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1 Anesth Pain Med 2010; 5: 146~150 임상연구 뇌하수체선종환자의수술전호르몬변화와 propofol, remifentanil 마취제요구량의상관관계 연세대학교의과대학마취통증의학교실, * 마취통증의학연구소 김은미ㆍ최은미ㆍ최승호 * ㆍ허상백ㆍ민경태 * Correlations of preoperative hormonal changes with propofol and remifentanil requirements in pituitary adenoma patients Eun-mi Kim, Eun Mi Choi, Seung-Ho Choi*, Sang-baek Heo, and Kyeong Tae Min* the maximal secretory capacity of prolactin also correlated positively with propofol induction Ce. Remifentanil consumption dose was not related with any hormones measured regardless of either preoperative basal levels or maximal secretory levels. Conclusions: Propofol requirements may be related with preoperative plasma level of ACTH or maximal secretory capacity of prolactin. (Anesth Pain Med 2010; 5: ) Department of Anesthesiology and Pain Medicine, Yonsei University Health System, *Research Instititute of Anesthesia and Pain, Seoul, Korea Key Words: Effect-site concentration, Hormones, Pituitary adenoma, Propofol, Remifentanil. Background: Anesthetic requirements are affected by the preoperative levels of some hormones. This study investigated to identify the hormonal status such as plasma level and maximal secretary capacity correlating with propofol and remifentanil requirements in pituitary adenoma patients who show various hormonal secretory states perioperatively. Methods: From 51 adult female pituitary adenoma patients, preoperative basal values and maximal stimulated levels of various hormones related to the axis of hypothalamus-pituitary-target organs on combined pituitary function test were recorded. Total intravenous anesthesia using target controlled infusion with propofol and remifentanil was administered. The effect-site concentration (Ce) of propofol reaching anesthetic induction and the consumed dosages of propofol and remifentanil during operation were measured. Anesthetic maintenance was controlled within 30% of preanesthetic hemodynamic variables by remifentanil and within ranges of BIS 45 ± 10 by propofol. Spearman correlations between hormonal status and anesthetic requirements such as propofol Ce for induction, total consumed doses of propofol and remifentanil were performed with a statistical significance at P of Results: The preoperative basal level of ACTH was correlated positively with propofol induction Ce and maintenance dose, and Received: February 22, Revised: 1st, March 4, 2010; 2nd, March 22, Accepted: March 23, Corresponding author: Kyeong Tae Min, M.D., Department of Anesthesiology and Pain Medicine, Yonsei University Health System, 250, Seungsan-ro, Seodaemun-gu, Seoul , Korea. Tel: , Fax: , ktmin501@yuhs.ac This study was supported by a faculty research grant of Yonsei University College of Medicine for 2007(SH Choi). 서론시상하부-뇌하수체-말단기관 ( 부신, 갑상선, 생식기관등 ) 에이르는축은신체의중요한호르몬분비를담당하고있으며, 이축으로부터분비되는 ACTH와 cortisol의분비에대한 methohexital, midazolam 그리고 ethanol의반응은다소다르게나타난다 [1]. 