ÇÐ¼úº¸°í5¾È¼÷Èñ

Size: px

Start display at page:

Download "ÇÐ¼úº¸°í5¾È¼÷Èñ"

솔비 이
5 years ago
Views:

1 병원약사회지 (2015), 제 32 권제 2 호 J. Kor. Soc. Health-Syst. Pharm., Vol. 32, No. 2, 140 ~ 146 (2015) Review Article 미숙아에대한 Caffeine 의투여효과 안숙희원광대학교약학대학 Caffeine Therapy in Preterm Infants Sook Hee An College of Pharmacy, Wonkwang University, 460, Iksandaero, Iksan, Jeonbuk, , Korea Abstract : Caffeine citrate is used as standard therapy for apnea of prematurity. The optimum dose and timing of caffeine therapy are controversial. The purpose of this article is to review therapeutic indications, influence on neonatal outcomes, and long-term effects of caffeine in preterm infants. Currently, the approved indications of caffeine citrate in Korea are the treatment of documented apnea and prevention of extubation failure. High doses of caffeine have been shown to improve acute outcomes such as a reduction in the frequency of apnea, days of documented apnea and extubation failure. Early caffeine therapy is associated with improvements in bronchopulmonary dysplasia and patent ductus arteriosus. However, an increased incidence of necrotizing enterocolitis in neonates receiving early caffeine therapy was reported. Additional research is needed to evaluate the longterm effects associated with high doses of caffeine. The recommendation of early caffeine prophylaxis in preterm infants also requires further study. 투고일자 ; 심사완료일자 ; 게재확정일자 교신저자안숙희 Tel: shan7@wku.ac.kr

2 안숙희 : 미숙아에대한 Caffeine 의투여효과 [Key words] Apnea of prematurity, Bronchopulmonary dysplasia, Caffeine, Neonate, Patent ductus arteriosus 서론 Caffeine은미숙아무호흡 (Apnea of prematurity, AOP) 치료를위하여사용되는 methylxanthine계약물이다. 미숙아무호흡은재태연령 (gestational age, GA) 이 37주미만으로태어난미숙아 (preterm infant) 에게흔한합병증이며, 발생빈도는재태연령및출생체중 (birth weight) 과관련이있어, 재태연령이 주인환자의 78%, 출생체중이 1000 g 미만인초극소저출생체중아 (extremely low birth weight infant, ELBWI) 환자의 84% 에서발생하나, 재태연령이 34-35주에해당하는환자는 7% 에서발생하는것으로보고되었다. 1) 2012년에조사한국내유병률은출생체중이 1500 g 미만인극소저출생체중아 (very low birth weight infant, VLBWI) 에서 45.4%, 출생체중이 g에해당하는신생아는 4.2% 로조사되었다. 2) 미숙아무호흡치료를위하여전통적으로많이사용하던약물은 aminophylline(theophylline) 이었으나, 2006년체중이 g인환자를대상으로한대규모의다국적임상시험이었던 Caffeine for Apnea of Prematurity(CAP) trial 결과가발표되면서 caffeine의사용이증가하게되었다. 3) Caffeine은 theophylline과 같은 methylxanthine계약물로 theophylline에비하여넓은범위의치료혈중농도 (therapeutic range) 를가지므로혈중농도를자주모니터링하지않아도되며, 반감기가길어 1일 1회투여가가능한장점이있다. 4) 임상의사들은 caffeine을미숙아무호흡의치료뿐아니라예방목적으로도사용하고있으며, 인공호흡기이탈의보조치료에도사용하고있다. 5) 또한, 미숙아의주요합병증인기관지폐이형성 (bronchopulmonary dysplasia, BPD) 의예방효과가있다는결과가발표되면서, caffeine의적절한투여시기에대한여러의견들이제시되고있다. 6)-9) 미숙아에게 caffeine을출생직후또는미숙아무호흡의진단이이루어지기전에예방목적으로투여하는것이적절한지에대하여여러연구가진행되었고, caffeine의부작용측면과미숙아합병증및예후에미치는영향에대하여논의되고있다. 따라서, 본종설에서는 caffeine의미숙아무호흡치료, 인공호흡기이탈의보조치료, 기관지폐이형성 ( 만성폐질환 ) 과같은미숙아합병증예방효과, 투여용량및투여시기, 장기적인결과에대하여고찰하고자한다. 본론

