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1 pissn: eissn: (3): , May ORIGINAL ARTICLE 소아급성호흡곤란증후군에서체외순환막장치적용에대한 RESP, PRESERVE, ECMOnet 점수체계의유용성 안원기, 한정호, 김윤희, 설인숙, 윤서희, 김민정, 김경원, 손명현, 김규언 연세대학교의과대학소아과학교실 Usefulness of the RESP, PRESERVE, and ECMOnet scores for extracorporeal membrane oxygenation in children with acute respiratory distress syndrome Won Kee Ahn, Jung Ho Han, Yoon Hee Kim, In Suk Sol, Seo Hee Yoon, Min Jung Kim, Kyung Won Kim, Myung Hyun Sohn, Kyu-Earn Kim Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea Purpose: With increasing use of extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) in children, development of standardized strategies for survival prediction has become crucial; however, this has not been accomplished yet. We evaluated the adult scoring systems for survival prediction used for their applicability in pediatric ARDS and validated them. Methods: A total of 11 children with ARDS receiving ECMO from 2013 to 2014 were evaluated with adult scoring systems, including the Respiratory Extracorporeal-membrane-oxygenation Survival Prediction (RESP), the PRedicting death for SEvere ARDS on VV- ECMO (PRESERVE), and the ECMOnet scores. We compared the scores on these scales and the clinical characteristics between survivors and nonsurvivors. Results: Eight of the 11 children died (72.7%). The PRESERVE score (survivors vs. nonsurvivors: 2 vs. 5.25, P= 0.048), and the ECMOnet score (4.1 vs. 5.63, P= 0.048) were lower in survivors than in nonsurvivors. They correctly predicted mortality prediction. There was no significant difference in the RESP score between survivors and non-survivors (-4.33 vs , P = 0.63). The parameters that showed significant differences in this study were peak inspiratory pressure, platelet, and delta neutrophil index. All children who were under immunocompromised conditions, such as those with tumors, or underwent hematopoietic stem cell transplantation died. The immunocompromised status should be considered an important factor for survival prediction in children with ARDS. Conclusion: This is the first pilot study to apply the survival prediction scoring system to pediatric ARDS with ECMO. It is necessary to establish and modify the survival prediction score system for pediatric ARDS with ECMO. ( 2017;5: ) Keywords: Extracorporeal membrane oxygenation, Acute respiratory distress syndrome, Survival, Child 서론 급성호흡곤란증후군 (acute respiratory distress syndrome, ARDS) 은약 60% 이상의높은사망률을보이고, 1-3 장기적으로육 체적기능장애를유발할수있는폐질환이다. 