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研究生:尹彙文
研究生(外文):Yien, Huey-Wen
論文名稱:全身性發炎反應症候群或深度昏迷病人及急性內毒素血症大白鼠之動脈壓頻譜分析
論文名稱(外文):Spectral analysis of systemic arterial pressure signals in patients with systemic inflammatory response syndrome or deep coma and rats with acute endotoxemia
指導教授:陳慶鏗陳慶鏗引用關係華瑜李德譽李德譽引用關係
指導教授(外文):Samuel ChenJulie ChanLee, Tak-Yu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:1997
畢業學年度:85
語文別:中文
論文頁數:266
中文關鍵詞:全身性發炎深度昏迷
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生物體的生命現象是由各種不同頻率的外在及內在律動 (rhythm)所支配,因此周期性是生物律動的特性,這些律動經過整合後可維持生物體的恆定性(homeostasis),而每一律動自然也受到其它調控律動之相互作用而產生變異性(variability,也就是說,變異性是生命力的基本法則。中樞神經系統及循環系統是表現生物體生命特質最重要的二個系統,所表現出的生命現象也各有其律動性(rhythmicity),二者之間必然是密切而且調諧的整合。
本論文是利用動脈壓訊號頻譜分析技術來探討危急重症狀態時,動脈壓波動中反應自主神經調控的較低頻成份與病人病情嚴重度及預後的相關性。研究的假說是,在危急重症的瀕死過程中,心臟停止其本身的律動之前,中樞自主神經系統對循環系統的調控律動已先喪失。研究的目的是將加護病房常規監測的動脈壓訊號,經由頻譜程式分析,建立連續、即時及線上的動脈壓頻譜圖,發揮監視指標的功能,來密切觀察及早期評估危急重症病人的預後。實驗內容共包括四部份:臨床實驗分別在非心臟加護中心及神經加護中心選擇全身性發炎反應症候群 (Systemic Inflammatory Response Syndrome,SIRS)或深度昏迷之病人為對象,探討動脈壓頻譜成份變化與預後的相關性;而基礎實驗則以Sprague-Dawley大白鼠進行二部份的實驗,先建立以動脈壓頻譜分期(Staging)的急性內毒素血症動物模式,再探討氧化氮(NO)合成酉每抑制劑在此模式之治療效果。
全身性發炎反應症候群病人之動脈壓及心跳訊號頻譜分析與預後評估
本實驗於52位全身性發炎反應症候群的危急重症病人,以動脈壓訊號頻譜成份,包括高頻(high frequency,HF,0.15-0.45Hz)、低頻(low frequency,LF,0.08-0.15Hz)及極低頻(Very low frequency,VLF,0.016-0.08Hz)連續監視其變化。結果發現:當動脈壓及心跳的極低頻與低頻成份的功率密度逐漸增加,表示正在復原狀態;反之,此二成份的功率密度逐漸降低,以至於零,則表示瀕臨死亡。此外,極低頻成份預測的準確性比低頻成份還高,且均與現行之 APACHE Ⅱ評分結果一致。所得的結論是:動脈壓極低頻成份可以當成預測危急重症病人預後的監視指標,此頻率極低的動脈壓波動並非來自於myogenic的反應,而可能源於neurogenic的調控。
深度昏迷病人之動脈壓及心跳訊號頻譜分析與預後評估
本實驗於 21位 Glasgow 昏迷指數小於 6分的深度昏迷病人,同樣以動脈壓極低頻成份連續監視其變化,發現動脈壓極低頻成份 (0.016-0.08Hz)是比Glasgow昏迷指數更敏感的預後預測的指標。亦發現當超低頻律動(ultra-low,equency,UTF,低於0.016Hz)逐漸出現高功率密度與規則化(regularity)及同步化(synchronization)的特慢血壓律動時,表示瀕臨死亡的狀態。所得之結論是:中樞神經系統對循環系統調控的整合功能消失時,動脈壓極低頻成份的功率密度變小,或者低於 0.016Hz之同步化及規則化的特慢律動出現,是可以當作預測深度昏迷之危急重症病人預後的指標。
急性內毒素血症大白鼠致死過程之動脈壓頻譜分析及血清正腎上腺素濃度之變化