3 JKSHP, VOL.32, NO.2 (2015) 1. 미숙아무호흡의치료미숙아무호흡은여러방식으로정의되고있으나, 임상적으로유의한무호흡은 15-20초이상숨을쉬지않거나, 숨을쉬지않는시간이 15-20초미만이라도서맥, 유의한저산소혈증, 청색증등을동반하는경우로정의되고있다. 10) 34주미만의미숙아에서 85% 이상발생하며, 주요한치료는지속적기도양압 (continuous positive airway pressure, CPAP) 의적용과 methylxanthine 계열의약물의투여이다. 11),12) Methylxanthine 계열의약물인 aminophylline, theophylline, caffeine은무호흡의횟수를감소시키고, 생후첫일주일동안인공호흡기치료의요구도감소시킨다. 13) 미숙아무호흡에대한 caffeine의효과는 1977년 Aranda에의해처음보고되었으며, 15) 년에 Schmidt 등에의해대규모의다국적임상시험 (CAP trial) 결과가발표되면서널리사용하게되었다. 3),15) 재태연령이 28-35주인환자들에게 caffeine 을투여하였을때위약과비교하여인공호흡기의적용기간, CPAP의적용기간, 산소투여기간을감소시켰으며, 스테로이드투여와적혈구수혈도감소시키는것으로나타났다. 3) Caffeine과 theophylline의비교연구결과에서 caffeine은미숙아무호흡에대한효과가 theophylline과유사하며, 빈맥, 섭취곤란 (feeding intolerance) 과같은부작용이더적은것으로나타났다. 16) 또한, caffeine은 theophylline 보다반감기가길어 1 일 1회투여가가능하며, 치료혈중농도의범위가더넓기때문에현재는 caffeine이미숙아무호흡의표준치료제로사용되고있다. Caffeine의치료혈중농도는 5-25 mcg/ml이며, mcg/ml를초과하면위험하다. 17) Alur P. 등의연구에의하면재태연령이 29 주미만인미숙아에서 caffeine의혈중농도를 14.5 mcg/ml 이상으로유지할때재원일수, 인공호흡기치료기간, 퇴원시산소요구도를감소시키며, 동맥관개존증과만성폐질환의발생을감소시켰다. 18) 현재 caffeine citrate의미숙아무호흡에대한국내요양급여인정기준은재태기간 33주미만에출생한미숙아에서 24시간동안 20초이상무호흡이 6회이상발생하는경우이며, 무호흡이 20초미만이더라도청색 증이나서맥을동반하는경우에는투여를인정하고있으며, 무호흡이 5-7일간없는경우중단하도록하고있다. 19) 2. 인공호흡기이탈의보조치료 Caffeine과같은 methylxanthine 계약물은인공호흡기이탈의성공률을높이는데효과적인것으로보고되었다. 5) 인공호흡기의이탈이계획되어있는경우에는 24 시간전에투여하고, 무계획이었던경우에는인공호흡기이탈후 6시간이내에투여하면효과적이다. 미숙아의재태연령이 28주미만이거나, 생후 1주이내에투여하는것이더효과적인것으로알려져있다. 5),20) 현재 caffeine citrate의인공호흡기이탈과정의투여에대한국내요양급여인정기준은교정연령 33주미만의미숙아에게인공호흡기를이탈하기 24시간전부터, 혹은갑작스럽게이탈이된경우에는 6시간이내에투여하는것을인정하고있으며, 중단시기는인공호흡기를이탈하고무호흡이 5-7일간없는경우이다. 19) 3. 투여용량미숙아무호흡에대한 caffeine의적정용량에대하여다양한정보가제시되고있다. 표준용량은부하용량으로 20 mg/kg/dose(caffeine base mg/kg/ day) 를투여하고, 유지용량으로 5-10 mg/kg/day (caffeine base mg/kg/day) 을투여하는것이다. 그러나, 고용량으로투여하였을때무호흡횟수를더감소시킨다는결과들이발표되고있다. Caffeine citrate의부하용량을 50 mg/kg/dose로투여하는것이 25 mg/kg/dose로투여하는것에비하여 8시간이내에무호흡횟수를더감소시킨다는보고가있다. 21) 또다른연구에서도부하용량을 40 mg/kg/dose로투여하고, 유지용량을 20 mg/kg/day로투여하는고용량요법이부하용량을 20 mg/kg/dose로투여하고, 유지용량을 10 mg/kg/day로투여하는표준용량요법에비하여무호흡횟수를감소시키고, 무호흡이발생한일수도감소시켰다. 22) 고용량투여가인공호흡기이탈의성공률도증가시키는것으로나타났다. 23),24) 그러나, 고용량요법을투여했을때빈맥의부작용발생은증가하