뇌하수체전엽종양의약 25% 는뇌하수체기능이정상이지만대부분의종양은분화된세포종류에따라 prolactin (PRL), adrenocorticotropin hormone (ACTH), growth hormone (GH), thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) 등의합성과분비가달라지고, 시상하부-뇌하수체-말단기관의축과관련된호르몬들과서로연결고리를통해이들호르몬의변화는쿠싱질환 (Cushing disease), 고티록신혈증 (hyperthyroxinemia), 말단비대증 (acromegaly), 고프로락틴혈증 (hyperprolactinemia), 생식샘저하증 (hypogonadism) 등의다양한임상양상을나타낸다 [2]. 정맥마취제와흡입마취제가여러가지내분비반응에미치는영향에대한연구는많이시행되었지만 [3,4], 역으로몇몇내분비호르몬들의수술전분비상태역시마취제의요구량에미치는것으로알려져있다. 갑상선기능항진 [5], 여성의생리주기 [6], 남, 녀의성별 [7] 에따라, 또는뇌에서합성, 분비되는신경스테로이드호르몬 [8] 과 dopamine[9], catecholamine[10] 등은마취제의요구량에영향을미치는것으로알려져있으나확실하지않을뿐아니라이들호르몬 146

2 김은미외 4 인 : 호르몬변화와 propofol, remifentanil 요구량 147 의분비상태외에분비능력이마취제의요구량에어떤영향을미치는지는아직밝혀진바가없다. 본연구는뇌하수체종양의세포종에따라호르몬들의분비상태와분비능력이매우다양하게나타나는여성환자를대상으로여러가지호르몬들의변화상태와마취제요구량의상관관계를알아보고자하였다. Table 1. Patients Characteristics 대상및방법 본연구는임상연구심의위원회의승인을얻고환자로부터연구동의서를취득한후 TSA가계획된 20세부터 60세이하의여성환자 51명을대상으로하였다. 환자의특성은 Table 1에나타내었으며, 연령별환자분포는 20대, 30대, 40 대및 50대가각각 15명, 13명, 10명및 13명이었다. 수술당시임상증상에따른환자의구성은호르몬과잉분비에의한증상을보인환자가 33명이고, 종괴효과로인해신경압박증세를보인환자가 13명그리고비특이적임상증세를보인 3명과 2명은신체검사에서우연히발견되었다 (Table 2). 이들환자의수술전혈색소 (13.1 ± 1.0 mg%) 와혈중전해질들 (Na ± 2.0 meq/l, K ± 0.2 meq/l) 은모두정상범위에속하였다. 모든환자에게마취전처치를시행하지않았으며, 심전도표준전극 II, 맥박산소포화도계측기, 요골동맥압, 체온, Number of patients 51 Age (yrs) 39.9 ± 12.5 Ht (cm) 160 ± 4.7 Wt (kg) 62.2 ± 11.0 Values are number of patient or mean ± SD. 호기말이산화탄소분압, BIS (A-2000 BIS monitor, Aspect Medical System, Norwood, MA, USA) 등의지속적인감시아래마취방법을표준화시켰다. 목표농도조절주입 (Target controlled infusion, TCI) 기기로 Base Primea (Fresenius Vial, Brezins, France) 를사용하여 propofol (Schnider pharmacokinetic model) 과 remifentanil (Minto pharmacokinetic model) 을이용한전정맥마취를시행하였다. 마취유도는 propofol 의 effect-site concentration (Ce) 를 2.0 μg/ml로부터시작하여 0.5μg/ml 단위로증가시키면서, 혈중농도와목표농도가평형상태에도달 15초후에구두명령과가벼운움직임에대한반응이없을때를마취유도가된것으로정의하고이때의 propofol Ce를기록하였다. 이어 remifentanil은직접후두경삽입에도맥박의변화가마취전기준치의 30% 이내를유지하는상태 (Ce, 3 7 ng/ml) 에서 rocuronium 0.8 mg/kg을정주하여기관내삽관을시행하였다. 수술중마취의심도는 propofol을이용하여 BIS 의범위에서유지하였으며, remifentanil을이용하여혈압과맥박이마취전기준치의 30% 변화이내에서유지하도록하였다. 필요시수액요법과소량의승압제를사용하였다. 2 L/min의산소와공기혼합기체 ( 흡입산소분압 0.5) 로호기말이산화탄소분압이 mmhg로유지되도록조절환기시켰 Table 2. Clinical Disease Entities Cushing disease 3 Acromegaly 9 Amenorrhea 19 Galactorrhea 2 Mass effects 13 Non-specific 3 Incidental finding 2 Values are numbers of patient. Table 3. Preoperative Blood Concentration of Each Hormone Basal value Maximal value from stimulation test Median (Min, Max) Incr/NR (No. of pt.) Median (Min, Max) Incr/NR (No. of pt.) Estradiol (pg/ml) 29.8 (7.9, ) UC* ND T3 (ng/dl) (71.0, 280.1) 2/49 ND ft4 (ng/dl) 1.1 (0.4, 2.9) 1/50 ND TSH (μiu/ml) 2.0 (0.0, 11.7) 16/ (0.4, 41.9) 44/5 ACTH (pg/ml) 28.2 (5.0, 241.0) 6/ (11.8, 546.6) 28/21 Cortisol (ng/ml) (14.3, 424.7) 5/ (21.1, 513.3) 16/33 FSH (miu/ml) 5.7 (0.4, 93.9) UC* 15.6 (0.7, 163.5) UC LH (miu/ml) 4.1 (1.0, 23.0) UC* 26.1 (2.1, 132.0) UC Prolactin (ng/ml) 16.7 (1.0, 310.0) 26/ (2.3, 310.0) 46/3 GH (ng/ml) 0.3 (0.0, 27.0) 6/ (0.2, 37.8) 25/24 T3: triiodothyronine, ft4: free thyroxine, UC*: uncounted due to wide rhythmic variabilities, ND: not determined, Incr/NR: increased/normal range.