4-6 기계환기로가스 교환이유지되지않는중증급성호흡곤란증후군에서체외막산소 Correspondence to: Kyung Won Kim Department of Pediatrics, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: , Fax: , KWKIM@yuhs.ac Received: September 5, 2016 Revised: October 24, 2016 Accepted: December 15, 2016 공급장치 (extracorporeal membrane oxygenation, ECMO) 는기계 환기로인한폐손상을막고, 효과적인산소와이산화탄소의가스 교환을위한고도의침습적치료요법으로대두되고있다. 1,2, 년대이전에는급성호흡곤란증후군에서체외막산소공급 장치를이용한치료가좋은성적을거두지못한다고보고되었다. 10 그러나체외막산소공급장치의회로와기계가발전하면서, 급성호 2017 The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (

2 Ahn WK, et al. Score systems for pediatric ARDS with ECMO 흡곤란증후군환자에게보다더생체적합하고, 합병증을최소화하는형태로발전하고있다. CESAR (conventional ventilator support versus extracorporeal membrane oxygenation for severe adult respiratory failure) 연구에서는중등도의성인급성호흡부전에서체외막산소공급장치를적용했을경우가기존의고식적기계환기만으로치료했을경우보다사망률을유의하게낮춘다고보고하였다. 11,12 급성호흡곤란증후군의체외막산소공급장치의사용이증가함에따라체외막산소공급장치적용전에환자의예후를평가하는것이중요해지고있다. 성인급성호흡곤란증후군에서체외막산소공급장치를적용했을때, 생존율을예측하는점수체계에는 EC- MOnet, PRedicting death for SEvere ARDS on VV-ECMO (PRE- SERVE), Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) 등이있다. 모든점수체계는개별항목마다부여되는점수가있고, 그총합계점수를계산하여사망률을예측하는방식이다 ECMOnet은 H1N1 독감으로인한성인급성호흡곤란증후군환자를대상으로이루어진전향적다기관연구를통하여, 체외막순환장치를적용하기전재원기간, 빌리루빈 (bilirubin), 크레아티닌 (creatinine), 적혈구용적률 (hematocrit), 평균동맥압 (mean arterial pressure) 의항목으로구성되며, 사망률을예측하기위한결정점수치 (cut-off value) 를설정한점수체계이다. PRESERVE는나이, 신체질량지수 (body mass index), 면역저하상태, sequential organ failure assessment (SOFA), 체외막산소공급장치를적용하기전기계환기기간, 복와위, 호기말양압 (positive end-expiratory pressure), 고평부압 (plateau pressure) 으로구성되며, 합계점수는 4단계로분류되어낮은점수일수록높은생존율과높은삶의질을나타내는체계이다. RESP는 2천여명의대규모연구를통해나이, 면역저하상태, 체외막산소공급장치적용전의기계환기기간, 급성호흡부전의원인질환, 중추신경계손상, 폐이외의급성감염, 신경근억제제나산화질소사용여부, 중탄산염사용여부, 심정지여부, 동맥혈탄산가스분압, 최고흡기압 (peak inspiratory pressure) 등의 12가지항목으로구성되며, 합계점수는 5단계로분류되어점수가높을수록높은생존율을나타내는점수체계이다 성인과소아급성호흡곤란증후군은기저질환, 역학및예후의차이를보이고있으나, 7,17 소아급성호흡곤란증후군의기계환기전략을포함한대부분의치료는성인의치료에기반을두고있는실정이다. 7-9,18-23 소아급성호흡곤란증후군에서도체외막산소공급장치적용이증가하고있지만, 그적응증과생존율을예측하는점수체계에대한연구는아직없다. 이에저자들은이를위한파일럿연구로, 성인급성호흡곤란증후군의체외막산소공급장치적용에대한생존율예측점수체계를소아에서적용하여, 그유용성을평가하고자하였다. 대상및방법 1. 