鄭劍廷Chien, Chiang-Ting吳峻宇Wu, Chun-Yu2019-09-052018-12-252019-09-052016http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22G080243002S%22.&%22.id.&amp;http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/103969靜脈輸液可視為一種藥物治療，為改善低血容狀態下身體循環的第一線治療方式，因此可算是所有外科病人最常接受到的治療項目。適當的靜脈輸液應包含三個層面：正確的輸液種類、正確的輸液時機以及正確的輸液總量，這三個層面只要有其中一項沒有達到，靜脈輸液便可能無法發揮療效，甚至導致傷害。 靜脈輸液治療的目的，在於改善低血容狀態(例如:出血性休克)下的循環狀態。目前文獻已經證明，微循環(小於100微米小血管)的改善，比傳統大循環系統指標(如:平均動脈壓、心跳數)，與預後有更高的關聯性。不同腹部臟器微循環，例如:肝、腎、腸組織，不但對低血容有不同的耐受度，也是病變發展成多器官衰竭的關鍵因子。治療低血溶狀態時，唯有改善腹部臟器微循環才可真正預防不可逆的器官傷害。因此本論文的第一部分前半段，乃是利用雷射斑駁影像技術，發展出可即時同步觀察在出血性休克時，腹部臟器微循環變化的大鼠模型。我們發現雖然微循環血氧濃度在各腹部臟器中，有等量下降的狀態，但以腸黏膜微循環血流量對於出血性休克有最差的耐受性，相對之下，肝腎與周邊肌肉組織的微循環血流量則有較佳的耐受性。 而本論文的第一部分後半段，則希望進一步探討臨床上常使用的靜脈液體製品包含晶體溶液(如:0.9%食鹽水)、膠體溶液(如:澱粉製品與明膠製品)以及高張溶液(如:3%食鹽水)，在出血性休克狀態下，對腹部臟器微循環的療效差異。以不同種類靜脈輸液治療，不僅可能會造成不同程度的循環改善，也可能伴隨不同程度的缺血再灌流症狀而造成不等量的氧化壓力。在腹部臟器中，以腎臟有最明顯的缺血再灌流效應。臨床上，以治療膠體溶液治療重症病人的低血溶狀態，被發現有較高機率在治療後發生急性腎損傷，這個現象可能與缺血再灌流與氧化壓力有關。因為氧化壓力產物有極短的半衰期，因此我們利用活體自由基偵測技術，精確定量大鼠在出血性休克下與靜脈輸液治療後，腎組織活體自由基產生的變化。我們發現，以靜脈輸液治療出血性休克，晶體溶液無法改善腸黏膜微循環血流量，只有膠體溶液與高張溶液可有效改善腸黏膜微循環血流量。但是膠體溶液，包含澱粉製品以及明膠製品，相較於晶體溶液與高張溶液，會產生極大量的腎臟自由基，此現象極有可能與臨床文獻觀察到膠體溶液造成的急性腎損傷相關。總結本論文第一部分的前半與後半段，我們發現到腸黏膜微循環血流量對於出血性休克狀態下有最明顯的損傷，臨床的靜脈輸液治療僅有膠體溶液與高張溶液可以有效改善腸黏膜微循環血流量。但是使用膠體溶液治療時，有可能造成缺血性再灌流症狀而產生大量腎臟氧化壓力而導致急性腎損傷。 臨床上，如何精確判斷適當的靜脈輸液量時機。目前臨床上最適合的輸液指標，當屬動態輸液反應性指標。這類指標可反映出在正壓呼吸下，心臟與肺部間相互影響下的變異率。體容越低的狀態下，心臟受到呼吸的吸氣期與吐氣期的擠壓影響變越大，反映在同一個呼吸週期下的脈搏壓、心輸出量的變異率變越大。因此當動態輸液反應性指標反映出變異率高過閾值時，給予靜脈輸液便有極高機率可提升心輸出量(此現象稱之為「輸液反應性」)，進而改善循環。但這類指標過去多半是在血管張力正常的病人中被應用，而臨床上有某一些特殊病理狀態會造成血管張力的異常，例如:肝硬化的患者，因為體內血管擴張物質無法被正常代謝，而有周邊血管阻力大幅下降的特徵。但是動態輸液反應性指標，卻從未在肝硬化病人身上證實有效。本論文的第二部分，探討我們在肝硬化病人，驗證目前臨床上最常見的三種動態輸液反應性指標，包括:脈搏壓變異率、心搏量變異率以及指端血容積變異率，是否在肝硬化病人也適用。結果我們發現，這三個指標在肝硬化病人身上，雖然較其他外科病人有較為下降的準確度，仍保有臨床實用的偵測度，足以幫助臨床醫師，判斷肝硬化病人是否可藉由靜脈輸液而改善心輸出量與循環。 本論文的第三部分，希望探討如何判斷正確的靜脈輸液總量，而此議題針對不同的手術器官，可能存在不同的標準。因為若器官沒有缺血風險存在，則即使在靜脈輸液可提升心輸出量而改善循環的時機下，過量的輸液仍可能導致組織水腫而造成傷害。以腦部手術而言，此類的臨床判斷充滿挑戰性。因為腦部組織佔總體心輸出量的比例極高，尤其在手術過程中可能有更高的血流量需求，但同時過多的輸液也可能因腦組織水腫而造成傷害。前述之動態輸液反應性指標，研究證實存在著一個「灰色地帶」，在此區間的下界限值與上界限值，分別代表了對輸液反應性高特異度與高敏感度的狀態，亦即手術中輸液若以下界限值與上界限值為目標，分別代表著儘量輸液增加心輸出量與謹慎(限制性)輸液以避免過多體液的輸液策略。依此特性，我們在腦部切除手術患者，驗證究竟腦部手術的靜脈輸液量較適合在動態輸液反應性指標灰色地帶的上界或下界。研究結果發現，靜脈輸液控制在下界的患者，有較短的加護病房停留時間、較少的術後神經學症狀、較佳的出院日常生活功能性評分、較少的術中乳酸堆積，以及較少的術後血清神經專一性蛋白表現。證實接受腦部手術患者 ，術中輸液量應以儘量增加心輸出量為目標，才是較佳的輸液策略。 靜脈輸液治療在手術狀態下的重要性，在現代醫學的進步下，不但沒有減少，反而更加重要。總結本論文的發現，我們從基礎醫學的動物模型探討腹部臟器微循環在低血容下的病理變化，進一步證實高張溶液與膠體溶液對腸黏膜微循環的效果，並且發現膠體溶液對於腎臟缺血再灌流的現象可能與急性腎損傷相關。進一步到臨床應用上，證實動態輸液反應性指標此類參數，在肝硬化此類血管張力特殊變化的病人，仍然足夠精確幫助臨床醫師判斷靜脈輸液的時機點。最後，在腦部手術中，證實靜脈輸液量已儘量增加心輸出量的目標的策略，對於預後有較佳的效果。對於靜脈輸液治療中，「正確的輸液種類、正確的輸液時機以及正確的輸液總量」這三個層面，未來有更進一步機制的探討，將有機會更加增進手術患者的臨床照護。我們的研究從此觀點出發，未來，也將在此層面做出更深入的探討。