4 안숙희 : 미숙아에대한 Caffeine 의투여효과 Table 1. Early caffeine therapy and clinical outcomes Study name Parameters Early caffeine Late caffeine Odds ratio (95% CI) P value Dobson NR et al, ) Gestational age, weeks, mean (5 th, 95 th percentile) (25.0, 31.0) (24.0, 32.0) 0.70 Birth weight, g, mean (5 th, 95 th percentile) 1055 (630, 1447) 1054 (590, 1460) 0.77 Duration of caffeine therapy, mean (5 th, 95 th percentile) 37 (5,72) 33 (5,68) BPD* or death, n (%) BPD* in survivors, n (%) Treatment of PDA, n (%) 3681 (27.6) 3070 (23.1) 1794 (12.3) 4591 (34.0) 4154 (30.7) 2765 (19.0) 0.74 ( ) 0.68 ( ) 0.60 ( ) Taha D et al, ) Gestational age, weeks, mean±sd Birth weight, g, mean±sd Duration of caffeine therapy, mean±sd BPD* or death, n(%) BPD*, n(%) PDA, n(%) Severe IVH, n(%) NEC, n(%) ROP requiring laser, n(%) ± ± ± (45.5) 716 (36.1) ± ± ± (54.9) 451 (46.7) ( ) ( ) ( ) ( ) ( ) ( ) NS NS NS Patel RM et al, ) Gestational age, weeks, median (IQR) Birth weight, g, median (IQR) Duration of caffeine therapy, median (IQR) BPD * or death, n(%) BPD *, n(%) Treatment of PDA, n (%) ( ) 940 ( ) 40 (21-58)) 21 (25) 17 (24) 8 (10) ( ) 910 ( ) 39.5 (28-61) 30 (53) 27 (51) 20 (36) 0.26 ( ) 0.33 ( ) 0.28 ( ) < Lodha A et al, ) Gestational age, weeks, median (IQR) Birth weight, g, median (IQR) Duration of caffeine therapy, median (IQR) BPD * or death, n (%) BPD * on 36 weeks PCA, n (%) PDA, n (%) ROP ( stage 3) NEC ( stage 2) Severe neurologic injury (26-29) 1070 ( ) 37 (21-55) 1197 (31.5) 999 (27.8) 1503 (40.5) 229 (9.8) 240 (6.5) 432 (12.0) (26-30) 1050 ( ) 30 (14-51) 403 (31.1) 340 (27.7) 576 (46.2) 95 (12.8) 78 (6.3) 167 (14.3) 0.81 ( ) 0.79 ( ) 0.74 ( ) 0.78 ( ) 0.88 ( ) 0.80 ( ) <0.01 * BPD: bronchopulmonary dysplasia PDA: patent ductus arteriosus NS: not significant IVH: intraventricular hemorrhage NEC: necrotizing enterocolitis ROP: retinopathy of prematurity