대상 2013년 3월부터 2014년 10월까지세브란스병원내과계중환자실에입실한생후 1개월에서 18세미만의중환자실입실환자는 205 명이었으며, 그중급성호흡곤란증후군환자가 44명이었고, 17 고식적치료에도중증의저산소혈증이지속되어체외막산소공급장치를적용한 11명을대상으로하였다. 기저질환을포함한보존적요법외에시행된고식적치료에는기계환기, 산화질소, 복와위, 전신스테로이드요법이포함되었다. 7 모든대상은중환자실에서의사망여부에따라생존군과사망군으로분류하였다. 출생 1개월미만의신생아나심장혈관질환과외과계중환자는이번연구에서제외되었다. 이번연구의자료수집당시에중환자실에서퇴실하지않았거나다른병원중환자실로전원한경우도제외하였다. 이연구는세브란스병원임상시험윤리위원회의심의를거쳐모든환아들의의무기록을후향적으로조사하였다 ( 승인번호 : ). 2. 자료수집과통계분석대상군 11명에대하여체외막산소공급장치를시작하기직전의나이, 성별, 급성호흡곤란증후군의주요원인질환, 기계호흡치료기간등의임상정보와치료인자들을수집하였다. 이자료를성인의급성호흡곤란증후군의점수체계인 RESP, PRESERVE, EC- MOnet 점수에적용하였다 사망과생존두군에서연속형변수를비교할때 Mann-Whitney test를시행하였고, 범주형변수를비교할때는 Fisher exact test를시행하였다. 모든통계분석은 IBM SPSS Statistics ver (IBM Co., Armonk, NY, USA) 를이용하였으며, P 값이 0.05 미만인경우를통계적으로유의한것으로판단하였다. 결과대상환아 11명중생존군은 3명 (27.3%) 이고, 사망군은 8명 (72.7%) 이었다. 생존군과사망군간에나이, 성별은통계적으로의미있는차이를보이지않았으며, 나이의중간값은 4.6세, 그중남자는 63% 였다. 급성호흡곤란증후군의원인질환으로바이러스성폐렴 ( 독감및메타뉴모바이러스 ) 이 4예 (36%), 세균성폐렴, 흡인성폐렴, 천식발작이각각 1예 (9%) 로감염성폐렴이가장주된원인이었다. 대상자의기저질환중에서뇌종양, 혈액암, 조혈모세포이식상태와같은면역기능저하상태가 5예 (45%) 에서동반되었고, 이환자들은모두사망하였다. 중추신경계이상이 6예 (55%) 에서있었고, 저산소성뇌병증, 간질성뇌병증등이포함되어있었다. 2예 (18%) 에서체외막산소공급장치를적용하기전에심정지가발생하 142

3 안원기외 소아급성호흡곤란증후군에서체외순환막장치적용에대한점수체계 Table 1. Clinical characteristics between the survivors and nonsurvivors Characteristic All patients (n= 11) Survival Survivors (n= 3) Nonsurvivors (n= 8) Age (yr) 4.8 ( ) 1.9 ( ) 5.8 ( ) Male sex 7 (63) 2 (66) 5 (63) Body mass index (kg/m 2 ) 15.5 ( ) 15.2 ( ) 15.4 ( ) Main causes of ARDS Bacterial pneumonia 1 (9) 0 (0) 1 (13) Viral pneumonia 4 (36) 1 (33) 3 (38) Aspiration pneumonitis 1 (9) 1 (33) 0 (0) Asthma 1 (9) 0 (0) 1 (13) Others 4 (36) 1 (33) 3 (38) Underlying disease Immunocompromised 5 (45) 0 (0) 5 (62) CNS dysfunction 6 (55) 3 (100) 3 (38) Bacterial sepsis 1 (9) 0 (0) 1 (13) Nonpulmonary infection 7 (64) 1 (33) 6 (75) Mean arterial pressure 56.5 (34 90) 49 (34 71) 59.3 (35 90) Cardiac arrest 7 (64) 2 (67) 5 (63) Laboratory data WBC (/μl) 12,948 (390 32,100) 15,613 (5,640 27,950) 11,949 (390 32,100) Platelet ( 10 3 /μl)* 164 (23 555) 332 ( ) 101 (23 269) Delta neutrophil count (%)* 12.6 (0 47.1) 1.1 (0 3.2) 17.0 ( ) Bilirubin (mg/dl) 10.8 ( ) 0.2 ( ) 1.4 ( ) Creatinine (mg/dl) 0.46 ( ) 0.24 ( ) 0.55 ( ) Hematocrit (%) 27.9 (17 36) 33.0 ( ) 26.0 ( ) Values are presented as median (interquartile range) or number (%). ARDS, acute respiratory