3 148 Anesth Pain Med Vol. 5, No. 2, 2010 다. 능동적대류가온기 (Bair Hugger, Arizant Healthcare Inc. Eden Prairie, MN, USA) 를장착하여액와체온 o C 를유지하였다. 수술전임상증상에따라내원일주일이내에환자들의혈중호르몬들 (estradiol, triiodothyronine [T3], thyroxine [T4], free thyroxine [ft4], thyroid-stimulating hormone [TSH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin [PRL], growth hormone [GH], adrenocorticotropic hormone [ACTH], cortisol) 의기저치와 luteinizing hormone release hormone (LH-RH), TSH, insulin을이용하여복합뇌하수체자극검사를통하여 TSH, LH, FSH, PRL, GH, ACTH, cortisol의 2시간동안최대반응치를기록하였다. 마취요구량의변수로마취유도시 propofol Ce와수술전과정에서사용된 propofol과 remifentanil의량 ( 용량 / 시간 / 체중 ) 과수술전에측정된각호르몬들의기저치와복합자극검사의 2시간동안의최대반응치들간의상관관계를 Spearman correlation (SPSS Inc., Chicago, IL, USA) 을이용하여구하였다. 유의수준 0.05 이하를통계적으로의의있는것으로간주하였으며각측정값들의기술은환자수, 평균 ± 표준편차또는정중값 ( 최소-최대 ) 으로표시하였다. 결과환자들의수술전호르몬의변화는 Table 3에나타내었다. T4는검사자의수가많지않아분석에서제외하였다. 수혈을요하는환자는없었으며, 수액공급과간헐적인 ephedrine 4 mg 정주만으로혈압이정상적인범위로유지되었다. 마취유도시 propofol Ce는 4.7 ± 1.2μg/ml였고이때의 BIS는 49.6 ± 11.8이었다. 총소요된평균마취시간은 ± 50.1분이며최소 155분에서최대 380분이소요되었다. 마취기간동안소요된 propofol과 remifentanil의량은각각 9.0 ± 3.1 mg/kg/hr ( ± mg) 과 8.4 ± 2.7μg/ kg/hr ( ± 834.5μg) 이었다. 마취유도시 propofol Ce와마취유지에소요되었던 propofol 량은 ACTH의수술전혈장기저치와양의상관관계를보였으며 (P < 0.05), 다른호르몬의수술전혈장기저치는통계적으로의미가없었다. 또한수술전의호르몬자극반응에의한 prolactin의최대혈장치또한 propofol의유도용량인 Ce와양의상관관계를보였으나 (P < 0.05), 다른호르몬들은통계적인의미가없었다. 이에반해마취유지에사용되었던 remifentanil 의사용량은어떠한호르몬의수술전상태 Table 4. Spearman Correlation (R) between Anesthetic Requirements and Preoperative Plasma Concentrations of Hormones Anesthetic induction Anesthetic maintenance Propofol (Ce) Propofol (mg/kg/h) Remifentanil (μg/kg/h) R P R P R P Age Basal value Estradiol T ft ACTH * * Cortisol FSH LH TSH PRL GH ACTH Maximal value Cortisol from stimulation test FSH LH TSH Prolactin * GH T3: triiodothyronine, ft4: free thyroxine, ACTH: adrenocorticotropic hormone, FSH: follicle-stimulating hormone, LH: luteinizing hormone, TSH: thyroid-stimulating hormone, GH: growth hormone, PRL: prolactin. *Notes the statical significances at P value of 0.05.

