의 정취가 듬뿍묻어나는 무뚝뚝한 토속 선율에 모차르트시대의 음악의 화려함을덧씌워 차이코프스키 특유의 ‘찬란한 슬픔’을 잘 표현하고 있다.그러면서도 ‘비가’를 노래한 악곡으로 그에 걸맞게 아름답고 슬픈곡의 느낌이다.제4악장 Finale: (Tema russo): Andante - Allegro con spirito두 개의 민요 선율이 주제를 이루고 있고, 첫 악장에서 들려주었던 주제를 마지막 악장의 두 번째 주제로 사용함으로써 전체적인 통일성을 강조하는 한편, 장대하면서도 우아한 코다를 강조하고 있다. 비탄에 잠겼지만 이내 환희와 희열을 맛보는 듯한화려한 음색으로 발전하며 마지막을 장식한다.

들을만한 음반

헤르베르트 폰 카라얀(지휘), 베를린 필하모닉 오케스트라

(DG, 1980)

게오르규 솔티(지휘), 이스라엘 필하모닉 오케스트라

(Decca, 1958)

오르페우스 쳄버 오케스트라(DG, 1986)

콜린 데이비스(지휘), 바이에른 방송 오케스트라

(Philips, 1986)

음악칼럼


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