5 JKSHP, VOL.32, NO.2 (2015) 는것으로나타났다. 22) 최근발표된 pilot study에서재태연령 30주미만의미숙아에게 caffeine을생후 24시간이내에고용량 (80 mg/kg) 을투여했을때표준용량 (20 mg/kg) 에비하여소뇌출혈 (cerebellar hemorrhage) 의발생이증가한다고보고되었다. 25) 4. 투여시기가미숙아합병증발생에미치는영향 Caffeine 투여는미숙아의주요합병증인기관지폐이형성 (bronchopulmonary dysplasia, BPD) 과동맥관개존증 (patent ductus arteriosus, PDA) 의발생빈도를감소시킨다. 3) 이러한효과는 caffeine을생후 2 일이내에투여하였을때더욱증가한다. Caffeine의투여시기에따른신생아합병증의차이에대한여러연구에서생후 2일이내에 caffeine 투여를시작하는것이생후 3일이후에투여하는것에비하여 BPD와 PDA의발생을감소시킨다. 6)-9) 뇌실내출혈 (intraventricular hemorrhage, IVH) 에대하여는 caffeine의조기투여가 IVH의위험을감소시킨다는보고가있다. 7) 괴사성장염 (necrotizing enterocolitis, NEC) 에대한결과에서는위약투여와비교하여 caffeine 투여가 NEC의발생을증가시키지않았으나, 3) 생후 2일이내에조기투여하는것이생후 3일이후에투여하는것에비하여 NEC 발생이증가한다고보고한연구가있다. 7) Caffeine의투여시기에따른신생아합병증의결과는 Table 1에기술하였다. 5. 성장에미치는영향미숙아는체중증가및성장이중요한이슈이다. CAP trial에서위약투여군과 caffeine 투여군의체중증가의차이를보았을때, caffeine 투여군이생후 3 주까지는일시적으로체중증가폭이감소하였으나, 생후 4주이후에는유의한차이가없는것으로나타났다. 3) 생후 2일이내에조기투여하는경우에도생후 3 일이후에투여하는것에비하여체중증가정도가생후 1주까지는감소하였으나, 생후 4주이후에는유의한차이가없었다. 6) Caffeine을투여한환자에서 18-21개월후측정한체중, 신장, 머리둘레도위약투여군과유의한차이가나타나지않았다. 15) 6. 신경발달에미치는영향 Caffeine을투여하고 18-21개월이후에뇌성마비 (cerebral palsy) 와인지지연 (cognitive delay) 의발생빈도가위약투여군에비하여감소하는경향이나타났으나, 15) 5년간추적조사한연구에서는운동기능저하, 인지저하, 난청, 실명등의신경학적예후에유의한개선효과가없는것으로나타났다. 26) Caffeine을투여하고 5년후에발달성협응장애 (development coordination disorder) 의빈도는위약투여군에비해감소하였다. 27) 결론미숙아에게 caffeine은무호흡의치료, 인공호흡기이탈의보조치료에효과적이며, 기관지폐이형성, 동맥관개존증과같은미숙아합병증의감소효과가있다. 장기적인예후에있어서도심각한부작용이나타나지않으며, 신경발달에긍정정인결과를보여주는연구들도발표되고있다. Caffeine을표준용량보다고용량으로투여하는것이무호흡의횟수를감소시키고, 인공호흡기이탈의성공률을증가시키는단기적인효과는있으나, 장기적인효과에대한연구가더욱필요하다. 미숙아에게 caffeine을무호흡이발생하기전인생후초기에예방목적으로투여하는것은만성폐질환, 동맥관개존증과같은미숙아합병증에긍정적인효과가있으나, 괴사성장염과생후초기체중증가에부정적인영향을미치므로신중하게고려해야하며, 추가적인연구가필요하다. 참고문헌 1) Poets C.F., Samuels M.P., Southall D.P. : Epidemiology and pathophysiology of apnea of prematurity. Biol Neonate, 65(3-4), (1994) 2) Kim T.H., Choi M.S., Chung S.H., Choi Y.S., and Bae C.W. : Morbidity of low birth weight infants in Korea (2012): A comparison with Japan and the USA. Neonatal Med, 21,