distress syndrome; CNS, central nervous system; WBC, white blood cell. *P< 0.05 survivors vs. nonsurvivors. Others are postpneumonectomy syndrome, pulmonary hemorrhage and 2 cases of lung graft-versus-host disease. Nonpulmonary infection is defined as another fungal, bacterial or viral infection confirmed through blood sample that did not involve the lung. 였고, 5예 (45%) 에서체외막산소공급장치적용시술중에심정지가발생하였다 (Table 1). 사망률을예측하기위한체계인 ECMOnet 점수는생존군 4.5, 사망군 5.5 (P = 0.048) 로생존군에서사망군보다더낮은값을보였으나 (Table 2), 13 체외막산소공급장치를적용하기전재원기간, 빌리루빈, 크레아티닌, 적혈구용적률, 평균동맥압등의개별항목에대하여는생존군과사망군사이에차이가없었다 (Table 3). 낮을수록높은생존율을갖는 PRESERVE 점수는생존군 2, 사망군 5.25 (P = 0.048) 로생존군에서의미있게낮았고 (Table 2), 14 PRE- SERVE 점수의개별항목인면역저하, 체외막산소공급장치를적용하기전기계환기만으로치료한기간, 호기말양압과패혈증과관련된장기부전정도 (SOFA 점수 ), 복와위자세등에서생존군과사망군간의차이를보이지않았다 (Table 3). 높을수록더높은생존율을보이는 RESP 점수는생존군 -4.33, 사망군 (P = 0.63) 로의미있는차이는보이지않았다 (Table 2). 15 체외막산소공급장치를적용할당시신경근차단제사용이 73%, 복와위 18%, 전신적스테로이드사용이 100% 였다. 체외막산소공급장치는기계환기를적용한시점부터 0.96 ( ) 일후시행되었으며, 체외막산소공급장치를적용하기직전기계환기설정중호기말양압은 9.36 (5 15) cmh 2O, 최고흡기압은 (19-40) cmh 2O였다. 동맥혈가스분석검사상높은동맥혈탄산가스분압 (PaCO 2, [22 90] mmhg) 및높은산소포화도지수 (oxygen saturation index) ( ) 을보였고, 체외막산소공급장치의적용기간은 (4 40) 일이었다. 각점수체계의개별항목중생존군과사망군사이에유의미한차이를보인항목을살펴보면, PRESERVE 점수의최고흡기압과호기말양압이사망군에서높게나타났고, RESP 점수의체외막산소공급장치를적용하기전기계환기의기간, 최고흡기압이사망군에서더높았다. 기존점수체계의항목들외에혈소판 ( 생존군대사망군, 332,000 대 101,000, P = 0.048) 이사망군에서더낮았고, 델타호중구지수 ( 생존군대사망군 1.06 대 16.96, P = 0.048) 가더높았다 (Table 3)

4 Ahn WK, et al. Score systems for pediatric ARDS with ECMO Table 2. Comparison of the scoring systems between survivors and nonsurvivors Score All patients (n= 11) Survival Survivors (n= 3) Nonsurvivors (n= 8) ECMOnet score* 5.5 ( ) 4.5 (2.8 5) 5.5 ( ) PRESERVE score* 4.4 (0 8) 2 (0 3) 5.3 (3 8) RESP score -3.1 (-8 to 4) -4.3 (-6 to -2) -2.6 (-8 to 4) Values are presented as median (interquartile range). ECMO, extracorporeal membrane oxygenation; PRESERVE score, PRedicting death for SEvere score; RESP score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction score. *P< 0.05 survivors vs. nonsurvivors Table 3. Comparison of each item for the PRESERVE, RESP, ECMOnet scores between survivors and nonsurvivors Variable All patients (n= 11) Pre-ECMO rescue therapy Survival Survivors (n= 3) Non-survivors (n= 8) NM blockade agents 8 (73) 3 (100) 5 (63) Prone position 