本實驗主要是在 Sprague-Dawley大白鼠,以致死劑量之 E-colilipopolysaccharide(LPS),誘發急性內毒素血症,全程以propofol 30mg/kg/h連續靜脈滴注,以維持穩定的麻醉深度及血流動力狀態,根據動脈壓訊號的極低頻成份功率密度之變化,將LPS誘導後至死亡的整個過程分期 (Staging),共分為三期;第一期:功率密度與誘導前相同,第二期:功率密度較誘導前增加,第三期:功率密度低於誘導前。動脈壓極低頻成份在瀕死過程之變化與前二部份臨床實驗之結果一致。在急性內毒素血症之大自鼠其正腎上腺素濃度與極低頻成份之功率密度,在第一期及第二期呈一致的正向變化,但在第三期則明顯的呈現dissociatio的反向變化。而在兩側腎上腺切除之大白鼠,全程正腎上腺素濃度均極低,沒有明顯的變化,但其動脈壓極低頻成份的變化,仍然顯示相同三個分期的型式,由此更加支持:在大白鼠急性內毒素血症致死過程中,極低頻成份之改變是源於neurogenic,可能源自於中樞交感神經對血管的調控,而非源自adrenal gland的sympathoadrenal activity。也因此血清正腎上腺素濃度和VLF的功率密度並不具相關性。
以動脈壓頻譜成份評估氧化氮 (NO)合成酉每抑制劑在急性內毒素血症大白鼠之治療效果
本實驗是延用上述已建立之動物模式,取不同的時間點給藥︰一為在給予LPS之前10分鐘給藥的前處理;一為第二期,在極低頻成份之功率密度開始增加後20分鐘給藥,分別給予的是對誘導性氧化氮合成酉每為非專一性之抑制劑L-NAME以及較具專一性的L-canavanine和aminouanidine。我們以存活時間作為觀察指標,根據動脈壓極低頻成份來評估這些NO合成酉每抑制劑的治療效果。結果發現:這三種抑制劑不論是否具專一性,均無法有效阻斷第三期病程的進行,最後仍終至死亡;其存活時間則與第二期所佔的時間長短(duration)呈正相關;高劑量的L-NAME經過前處理後不但無效,反而是加速死亡;低劑量的L-canavanine及 aminoguanidine在第二期給藥時,可明顯增加第二期所佔的時間長度,以延長存活時間。另外,在正常大白鼠,分別單給這三種抑制劑,結果都造成死亡,其存活時間與劑量大小呈負相關。所得的結論是:NO雖然在敗血症扮演極重要的角色,但是若單獨給予NO合成酉每抑制劑來治療是無效的;即使低劑量的誘導性NO合成酉每抑制劑可延長存活時間,卻仍無法有效阻斷病情之惡化。
結論:在全身性發炎反應症候群或昏迷病人及急性內毒素血症大白鼠,在心臟律動停止之前,自主神經系統對循環系統調控的律動已先喪失。動脈壓頻譜極低頻成份之功率密度增加,表示正在康復中,反之,若減少以至於零,則表示瀕臨死亡。此極低頻成份是源於neurogenic,而非myogenic的反應。可能源自於中樞交感神經對血管的調控,而非源自adrenal gland的sympathoadrenal activity,所以血清中正腎上腺素濃度和VLF的功率密度並不具相關性。而以氧化氮合成酉每抑制劑來治療急性內毒素血症,並不能有效阻斷第三期病程(極低頻成份功率密度減小)的進行而終至死亡,且其極低頻成份的變化與不經治療而自然死亡的形式是一致的。本論文的結論是利用動脈壓頻譜分析技術,動脈壓極低頻成份可以當成預測死亡的指標及病期嚴重度的分期依據。
All living organisms are under the summation oscillation of all external or internal rhythms. Biological homeostasis is therefore the integration of these different rhythms in one system. The counteraction between different oscillations produces variability, which is the law of life. Central nervous system and cardiovascular system are two most fundamental representatives of living being. All the physiological phenomena in these two systems not only show their own rhythmicity per se but also integrate as harmonic fluctuation.