4 김은미외 4 인 : 호르몬변화와 propofol, remifentanil 요구량 149 와도상관관계가없었다 (Table 4). 고찰본연구결과뇌하수체선종으로수술을받는환자들을통하여수술전 ACTH 혈장기저치는 propofol의마취유도 Ce와마취유지에소요된양과양의상관관계를보였지만다른호르몬들의술전기저치는상관관계가없었으며, 수술전측정된 prolactin의최대분비능력은 propofol의마취유도 Ce와양의상관관계가있었으나다른호르몬들의최대분비능력은상관이없었다. 또한 remifentanil의마취유지소모량은측정된호르몬들의술전상태 ( 혈장기저치와최대분비능력 ) 와연관이없었다. 뇌하수체전엽종양환자의 75% 정도는분화된세포종류에따라여러가지호르몬의과잉분비를보이는선종을형성하는데 [2], 뇌하수체전엽호르몬의분비정도는시상하부-뇌하수체-말단기관 ( 부신, 갑상선, 생식기관 ) 에이르는상호양, 음의 feedback을통하여 Cushing s disease, 말단비대증, 유즙과다분비, 무월경및불임등다양한임상양상을나타내거나, 뇌하수체자체의증대된크기로인해뇌하수체줄기 (stalk) 가압박되어이차적인호르몬의변화가초래될수있다. 따라서이들환자들은수술전호르몬의분비상태와분비능력에따른마취제요구량과의상관관계를연구하기에유용할것으로사료되었다. 스트레스호르몬의분비상태가마취제의요구량에영향을미칠수있음은이미많은연구에의해제시된바가있는데, Torres 등에의하면실험쥐에서외부로부터투여된 ACTH은혈장과뇌에서 neurosteroid인 allopregnanolone을증가시키고 [11], allopregnanolone은마취제의작용처로생각되는 GABA 수용체의기능을조절하여불안, 공포등의행동양상에영향을미친다고하였다 [12]. 그러나또다른 neurosteroid인 progesterone도항불안효과를가지고있다고알려져있다 [13]. 따라서 ACTH가보이는마취유사효과들은직접적인효과보다는 allopregnanolone을통한 GABA 수용체의작용으로나타난다고하여 [14], ACTH와같은스트레스호르몬이마취제의소모량에연관이있음을시사하였다. 그러나본연구에서는 ACTH의수술전혈장기저치는 propofol의마취유도뿐아니라유지에필요한용량과양의상관관계를보였으므로 ACTH의기저치가높을수록 propofol 의요구량이많아짐을의미한다. 이는아마도 ACTH의혈장치가지속적인증가로인해수용체특히, propofol의마취작용이나타나는 GABA 수용체의구조적인변형이나숫적인변화가 [15] 이미수반되어있을것으로생각할수있으나 [16], 아직이를증명할만한연구가없다. Prolactin (PRL) 의수술전기저치는 propofol의마취유도용량과연관관계를보이지않았으나최대분비능력은 propofol 의마취유도 Ce와양의상관관계를보였다. 흥미롭게도 Torner 등은 [17] prolactin이항불안및항스트레스효과를보인다고밝힌실험결과가있었는데, 이들의연구에서는내재적인 prolactin의증가에의한결과가아니고외부에서 prolactin을주입한쥐에서행동양식의변화를관찰하였다. 본연구결과와다소다른임상결과를보인연구를 Hong 등이보고한바있는데, 체외수정을위해난자채취술을시행받은여자환자들을대상으로한연구에서 PRL의혈중농도가높을수록진정에필요한 propofol 요구량이증가하는상관관계를보였다고하였다 [18]. Prolactinoma환자에게효과적으로사용되는 dopamine은 prolactin의분비를효과적으로줄이는효과가있으며실험에서도외부로부터뇌실질내로주입된 dopamine은흡입마취제의요구량이감소됨을관찰하였으므로 [9] prolactin의분비능력이마취제의요구량에영향을미칠수있을가능성은있지만다양한환경에노출이되는임상에서확인하기는어려울것같다. 이외에도마취제의요구량에영향을미칠수있는호르몬들이몇가지제시된바있는데, 시상하부-뇌하수체-생식기계축에서분비가조절되는 estradiol 성호르몬에대한연구에서 BIS를이용하여부인과수술을받는 44명의마취심도가평가되었는데, 수술전 estradiol 수치가높을수록마취제요구량이감소하는상관관계가있다고 Yavuz 등이보고하였지만 [19] 이연구자들역시대상환자의수가적기때문에많은환자를통한연구의필요성을강조하였다. 여성의 luteal phase 생리기간에증가되는 progesterone은 [13] 마취제의소모량을감소시킨다는연구결과가있었고, 동양인의경우여성이남성보다 xenon 요구량이 26% 적었다는보고도있었다 [7]. Fillingim과 Ness는 [20] FSH, LH, progesterone 등성관련호르몬들이통증반응에미치는영향에대한 31 개의연구들을분석하였는데, 성과관련하여말초와중추신경계로의통증유입체계에영향을미칠것으로생각되고일부연구에서는여성의생리주기에따른통증역치가차이가날수있었다는사실만제시하였다. 그렇지만생식기계의호르몬이마취제의요구량과무관하다는상반된결과도 [21] 보고되었다. 본연구에서정상생리주기를고려하지않은뇌하수체종양환자에서적어도 LH, FSH는정맥마취제인 propofol과 remifentanil의소모량과의상관관계는없었음을확인하였다. 갑상선자극호르몬 (TSH) 에의한갑상선기능항진증환자는 propofol의제거율과분포구획량 (distribution volume) 이증가하여마취유도시 propofol의요구량이증가할수있다고하여마취제소요량과의연관성을보고한바있다 [22]. 갑상선기능에따라 propofol의단백질결합또한변하게되므로마취제소모량이영향을받을수있다. 최근의연구에의하면마취제소요량은비교하지않았지만술전 T3를복용한심장수술환자에서대조군에비해수술중혈역학