2 (18) 1 (33) 1 (13) Systemic steroids 11 (100) 3 (100) 8 (100) Bicarbonate infusion 11 (100) 3 (100) 8 (100) Interval MV-ECMO (day) 1.0 ( ) 0.3 ( ) 0.8 ( ) Pre-ECMO ventilator settings PaO2 /FiO (40 232) ( ) (40 256) FiO2 0.9 ( ) 0.9 ( ) 0.9 ( ) PIP (cmh2o)* 32.1 (19 40) 25.7 (19 30) 34.5 (26 40) MAP (cmh2o) 16.7 ( ) 13.0 ( ) 11.7 ( ) PEEP (cmh2o) 9 (5 15) 6 (5 10) 10 (5 15) Pre-ECMO Gas study PaCO2 (mmhg) 56.1 (22 90) 43 (22 67) 61 (28 90) PaO2 (mmhg) 97 (40 232) 132 (69 232) 85 (40 128) Oxygenation index 17.8 (4.0 53) 13.7 ( ) 24.2 (6 53) Oxygen saturation index 19.0 (8 28.3) 15.3 ( ) 13.0 ( ) Duration of ECMO support (day) 12.2 (4 40) 7.7 (6 10) 18 (4 40) Values are presented as number (%) or median (interquartile range). PRESERVE score, PRedicting death for SEvere score; RESP score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction score; ECMO, extracorporeal membrane oxygenation; NM blockade, neuromuscular blockade; Interval MV-ECMO, duration of mechanical ventiliation before extracorporeal membrane oxygenation; PIP, peak inspiratory pressure; MAP, mean airway pressure; PEEP, positive end-expiratory pressure. *P< 0.05 survivors vs. nonsurvivors. 고찰이번연구는체외막산소공급장치를적용한소아급성호흡곤란증후군환자의생존율예측을성인의점수체계에적용하고, 그유용성을분석한첫파일럿연구이다. 사망군에서 ECMOnet과 PRE- SERVE 점수는높았고, RESP 점수는의미있는차이를보이지않았다 기저질환으로면역저하상태를보이는대상자들은모두사망하였으며, 중추신경계기능이상을보이는대상자는 50% 의생존율을보였다. 기존의예후와관련된점수체계의항목들외에델타호중구지수, 혈소판수치등의패혈증과관련된지표가생존군과사망군에서의미있는차이를보였다. 24 ECMOnet은 60명의 A형독감 (H1N1) 과관련된성인급성호흡곤란증후군환자를대상으로이루어진연구를통해서체외막순환장치적용에대한사망률을예측하는점수체계로총점수가높을수록더높은사망률을보인다. 13 이번연구의대상자들에서는 EC- MOnet 점수의개별항목에서생존군과사망군간에의미있는차이를확인하지못하였으나, 총합에서사망군이더높은값을보여소아사망률예측에도유용함을확인하였다. 이점수체계의항목들은다양한장기부전에대한항목으로구성되며, 이연구결과를바탕으로전반적인장기부전이진행되면체외막산소공급장치의적용이생존율을개선시키지못함을확인할수있었다. 그러나 ECMOnet은급성호흡곤란증후군의원인질환과환자의기저질환 144

5 안원기외 소아급성호흡곤란증후군에서체외순환막장치적용에대한점수체계 에대하여고려하지않고있다. 소아에서면역저하상태및기저질환의중증도가생존에중요한인자로보여, ECMOnet을소아급성호흡곤란증후군환자에직접적으로적용하는데한계가있는것으로보인다. PRESERVE는성인호흡곤란증후군환자 140명을대상으로, 체외막산소공급장치를적용한시점부터 6개월이경과되었을때의삶의질및사망률을예측한점수체계로, 높은점수일수록사망률이더높다. 14 이번연구에서도사망군에서유의하게 PRESERVE 점수가높았다. 그러나 PRESERVE 점수에있는나이에대한항목은 18 세가기준으로소아청소년을대상으로할때유효하지않은항목으로적용할수없었다. 체질량지수가높을수록좋은예후를보이나, 이번연구에서는생존군과사망군사이에의미있는결과를얻지못하였으며, 전체대상자의체질량지수의편차가적어이연구에서체질량지수항목을비교하는것은한계가있었다. 체외막산소공급장치적용전기계환기기간의경우, 사망군에서기계환기의기간이길었으나, 기간의편차가커서두군간에통계적으로의미있는차이를보이지않았지만뚜렷한경향을확인할수있었다. 