We used the power spectral analysis (PSA) of systemic arterial pressure (SAP) and heart rate (HR) signals to predict outcome in critically ill patients. In particular, we evaluated the relationship between the very low frequency component of SAP signals and the patients'' viability. We hypothesized that in terminal stage of patients with systemic inflammatory response syndrome (SIRS) or deep coma and acute endotoxemic rats, decrease or absence of neurogenic control of cardiovascular system may precede cardiac arrest. Continuous, on-line, real-time PSA of SAP and HR signals was carried out in four sets of experiments. Two sets were on patients with SIRS in the noncardiac intensive care unit (ICU) and deep coma patients in the neurological ICU to predict patient outcome. Two other studies were performed in Sprague-Dawley rats to stage acute endotoxemic shock and determine the therapeutic effects of nitric oxide synthase inhibitors.
Spectral analysis of systemic arterial pressure and heart rate signals as aprognostic tool for prediction of patient outcome in the intensive care unit
We observed 52 cases of SIRS patients in adult ICU to correlate the changes in three specific spectral components (high frequency, HF, 0.15-0.45 Hz; low frequency, LF, 0.08-0.15 Hz; and very low frequency, VLF, 0.016-0.08 Hz) of SAP and HR signals with the Acute Physiology, Age and Chronic Health Evaluation II (APACHE II) score. A progressive increase in the power density of both LF and VLF components of SAP and HR signals appeared to be related to recovery. Conversely, a progressive decrease in the power density of these spectral components was indicative of deterioration and near-zero density means fatality. The VLF component has higher precision of predictability than the LF power and is the same as the APACHE II scoring system. Our conclusion in this study is that power spectral analysis of SAP and HR signals offers a reasonable monitor for acute, critically ill patients, and may be used as an alternative prognostic tool for prediction of patient outcome in the ICU.
Spectral analysis of systemic arterial pressure and heart rate signals in deep coma patients as outcome predictor in the neurological intensive care unit
We evaluated 21 deep coma patients who had severe brain damage, with less than 6 points in the Glasgow Coma Scale. We found the VLF power density of SAP signals could be a more sensitive index for outcome prediction than the Glasgow Coma Scale. With the appearance of ultra-low (< 0.016 Hz) oscillation, a regular, synchronized SAP fluctuations appeared and sudden termination of cardiac activity would occur at any time. Our conclusion is that a decrease in the power density of VLF component of SAP signals to near-zero or an slow down of SAP fluctuations to the ultra-low frequency(< 0.016 Hz) may be used for outcome prediction in deep coma patients.
Spectral analysis of systemic arterial pressure signals in acute endotoxemic rats and its correlation with serum norepinephrine concentration
We staged the course of death in acute endotoxemic rats injected with a lethal dose of lipopolysaccharide (LPS) by power spectral analysis of SAP signals. We identified three phases after i.v. injection of LPS (15 mg/kg) to Sprague-Dawley rats under propofol anesthesia (30 mg/kg/hr, i.v.), based on the changes in the power density of the VLF (0.0-0.25 Hz) signals.The power density of VLF remained stable at the control level after LPS injection (Phase I), gradually increased, reached a peak, then declined to the control level (Phase II), finally fell to near-zero level (Phase III). The VLF power changes during the course of death in this animal study were almost the same as those in the above two clinical studies. Serum norepinephrine (NE) concentration was positively associated with changes in the power density of the VLF component of SAP signals during Phase I and II but dissociated in Phase III. However, LPS induced the same spectral pattern in rats that received bilateral adrenectomy without concurrent changes in serum NE concentration. This evidence support that in acute endotoxemic rats, changes in the VLF components is neurogenic in origin and unrelated to serum NE concentration. We conclude that staging based on power density of BVLF component may offer a much earlier and more reliable index to predict mortality in rats with acute endotoxemia.
Evaluation of the therapeutic outcome of nitric oxide synthase inhibitors by spectral analysis of systemic arterial pressure signals in acute endotoxemic rats
Using the above animal model, we studied the therapeutic outcome (survival time) of different nitric oxide synthase inhibitors (NOSI), including nonspecific NOSI, L-NAME (5, 20, or 60 mg/kg), specific inducible NOSI, L-canavanine (50, 100, or 300 mg/kg), and aminoguanidine (15, 45, or 90 mg/kg) in acute endotoxemic rats. Two dosing regimens, pretreatment ( 10 min before LPS injection) and Phase II treatment (20 min after VLF power started to increase), were used. Our results showed that none of these treatments prevented the advancement to Phase III and fatality. However, low dose L-canavanine (50 mg/kg) and aminoguanidine (15 mg/kg) in Phase II treatment could prolong the duration of Phase II and total survival time. High dose L-NAME (60 mg/kg) by pretreatment accelerated death. In rats without receiving endotoxin, all three NOSI shortened the total survival time. Our conclusions in this study are: (1). although nitric oxide has a role in endotoxemic shock, treatment with NOSI alone for sepsis is ineffective. (2). low dose of inducible NOSI can prolong the survival time but the fatality is inevitable.
Conclusions:In patients with systemic inflammatory response syndrome or deep coma and rats with acute endotoxemia, a decrease or absence of neurogenic control of cardiovascular system may precede cardiac arrest. The progressive changes in the power density of VLF component of SAP signals towards death during peripheral vasomotor failure (SIRS) or central failure (deep coma) in both animal and human studies demonstrated similar patterns. The VLF rhythm is neurogenic in origin, but not myogenic, and is not related to serum NE concentration in rate. Treatment with NOSI alone for acute endotoxemia is ineffective and cannot prevent the advancement to Phase III and inevitable death. We conclude that the VLF component of SAP signals can be used as a quantitative marker for prediction of death and staging of disease severity.
封面
目錄
中文摘要
英文摘要
前言
第一章 文獻回顧
第一節 生命律動的整合與協調
第二節 血流動力參數頻譜分析之生理與藥理研究
第三節 血流動力參數頻譜分析之臨床應用
第四節 加護病房情嚴重度評分系統與預後評估
第五節 全身性發炎反應症候群病人之血流動力參數變化與病情嚴重度及預後評估
第六節 深度昏迷病人昏迷指數與預後評估
第七節 急性內毒素血症大白鼠致死機轉之研究-氧化氨之角色
第二章 研究動機,假說,目的與實驗內容
第一節 研究動機
第二節 假說
第三節 研究目的
第四節 實驗內容
第三章 全身性發炎反應症候病人之動脈壓及心跳訊號頻譜分析與預後評估
第一節 背景與目的
第二節 材料與方法
第三節 結果
第四節 討論
第四章 深度昏迷病人之動脈壓及心跳訊號頻譜分析與預後評估
第一節 背景與目的
第二節 材料與方法
第三節 結果
第四節 討論
第五章 急性內毒素血症大白鼠致死過程之動脈壓頻譜分析及血清正腎上腺素濃度之變化
第一節 背景與目的
第二節 材料與方法
第三節 結果
第四節 討論
第六章 以動脈壓頻譜分析評估氧化氮合成梅抑制劑在急性內毒素血症大白鼠之治療效果
第一節 背景與目的
第二節 材料與方法
第三節 結果
第四節 討論
第七章 綜合討論
第一節 結論
第二節 本論文的特色
第三節 本論文的應用價值
第四節 本研究的受限因素
第五節 未來展望
參考文獻
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