5 150 Anesth Pain Med Vol. 5, No. 2, 2010 적관리가유리하였다고하였다 [23]. 본연구에서 T3, ft4, TSH는마취유도시 propofol Ce와수술전과정에서소요된 propofol과 remifentanil의소모량과연관성이없었다. 마취제는호르몬들의분비상태에영향을미치는것으로알려져있지만, 역으로마취제의요구량또한성호르몬이나스트레스호르몬들의수술전분비상태에의해영향을받을수있음이보고되었지만명확하지않다. 본연구에서는뇌하수체선종환자들을대상으로, 시상하부-뇌하수체-말단기관축에연관되는호르몬들의수술전에다양하게변화된기저치뿐아니라분비능력에따라마취제요구량과상관관계를보이는호르몬을알아보고자하였는데임상적으로많은환자를연구대상에포함하기가현실적으로어려움이많기때문에각각호르몬들을지표로한요인분석을시행할수없었고상관관계만제시할수밖에없었던아쉬움이있었으며, estradiol, LH, FSH 등은오전중에혈액을채취하였지만 wide diurnal variation으로인해 Table 3에기저치의증감을표시할수없었으며혈장내의농도에따라상관관계만을조사하였다. 결론적으로수술전 ACTH와 prolactine의수술전기저치는 propofol 마취유도용량과양의상관관계를보였으며, ACTH 기처치는마취전과정에서소요된 propofol의요구량과도양의상관관계가있음을관찰하였다. 그러나, remifentanil은본연구에서관찰한어떠한호르몬들의수술전분비상태나분비능력과상관관계를보이지않았으나, 향후보다많은대상의 cohort 연구가필요할것으로생각한다. 참고문헌 1. Broadbear JH, Winger G, Woods JH. Self-administration of methohexital, midazolam and ethanol: effects on the pituitary-adrenal axis in rhesus monkeys. Psychopharmacology (Berl) 2005; 178: Melmed S. Mechanisms for pituitary tumorigenesis: the plastic pituitary. J Clin Invest 2003; 112: Adams HA, Schmitz CS, Baltes-Goetz B. Endocrine stress reaction, hemodynamics and recovery in total intravenous and inhalation anesthesia. Propofol versus isoflurane. Anaesthesist 1994; 43: Mistraletti G, Donatelli F, Carli F. Metabolic and endocrine effects of sedative agents. Curr Opin Crit Care 2005; 11: Tsubokawa T, Yamamoto K, Kobayashi T. Propofol clearance and distribution volume increase in patients with hyperthyroidism. Anesth Analg 1998; 87: Sener EB, Kocamanoglu S, Cetinkaya MB, Ustun E, Bildik E, Tur A. Effects of menstrual cycle on postoperative analgesic requirements, agitation, incidence of nausea and vomiting after gynecological laparoscopy. Gynecol Obstet Invest 2005; 59: Goto T, Nakata Y, Morita S. The minimum alveolar concentration of xenon in the elderly is sex-dependent. Anesthesiology 2002; 97: Belelli D, Herd MB, Mitchell EA, Peden DR, Vardy AW, Gentet L, et al. Neuroactive steroids and inhibitory neurotransmission: Mechanisms of action and physiological relevance. Neuroscience 2006; 138: Onozawa H, Miyano