이는적은모집단으로인해통계학적효용성을확인할수없었지만, 대규모연구가필요한부분이다. RESP는 2,355명의체외막산소공급장치를적용한성인중증급성호흡곤란증후군환자들을대상으로한대규모연구를통하여체외막산소공급장치를적용하기직전의변수들을회귀분석을통해생존율을예측한점수체계이며, 점수가높을수록더좋은생존율을보인다. 15 면역저하상태는비교적높은개별점수를갖지만, 이번연구에서면역저하상태를보인대상자들은모두사망하였고, 그대상자들은모두낮은 RESP 총합점수를보였다. 또한 RESP 점수에서중추신경계기능이상은가장낮은개별점수를갖지만, 이번연구에서는생존군과사망군간의차이는보이지않았다. 이는성인의중추신경계기능이상이뇌경색, 뇌색전증, 신경외상등의비가역적인손상인반면, 이연구의대상자들은저산소뇌병증, 뇌전증등으로성인과는다른종류의중추신경계이상이므로동일하게적용하기는어려울것으로보인다. 즉, 소아에서면역저하상태, 중추신경계이상등을포함하는기저질환이체외막산소공급장치적용후생존율에미치는영향에대하여추가연구가필요하다. 기존점수체계항목에없는델타호중구지수 (delta neutrophil index), 혈소판은소아급성호흡곤란증후군환자의생존율을예측하기위한인자중하나로생각해볼수있다. 델타호중구지수와혈소판은소아중환자에서의예후예측인자이며특히패혈증환자에대하여더욱의미가있는것으로알려져있다. 24 이번연구에서도델타호중구지수는사망군에서높은수치를보였고혈소판은낮은수치를보여소아급성호흡곤란증후군환자의생존율예측인자로도사용할수있을것으로생각한다. 이번연구는우리나라소아급성호흡곤란증후군에서성인급성 호흡곤란증후군의체외막산소공급장치적용에대한예후를예측 하는 ECMOnet, PRESERVE, RESP 점수체계의유용성을평가한 첫연구라는점에서의의가있지만, 적은규모의연구로통계적의 의를평가하고새로운체계를제시하는데한계가있다. 이연구를 통하여성인의점수체계를직접적으로소아에적용하는것은어려 움이있을것으로생각하지만, 의미가있는점수체계의세부항목 중면역저하상태, 중추신경계이상등의기저질환, 감염성질환및 장기부전정도를평가하는것이예후예측에필요함을확인하였 다. 또한체질량지수, 신경근이완제의사용, 복와위와같은체외막 산소공급장치를적용시키기전개별항목들에대한의미를검증하 여적용해야할것으로생각한다. 결론적으로이번연구는체외막산소공급장치를적용한성인급 성호흡곤란증후군환자들의생존율예측점수체계를소아급성호 흡곤란증후군환자에게적용한파일럿연구이다. 우리는기존점 수체계의유용성을분석하였고, ECMOnet 점수및 PRESERVE 점 수체계가소아에서도적용이가능함을확인하였다. 그러나소아에 직접적용하기어렵거나생존율에의미있는영향이없을것같은 항목에대한재검토가필요할것으로생각한다. 또한기존의점수 체계에포함되어있지않은델타호중구지수, 혈소판에대한적용 이고려되어야할것으로생각한다. 향후소아급성호흡곤란증후 군환자의체외막산소공급장치의적응증및생존율예측을위한 더큰규모의연구가필요하다. REFERENCES 1. Combes A, Bacchetta M, Brodie D, Müller T, Pellegrino V. Extracorporeal membrane oxygenation for respiratory failure in adults. Curr Opin Crit Care 2012;18: Peek GJ, Clemens F, Elbourne D, Firmin R, Hardy P, Hibbert C, et al. CE- SAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure. BMC Health Serv Res 2006; 6: Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007;131: Davidson TA, Caldwell ES, Curtis JR, Hudson LD, Steinberg KP. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients. JAMA 1999;281: Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348: Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N, Cooper A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364: Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome: consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015;16: Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute 145

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar