REVIEW J Neurocrit Care 2015;8(2): ISSN 중환자실에서의섬망 계명대학교동산병원신경과 홍정호 Delirium in the Intensive

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1 REVIEW ISSN 중환자실에서의섬망 계명대학교동산병원신경과 홍정호 Delirium in the Intensive Care Unit Jeong-Ho Hong, MD, PhD Department of Neurology, Keimyung University Dongsan Medical Center, Daegu, Korea Delirium is a cognitive disturbance with acute onset or fluctuating clinical course. It is recognized as one of the most common complications in the intensive care unit (ICU). The impact of delirium in the ICU on mortality, hospital or ICU length of stay, cost burden and post- ICU cognitive impairment is well documented. Although the underlying pathophysiology is poorly understood, numerous predisposing and precipitating risk factors for delirium are suggested. Prevention strategy, early detection using screening tools, and control of the underlying causes are crucial to improve clinical outcomes of delirium. Pharmacological treatment such as antipsychotics may also be considered as a treatment option, although its efficacy and safety are not yet established. The purpose of this review was to provide an overview of clinical characteristics, risk factors and treatment for delirium in the ICU. Key Words: Delirium; Delirium tremens; Intensive care unit; Critical illness 서 론 신경계중환자실뿐만아니라내과계혹은외과계중환자실 에서흔히접하게되는것이섬망이다. 특히중환자실에서섬 망의유병률은약 30% 에달하며, 인공호흡기를사용하고있 는환자에서는 60-80% 까지보고되고있다. 1-7 이러한섬망은 주로의식의저하나변화, 광범위한인지기능의손상, 비정 상적인지각과행동및기분등의정신증상과떨림, 운동실조, 요실금등의신경증상으로나타나며, 갑자기발병하여증상의 변동이심하다. 중환자에서섬망의발생은사망률을증가시키 며중환자실체류기간뿐만아니라전체재원일수도늘이게 된다 또한, 섬망은중환자실퇴실후발생할수있는인지 장애 (post-icu cognitive impairement) 도야기할수있다. 12 Received: October 24, 2015 / Revised: October 31, 2015 Accepted: October 31, 2015 Address for correspondence: Jeong-Ho Hong, MD, PhD Department of Neurology, Keimyung University Dong San Medical Center, 56 Dalseong-ro, Jung-gu, Daegu 41931, Korea Tel , Fax neurohong79@gmail.com 본논문에서는중환자실에서비교적흔히접할수있는섬망의임상증상, 원인과감별진단및치료에대해전반적으로검토를하고자한다. 본론 섬망의임상증상섬망은의식혼탁이동반되고, 증상의변동폭이커서하루에도증상이변화하는경향이있으며주로저녁에증상이악화된다. 이러한의식변화가환자가가지고있는기존의질환으로설명되지않는다. 이외에도인지장애, 정신장애, 수면장애및신경학적증상이동반되는데, 우선인지장애는주의력과지남력의장애가가장특징적이다. 정신장애로는환시와같은환각증상이흔하며, 불안, 공포등자극과민증상이나타날수도있다. 수면장애로는불면증이흔하며주로밤에수액줄을뽑거나침대에서뛰쳐나가려고하다가낙상사고로이어지는요인이되기도한다. 신경학적증상으로는자율신경항진이생길수있으며경우에따라떨림 (tremor) 이나자세고정불능 (asterixis) 등이동반될수있다 Copyright 2015 The Korean Neurocritical Care Society

2 Delirium in the ICU Hong JH 섬망은활동과잉형 (hyperactive), 활동저조형 (hypoactive), 혼합형 (mixed) 으로나눌수있다. 활동과잉형환자는흥분되고공격적이어서자극에과한반응을하여환자관리에어려움이있다. 반면활동저조형은대부분수면상태에있거나깨어있더라도집중력저하와무기력증에빠져있기때문에진단이늦어져치료가늦어질수있으며예후도활동과잉형보다더안좋다. 특히중환자실에서는혼합형이나활동저조형이더많아진단에주의가필요하다. 14,15 보통갑작스럽게발병한경우의임상경과는원인이되는인자를제거하면대개일주일이내증상이호전된다. 하지만, 관련원인이존재한다면증상은지속될수있으며, 특히고령의환자에서는회복기간이더욱긴것으로알려져있다. 섬망의원인및감별진단섬망의원인에대해서는많은연구가이루어져있으나, 이들대부분은중환자실밖에서의섬망발생에대한것들이다. 위험인자를크게두가지로나누어보면, 이미존재하고있는소인인자 (predisposing factor) 와주로환경적인요인과질병과관련된유발인자 (precipitating factor) 로나뉘며, 상기인자들의유기적인연관에의하여섬망이발생하게된다. 자세한내용은 Table 1에기술하였다. 16 중환자실에서섬망발생의중요한요인은친숙한존재와의격리, 부동상태 (immobilization) 및억제, 치료를위한기계화된환경에노출, 검사들로인한수면박탈, 밤과낮의구별이되지않는등의환경적인요인이다. 이외에아직근거가부족하나 2013년미국중환자의학회 (Society of Critical Care Medicine) 의진료지침에는중환자실환자들에서상기인자들중기존의치매, 고혈압, 알코올중독의기왕력과입원당시의질병 의중증도를위험인자로기술하였으며, 의식장애중혼수상태와 benzodiazepine 사용역시위험인자로간주하였다. 3,17,18 고령은중환자실밖에서는중요한위험인자인것은맞지만, 중환자실환자에서는아직논란이많다 수술후중환자실로입실한환자들에서도섬망의발생률은높으며, 수술중출혈정도와수혈, 낮은헤마토크리트등이위험인자로생각된다 약물역시흔한섬망의원인이며, 특히수면진정제, 항불안제, 마약성진통제, 항콜린성약제등과같은향정신성약제들로이들약제들의사용은섬망발생을증가시키는것으로알려져있다 (Table 2). 특히, 중환자실에서는진정및진통조절을위해 benzodiazepine 계열약과마약성진통제가흔히투약되는데, benzodiazepine 의경우잘알려진섬망의위험인자들로정확한사정을통해최소한의용량을사용하도록한다. 18,22,28 하지만, 마약성진통제와섬망발생과의관련성에는아직연구들간에차이를보이고있어논란이되고있지만사용에있어서주의를기울여야하겠다. 3,18-20,22,29-31 약물관련성에있어서중환자실에서흔히접할수있는또다른섬망은알코올금단섬망혹은진전섬망 (delirium tremens) 이다. 아직국내에도중환자실에입원하는환자의상당수가알코올의존환자이며갑작스러운중환자실입원으로알코올섭취가중단되고금주후 12-48시간이후알코올금단증상이발생하게되는데, 대부분경미한증상으로끝나나약 5% 에서갑작스러운자율신경계의증상 ( 빈맥, 발열, 발한등 ) 과의식변화를동반한진전섬망으로발전하기도한다 감별진단으로는치매와정신병 (psychosis) 등이있으며각각의특징에대해서는 Table 3에기술하였다. 간단히요약해보면, 치매는원인에따라다소차이는있으나일반적으로증상이서서히시작및악화되는인지기능저하가특징이다. 평상 Table 1. Predisposing and precipitating risk factors for delirium Predisposing factors Preexisting dementia or underlying cognitive impairment Sever illness at admission Comorbidity Depression Visual and/or hearing impairment Dehydration Chronic kidney disease Structural brain injury or previous stroke Advanced age History of alcohol abuse or delirium Baseline use of psychoactive drugs Male gender Malnutrition Precipitating factors Psychoactive drugs Immobilization Indwelling bladder catheters Physical restraints Dehydration Poor nutritional state Iatrogenic complications Intercurrent medical illness Major surgical procedure Metabolic derangements (eg. electrolytes, acid-base imbalance) Infections Hypoxia Alcohol or drug intoxication or withdrawal Pain Emotional stress Sleep deprivation 47