6 안숙희 : 미숙아에대한 Caffeine 의투여효과 223 (2014) 3) Schmidt B., Roberts R.S., Davis P., Doyle L.W., Barrington K.J., Ohlsson A., Solimano A., Tin W. : Caffeine therapy for apnea of prematurity. N Engl J Med, 354(20), (2006) 4) Natarajan G., Botica M.L., Thomas R., Aranda J.V. : Therapeutic drug monitoring for caffeine in preterm neonates: an unnecessary exercise? Pediatrics, 119, 936?940 (2007) 5) Henderson-Smart D.J., Davis P.G. : Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev, 8(12), CD (2010) 6) Dobson N.R., Patel R.M., Smith P.B., Kuehn D.R., Clark J., Vyas-Read S., Herring A., Laughon M.M., Carlton D., Hunt C.E. : Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr, 164(5), (2014) 7) Taha D., Kirkby S., Nawab U., Dysart K.C., Genen L., Greenspan J.S., Aghai Z.H. : Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm infants. J Matern Fetal Neonatal Med, 27(16), (2014) 8) Patel R.M., Leong T., Carlton D.P., Vyas- Read S. : Early caffeine therapy and clinical outcomes in extremely preterm infants. J Perinatol, 33(2), (2013) 9) Lodha A., Seshia M., McMillan D.D., Barrington K., Yang J., Lee S.K., Shah P.S. : Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr, 169(1), (2015) 10) Zhao J., Gonzalez F., Mu D. : Apnea of prematurity: from cause to treatment. Eur J Pediatr, 170, (2011) 11) Barrington K., Finer N. : The natural history of the appearance of apnea of prematurity. Pediatr Res, 29, (1991) 12) Martin R.J., Abu-Shaweesh J.M., Baird T.M. : Apnoea of prematurity. Paediatr Respir Rev, 5(Suppl A), S377-S382 (2004) 13) Henderson-Smart D.J., Steer P. : Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev, 3, CD (2001) 14) Aranda J.V., Gorman W., Bergsteinsson H., Gunn T. : Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr, 90, (1977) 15) Schmidt B., Roberts R.S., Davis P., Doyle L.W., Barrington K.J., Ohlsson A., Solimano A., Tin W. : Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med, 357(19), (2007) 16) Henderson-Smart D.J., Steer P.A. : Caffeine versus theophylline for apnea in preterm infants. Cochrane Database Syst Rev. 20(1), CD (2010) 17) Young T.E., Mangum B. : Neofax, 18th ed. Acorn Publishing, Raleigh NC, (2005) 18) Alur P., Bollampalli V., Bell T., Hussain N., Liss J. : Serum caffeine concentrations and short-term outcomes in premature infants of < 29 weeks of gestation. J Perinatol, 18, doi: /jp , [Epub ahead of print] (2014) 19) The ministry of Health and Welfare Notice No ) Davis P.G., Schmidt B., Roberts R.S., Doyle L.W., Asztalos E., Haslam R., Sinha S., Tin W. : Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. J Pediatr, 156(3), (2010)

7 JKSHP, VOL.32, NO.2 (2015) 21) Scanlon J.E., Chin K.C., Morgan M.E., Durbin G.M., Hale K.A., Brown S.S. : Caffeine or theophylline for neonatal apnoea? Arch Dis Child, 67(4), (1992) 22) Mohammed S., Nour I., Shabaan A.E., Shouman B., Abdel-Hady H., Nasef N. : High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial. Eur J Pediatr. [Epub ahead of print] (2015) 23) Steer P., Flenady V., Shearman A., Charles B., Gray P.H., Henderson-Smart D., Bury G., Fraser S., Hegarty J., Rogers Y., Reid S., Horton L., Charlton M., Jacklin R., Walsh A. : High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed, 89(6), F (2004) 24) Gray P.H., Flenady V.J., Charles B.G., Steer P.A. : Caffeine citrate for very preterm infants: Effects on development, temperament and behaviour. J Paediatr Child Health, 47(4), (2011) 25) McPherson C., Neil J.J., Tjoeng T.H., Pineda R., Inder T.E. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. doi: /pr [Epub ahead of print] (2015) 26) Schmidt B., Anderson P.J., Doyle L.W., Dewey D., Grunau R.E., Asztalos E.V., Davis P.G., Tin W., Moddemann D., Solimano A., Ohlsson A., Barrington K.J., Roberts R.S. : Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA, 307(3), (2012) 27) Doyle L.W., Schmidt B., Anderson P.J., Davis P.G., Moddemann D., Grunau R.E., O'Brien K., Sankaran K., Herlenius E., Roberts R. : Reduction in developmental coordination disorder with neonatal caffeine therapy. J Pediatr, 165(2), (2014)

386-390.hwp

386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon