應用中西醫學在預防與治療嚴重腦傷後缺氧病變之基礎與臨床研究

The basic and clinical researches of Chinese and Western medicine in the prevention and treatment of severe brain injury with hypoxic change

林乾閔(Chien-min Lin)

指導教授 ： 邱文達

共同指導教授 ： 李美賢(Mei-Hsien Lee)

臺北醫學大學/醫學院/臨床醫學研究所/博士(2012年)

摘要

頭部外傷是外傷中最致命也是導致失能的最主要因素，在台灣邱文達教授自1988~2002年15年之研究亦發現頭部外傷是外傷中最致命的，其死亡率是所有外傷中最高，估計美國每年就有150萬外傷性腦損傷的病人，並且估計有80,000- 90,000人將長期的失能。估計1995年美國外傷性腦損傷的直接和間接的費用總計563億美金，可見頭部外傷之預防及治療之重要性。頭部外傷之預防主要是防止腦部之初級傷害(primary injury)，但若不幸造成了primary injury則如何防止腦部的繼發性傷害(secondary injury)則為治療之首要目標。
在美國 Brain Trauma Foundation and American Association Neurolgic Surgeons於1995年根據實証醫學訂定了 Guidelines for the manage of severe head injury 而且依據準則併以顱內壓ICP為治療主軸的病人，確實能降低死亡率。2000年的準則提出腦灌流壓CPP須大於70mmHg才足以維持腦部灌流的最基本要求，但2003年則反而提出只要大於60mmHg即可維持腦部灌流的最基本要求，併可以防止過度使用升壓劑而造成併發症。無論以ICP或CPP為治療主軸的方式都是為了防止腦部的灌流不足進而導致缺血缺氧及腦細胞的凋亡及壞死，但以目前的治療方式是否真正足以防止缺氧呢?是否有藥物可降低腦部缺氧後的傷害呢?
因此研究如何預防與治療腦細胞之缺氧正是本論文之研究主題，本論文之研究方向主要是針對四大主題進行相關之基礎及臨床研究，其結論與摘要如下：
1. 以氧分壓監測器為主之治療防止腦部之缺氧。ICP及CPP是監測全部腦血流平均值，無法提供局部受傷腦細胞的真實狀況，而pbtO2是直接監測局部受傷腦細胞的氧分壓，因此如何才能達到確實防止腦部缺氧是本研究的目標。由本研究發現，PbtO2組確實會改善死亡率、3個月及6個月後的GOSE，因此以PbtO2為導向的治療方法,在中度和重度腦外傷的病人可能是有價值的，而且我們意外發現要維持受傷腦細胞之腦組織氧分壓大於20mmHg其血氧分壓必須大於150mmHg，有別於正常人大於60mmHg已經足夠。
2. 適當的腦灌流量以減少腦傷之缺氧。何謂適當的CPP呢?是否為每個人都相同呢?依受傷的程度年齡是否也有差異呢? 本研究共搜集180例嚴重腦傷病患。若將病人依年紀來分，小於65歲的人需要積極維持CPP大於60mmHg有明顯改善存活率及GOS；大於65歲的人，可能因為維持CPP而產生更多的併發症，進而影響預後。將病人分為三組 A：為3分 B：4及5分 C：6.7.8分 來探討各組適當的CPP。在C組（GCS：6.7.8）者能將CPP維持在60mmHg以上者有較佳的預後，其它A及B組則無顯著差異。但對於腦壓高且腦幹受傷的病人則須要比較高的CPP > 70 mmHg 。
3.特殊狀況下之治療模式--改善癲癇與防止腦缺氧之研究。腦部受傷後的病人，增厚的疤痕組織常常被認為與阻礙神經發展恢復的原因，甚至於被認為與頭部外傷後的癲癇。當癲癇發作時，因暫時停止呼吸，同時因腦部放電亦造成水腫，兩者都可能造成腦細胞缺氧。因此改善癲癇的發作，可防範腦部的缺氧避免腦細胞的損傷。 腦部受傷後減少大腦皮質疤痕組織的成長可減少癲癇的發作。如何能減少大腦皮質疤痕組織的成長﹖在本研究中，使用玻尿酸組(實驗組)無論是4週，8週，或是12週的老鼠，中樞神經系統受傷表面疤痕組織中GFAP+細胞的數目都較對照組的老鼠受傷腦部表面少。受傷後神經疤痕組織的厚度及神經膠質化的程度也較趨於緩和。這可改善癲癇的發作防範腦部的缺氧 。
4.使用神經保護藥物來防止腦部缺氧。 據我們所知，腦細胞的缺氧會導致caspase 3、8的活化與表現，若能使用藥物防止細胞凋亡(apotosis)的產生也可改善腦細胞缺氧後的病變。葛根(Pueraria Kadix)是傳統的中藥材，中醫上是用來退燒解痙的藥材，本研究乃由葛根(pueraria radix)分離五種異黃酮化合物(isoflavone compounds)：daidzein (1)、daidzin (2)、puerarin (3)、genistin (4)和genistein(5)等，本研究發現其中daidzein (1)及genistin (4)具有神經保護作用，我們用此二化合物來防止6-OHDA對NGF分化的PC 12 cell的傷害，此二種化合物不會影響6-OHDA的自身氧化反應及活性氧的產生。而可藉由抑制caspase-8及部分caspase-3來防止細胞死亡進而達到神經細胞之保護作用。
本論文從臨床適當的腦灌流量及維持足夠之腦組織氧分壓之研究，到基礎以玻尿酸改善癲癇進而防止腦缺氧，更進而使用中藥葛根來阻止因腦組織缺氧造成凋亡途徑, 期能在腦傷後能更有效防止腦細胞壞死，進而得到較佳之預後。

關鍵字

腦組織氧分壓 ； 顱內壓 ； 腦部灌流壓 ； 昏迷指數 ； 預後量表 ； 玻尿酸 ； 葛根 ； 6-羥基多巴胺 ； 凋亡 ； 半胱氨酸天冬氨酸酶-3 ； 半胱氨酸天冬氨酸酶-8 ； 活性氧化物

並列摘要

Traumatic brain injury is the most important factors mortality and disability.In Taiwan, professor Chiu Wan-ta from 1988 to 2002, the 15-year study also found that head trauma is the most factor of mortality in the trauma, the mortality rate can be as high as 28.7%, it is estimated that 1.5 million patients with traumatic brain injury each year in the United States. Because of these injuries resulting in 50,000 deaths, 230,000 people receiving hospital treatment, and an estimated 80,000 - 90,000 people will be long-term disability. The estimated direct and indirect costs of traumatic brain injury was a total of 563 billion U.S. dollars in the United States in 1995. It is important to prevent and treat the head trauma . The prevention of head injury is to prevent the primary injury. If unfortunately the primary injury happened, It is important that how to prevent and treat brain secondary injury.

Whether ICP or CPP treatment guided in order to prevent the hypoperfusion of the brain leading to ischemic hypoxia and brain cell apoptosis and necrosis, but the treatment is really sufficient to prevent hypoxia it? Whether theredrugs can reduce the damage in the brain after hypoxia. How prevention and the treatment of brain cells hypoxia is the topic of this thesis. This thesis research is mainly related to basic and clinical research for the four main themes, its conclusions are summarized as follows: (A) Oxygenpressure monitor mainly for treatment to prevent brain of hypoxia. Monitoring brain tissue oxygen pressure (PbtO2) was recommended to accompany with intracranial pressure (ICP)/cerebral perfusion pressure (CPP) management for a better outcome in recent years. . The aim of this prospective randomized study was to evaluate the effect of PbtO2 guided therapy (mainly maintain a PbtO2 > 20 mmHg) on the management of cerebral variables, therapeutic interventions, survival rate, and neurological outcome of moderate and severe TBI patients compared with traditional ICP guided treatment This finding demonstrates that PbtO2 absolutely correlated with neurological outcome, and therapy directed by PbtO2 may be valuable to treat patients sustained moderate and severe TBI.(B)The appropriate brain perfusion in order to reduce the hypoxia of the brain injury. If we divided patients according to age, less than 65 years of age need to actively maintain CPP greater than 60mmHg had significantly improved survival and GOS. The patient with high intracranial pressure and brain stem injury is required for CPP> 70 mmHg. Therefore, the various status of the patient need to CPP is not the same(C) special conditions of treatment modalities - to improve epilepsy and to prevent the study of cerebral hypoxia. Seizures, due to a temporary cessation of breathing, while the discharge of the brain has resulted in edema, both of which may result in cerebral hypoxia. Therefore, to improve the seizures can prevent brain hypoxia to avoid the damage of brain cells. The results supported the hypothesis that HA inhibited glial scarring not only in the thickness but also in the number of the glial cell. In the further, HA might be used in CNS surgery for the scarring reduction regimen to prevent the post operation or post traumatic seizure incidence (D) the use of neuroprotective drugs to prevent brain hypoxia. Daidzein(1) and genistein (4),from Pueraria radix have neurocytoprotective effects against 6-OHDA-induced cytotoxicity in NGF-differentiated PC12 cells. Neither daidzein (1) nor genistein (4) affected 6-OHDA-induced ROS generation; however, both compounds suppressed caspase-8 and partially suppressed caspase-3 activation as well as protected against 6-OHDA-induced cytotoxicity in NGF-differentiated PC12 cells.

並列關鍵字

Partial pressure of brain tissue oxygen ； Intracranial pressure ； Cerebral perfusion pressure ； Glasgow coma score ； Glasgow outcome score ； Hyaluronic acid ； Pueraria thomsonii ； 6-OHDA ； apotosis ； Caspase-3 ； Caspase-8 ； Reactive oxygen species

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