3 Table 2. Drugs that can cause delirium Alcohol (withdrawal) Antibiotics and antivirials Acyclovir Aminoglycosides Amphotericin B Cephalosporins Isoniazid Interferon Metronidazole Penicillins Rifampin Analgesics NSAIDs (ibuprofen) Opioids (especially meperidine) Anticholinergics Atropine Benztropine Diphenhydramine Scopolamine Anticonvulsants Carbamazepine Levetiracetam Phenytoin Valproate Antidepressants SSRI TCA Cardiovascular drugs ACE inhibitors Antiarrhythmics (quinidine, amiodarone) Beta blockers Digitalis Digoxin Diuretics Corticosteroids Dopamin agonists Gastrointestinal agents Antiemetics (metoclopramide) H2 receptor blockers (cimetidine, raniditine) Loperamide Hypoglycemics Hypnotics and sedatives Barbiturates Benzodiazepines Muscle relaxants Baclofen Cyclobenzaprine NSAIDs, nonsteroidal anti-inflammatory agents; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; ACE, angiotensinconverting enzyme. Table 3. Differential diagnosis of delirium Characteristic Delirium Dementia Psychosis Symptoms Age at onset <12 or >40 yr Usually elderly, >50 yr yr Onset Acute Gradual or insidious Gradual Symptom course Rapid, fluctuating Stable and progressive Stable Duration Days to weeks Months to years Months to years Reversibility Usually Rarely Rarely History Past medical history Substance abuse, medical illness Comorbid conditions of aging Previous psychiatric history Family history Unusual History of dementia History of psychiatric illness Physical Examination Vital signs Usually abnormal Usually normal Usually normal Involuntary activity May have tremors, asterixis, etc. None unless coexistent disease None Mental Status Affect Emotional lability Flat affect with advanced disease Flat affect Orientation Usually impaired Impaired with advanced disease Rarely impaired Attention Impaired Slow to focus Disorganized Hallucinations Primarily visual Rare Primarily auditory Speech Slow, incoherent, dysarthric Usually coherent Usually coherent Consciousness Decreased to impaired Normal (clear) Alert Intellectual function Usually impaired Impaired Intact From Adams JG et al: Emergency medicine, clinical essentials, 2 nd Edition, Philadelphia, 2013, Elsevier. 48

4 Delirium in the ICU Hong JH 시특별한기왕력이없던노인에서입원후갑자기지남력장애가생기고가족마저못알아보며증상의변동이심할경우치매보다는섬망일가능성이높다. 노인의경우치매와섬망이공존하는경우도많아감별진단에주의를요한다. 정신병은의식의명료성이유지된다는점에서섬망과큰차이를보인다. 섬망은만성질환이아니다. 그러므로중환자실에서오랜기간동안의의식변화에대해원인이규명되지않는다면다른원인을감별할필요가있다. 섬망의치료중환자실에서는적절한선별검사를통한일차예방이무엇보다중요하다. 예방및치료의원칙은 1) 환경적요인조절 2) 앞서언급한약물과탈수등원인인자와섬망과관련된기저질환의조기식별및치료, 3) 약물적요법으로요약된다. 1) 환경적요인조절예방에서중요한부분은환경적요인및위험인자조절인데, 이는치료에도동일하게적용된다. 중환자실에서는기저질환이나위험인자들을쉽게조절할수없는경우가많아진료와관련된환경적요인을조절하는것이중요하다. 