K, Tanifuji Y. Effect of dopamine content in rat brain striatum on anesthetic requirement: an in vivo microdialysis study. Brain Res 1999; 817: Nakao H, Ono J, Nogaya J, Yokono S, Yube K. The relationship of brain catecholamine levels to enflurane requirements among three strains of mice with different anesthetic sensitivities. J Anesth 2001; 15: Torres JM, Ruiz E, Ortega E. Effects of CRH and ACTH administration on plasma and brain neurosteroid levels. Neurochem Res 2001; 26: Pinna G, Agis-Balboa RC, Pibiri F, Nelson M, Guidotti A, Costa E. Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice. Neurochem Res 2008; 33: Erden V, Yangin Z, Erkalp K, Delatioglu H, Bahceci F, Seyhan A. Increased progesterone production during the luteal phase of menstruation may decrease anesthetic requirement. Anesth Analg 2005; 101: Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol 1995; 7: Krasowski MD, Koltchine VV, Rick CE, Ye Q, Finn SE, Harrison NL. Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane. Mol Pharmacol 1998; 53: Pisu MG, Mostallino MC, Dore R, Mura ML, Maciocco E, Russo E, et al. Neuroactive steroids and GABAA receptor plasticity in the brain of the WAG/Rij rat, a model of absence epilepsy. J Neurochem 2008; 106: Torner L, Toschi N, Pohlinger A, Landgraf R, Neumann ID. Anxiolytic and Anti-Stress Effects of Brain Prolactin: Improved Efficacy of Antisense Targeting of the Prolactin Receptor by Molecular Modeling. J Neurosci 2001; 21: Hong JY, Kang IS, Koong MK, Yoon HJ, Jee YS, Park JW, et al. Preoperative anxiety and propofol requirement in conscious sedation for ovum retrieval. J Korean Med Sci 2003; 18: Yavuz L, Eroglu F, Ceylan BG, Ozsoy HM, Ozbasar D. High estradiol levels and depth of anaesthesia. Clin Exp Obstet Gynecol 2007; 34: Fillingim RB, Ness TJ. Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev 2000; 24: Tanifuji Y, Mima S, Yasuda N, Machida H, Shimizu T, Kobayashi K. Effect of the menstrual cycle on MAC. Masui 1988; 37: Ishizuka S, Tsubokawa T, Yamamoto K, Kobayashi T. Propofol pharmacokinetics in a patient with TSH producing pituitary adenoma. Masui 2001; 50: Lee JY, Park HY, Kim BS, Kwak YL. Cardiovascular effects of oral tri-iodothyronine in patients undergoing valvular cardiac surgery. Korean J Anesthesiol 2009; 56:

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