중환자실에서낮에는적절한조명과자극을유지하고, 밤에는가능하다면낮은조도의불빛을이용하며귀마개나소음감소를통한수면각성주기를유지시키려는노력이필요하다. 35 불필요한간호업무나시술을밤에하는것에도삼가도록해야한다. 동시에낮시간에가족, 가까운친구들의방문이나시계, 달력사용을통한지남력을일깨워주는노력이필요하나밤시간에과도한자극은도움이되지않는다. 36,37 감각장애를보이는환자에게는이전사용중이던안경과보청기의착용으로감각을유지시켜주도록하는노력이필요하다. 억제대의경우낙상, 갑작스러운기관지튜브발관, 카테터제거등의중환자실에서의우발적이고위험한행동을막는데는중요하나그자체가환자를흥분시키며섬망발생과관련된상황들을악화시키게되므로최소한의선에서만환자나보호자의동의후사용하도록권장한다. 38,39 동시에중환자실에서조기물리치료와작업치료는섬망의발생을줄인다. 40 2) 원인인자와섬망과관련된기저질환의조기식별및치료섬망의치료에가장중요한것은원인이되는상태를조기에알아내고제거하는것이다. 38,41,42 예를들어탈수나감염, 발열, 대사장애등과같은내과적질환이원인이라면해당질환에대한적극적인치료를해야하며, 치료과정중발생할수있는전해질불균형이나탈수와부종등도모니터를통해미연에방지하고발생시에는조기치료가필요하다. 36 또한, 앞 서섬망의원인에서언급한데로약제사용혹은금단으로인해나타날수있는가능성을꼭염두에두고조기식별하려는노력이필요하다. 3) 약물적요법섬망증상에대한약물치료원칙은가능한최소종류의약제를최소한의용량과기간만사용하는것이며, 앞서언급한비약물적요법을먼저시도하거나약물적요법을시행할시에도비약물적요법과병행하는것이바람직하다. 현재까지중환자실에서섬망발생과기간을줄이기위한예방적목적으로추천되는약물적요법은없다. 17 다만, 인공호흡기를적용중인중환자에서진정을목적으로 dexmedetomidine의사용은 benzodiazepine과비교하여섬망의발생률을낮추는것으로알려져있으나, 43,44 중환자에서섬망의예방목적으로 dexmedetomidine의사용은아직근거가불충분하여추천되고있지는않으며이에대해서는추가적인연구가필요하다. 17,45 최근 2개의무작위배정대조군연구에서멜라토닌이섬망발생예방에효과를보이고, 고관절수술을받은환자에서도수술후발생하는섬망의발생률을줄인다는보고가있어이역시추가적인연구가필요한것으로생각된다 현재급성섬망을치료하기위해항정신병약물이많이상용되고있으며, 그중대표적인 1세대약물이 haloperidol 이다. 하지만놀랍게도현재까지중환자실에서 haloperidol 을사용해섬망치료의효능과안전성을입증한전향적무작위대조연구는없으며가장최근결과가발표된 2005년 MIND 연구에서도임상적결과에영향을주지못하였다. 49 이로인해과거 2002년미국중환자의학회의진료지침에서는소수의환자들을대상으로한연구를근거로 haloperidol 을치료약물로고려할수있다고 (Level C) 권고했지만, 년진료지침에는근거없음 (No evidence) 으로수정명기하였다. 17 이렇듯사용근거가낮음에도불구하고 haloperidol 은최근까지중환자실에서가장많이사용되고있으며, 권장되는초기용량은 mg 으로, 환자의초조 (agitation) 정도와의식수준, 나이등을고려하여용량을서서히증량할수있다. 하지만, 하루 4.5 mg 이상투약할경우추체외로증상 (extrapyramidal symptoms) 발생위험이높기때문에주위를요한다. 1세대약물인 Haloperidol 외에도비정형항정신병약물 (atypical antipsychotics) 들이급성섬망의치료에사용되고있으며대표적인것이 quetiapine, risperidone, olanzapine이있다. 비정형항정신병약물은 haloperidol 과비교시효과는비슷하나추체외로증상이적게나타나는것으로알려져있다 최근연구에서는중환자실에서경구용 quetiapine과필요시정주용 haloperidol 투약치료를병합한것이경구용위약과필요시 49

5 정주용 haloperiodol 투약치료를병행한경우보다섬망에서빨리회복되고초조한정도가적었으며빨리퇴원하는경향을보였다. 55 이를근거로최근미국중환자의학회진료지침에서비정형항정신병약물의사용은섬망회복기간을줄일수있다고명기하였다. 17 (Level C) Risperidone 은 mg 1일 2회로시작하여증상을보아가며 1일 2-3 mg까지증량하며, Olanzapine은 mg 1일 1회취침전투약으로시작하여 1일 10 mg까지증량가능하다. Quetiapine의경우 1일 2회 12.5 mg으로시작하여최대 mg까지사용가능하나 QTc 간격연장을시킬수있어 torsades de point의위험이있는환자 ( 예를들어, QTc 간격이연장되어있거나연장시킬수있는약물을병행하고있는환자등 ) 에서는사용이권장되지않는다. 섬망치료에서 benzodiazepine의효과는제한적이며, 과도한진정효과및갑작스러운인지기능의악화를유발할수있어가급적피하도록한다. 앞서언급하였지만, 중환자실에서의 benzodiazepine 의사용은섬망을일으킬수있는위험인자이기도하기때문에사용에주의를요한다. 3,6,18 하지만, 항정신병약물을사용할수없을때나, 알코올금단혹은약제금단으로인한섬망에서는사용을고려해볼수있겠다. 특히진전섬망의경우전신운동초조 (psychomotor agitation) 증상에 benzodiazepine이효과가있으며주로정맥내 lorazepam을 5 mg에서 10 mg 정도로시작하여매 5-10분마다투약해볼수있다. 최근에는진전섬망등알코올금단증상을조기에대응하면서과거보다는사망률이많이감소하였으나중환자실에서치료를하지않고방치하면사망까지이를수있다. 33,34 섬망전치매를앓고있었던고령환자의경우아세틸콜린분해효소억제제등의사용을고려해볼수도있으나, 56 일반적으로중환자에서섬망치료제로서아세틸콜린분해효소억제제의사용은효과를입증받지못하였다. 특히중환자실에서 rivastigmine의사용은오히려사망률을증가시키고섬망의기간을늘리는결과를보여중환자실환자에게추천되지않는다. 57 이외에도심장수술을받은환자에게서섬망예방목적으로사용한 rivastigmine의경우에도효과는없었다. 58 다만, 항콜린성약제독성 (anticholinergic toxicity) 에의한섬망의경우 donepezil 사용이효과가있다는보고는있지만추가연구가필요하다. 59 결론 단순히섬망을가역적이고일시적인증상으로가볍게여겨질수있지만, 중환자실에서섬망은중환자실입원기간및병원전체재원기간장기화와사망률증가시킬뿐만아니라중환자실퇴실이후에도인지기능저하등을일으킬수있다. 이 러한중환자실에서의섬망관리를위해서는환경적요인및 위험인자제거를통한예방과적절한선별도구를통한규칙적 인모니터링으로조기에발견하려는노력그리고적극적인치 료가필요하다. REFERENCES 1. Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286: McNicoll L, Pisani MA, Zhang Y, Ely EW, Siegel MD, Inouye SK. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003;51: Pandharipande P, Cotton BA, Shintani A, Thompson J, Pun BT, Morris JA Jr, et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma 2008;65: Salluh JI, Soares M, Teles JM, Ceraso D, Raimondi N, Nava VS, et al. Delirium epidemiology in critical care (DECCA): an international study. Crit Care 2010;14:R Sharma A, Malhotra S, Grover S, Jindal SK. Incidence, prevalence, risk factor and outcome of delirium in intensive care unit: a study from India. Gen Hosp Psychiatry 2012;34: Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med 2010;38: Tsuruta R, Nakahara T, Miyauchi T, Kutsuna S, Ogino Y, Yamamoto T, et al. Prevalence and associated factors for delirium in critically ill patients at a Japanese intensive care unit. Gen Hosp Psychiatry 2010;32: Schuurmans MJ, Duursma SA, Shortridge-Baggett LM. Early recognition of delirium: review of the literature. J Clin Nurs 2001;10: Rabinowitz T. Delirium: an important (but often unrecognized) clinical syndrome. Curr Psychiatry Rep 2002;4: Trzepacz PT. The neuropathogenesis of delirium. A need to focus our research. Psychosomatics 1994;35: Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 nonventilated patients. Crit Care 2005;9:R Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. Long-term cognitive impairment after critical illness. N Engl J Med 2013;369: Lipowski ZJ. Delirium (acute confusional states). JAMA 1987;258: Guenther U, Popp J, Koecher L, Muders T, Wrigge H, Ely EW, et al. Validity and reliability of the CAM-ICU Flowsheet to diagnose delirium in surgical ICU patients. J Crit Care 50

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R