Intravenous fluid therapy is considered the first-line drug treatment for hypovolemia, which is common in surgical patients. Appropriate intravenous fluid therapy comprises three aspects: the correct type of fluid, correct timing of fluid infusion, and correct amount of fluid infusion. If even one of these aspects is not achieved, intravenous fluid infusion may become injurious instead of being therapeutic. The aim of intravenous infusion therapy is to improve circulation during hypovolemia or hemorrhaging. Recent studies have demonstrated that microcirculatory (blood vessels<100 µm in diameter) improvement is more strongly associated with favorable outcomes than are traditional macrocirculatory indicators (e.g., mean arterial pressure and heart rate). Splanchnic microcirculatory impairment during hypovolemia may not only vary among organs (e.g., the liver, kidneys, and intestine) but is also associated with the development of multiple organ dysfunction syndrome. Only those fluid infusion therapies that improve splanchnic microcirculation can actually prevent irreversible organ damage during resuscitation from hypovolemic shock. Therefore, the first part of the first section of this dissertation addresses the development of a method for the real-time simultaneous observation of splanchnic microcirculatory changes during hemorrhagic shock by using laser speckle contrast imaging and tissue oxygen saturation in a rat model. We found that although the tissue oxygen saturation decreased homogeneously in multiple splanchnic organs, the microcirculatory blood flow was more vulnerable to hemorrhaging in the intestinal mucosa than in the liver, kidneys, and skeletal muscles. In the second part of the first section of this dissertation, we describe an exploration of the microcirculatory therapeutic effects of several common clinical intravenous fluid products, including crystalloid solutions (e.g., 0.9% saline), colloidal solutions (e.g., starch and gelatin products), and hypertonic solutions (e.g., 3% saline) during resuscitation from hemorrhagic shock. The use of different types of resuscitation fluids not only may result in variations in the extent of microcirculatory improvement but may also be associated with varying degrees of ischemia-reperfusion injury, expressed as oxidative stress. Among the abdominal organs, the kidneys are the most vulnerable to ischemia-reperfusion injury. In the clinical scenario, resuscitation from shock in critically ill patients by using colloidal fluids is associated with an increased risk of acute renal injury after treatment. This phenomenon is closely related to ischemia-reperfusion injury and oxidative stress. Because the products of oxidative stress have a very short half-life, we used an in vivo method to accurately quantitatively measure the amount of renal reactive oxygen species in rats during fluid resuscitation from hemorrhagic shock. We found that fluid resuscitation with a crystalloid solution could not restore microcirculatory blood flow in the intestinal mucosa. Instead, only colloidal and hypertonic solutions improved the microcirculatory blood flow in the intestinal mucosa. However, colloidal solutions, including starch and gelatin products, produce a considerably larger amount of renal reactive oxygen species than do crystalloid and hypertonic solutions. This phenomenon may be associated with acute renal injury after colloidal fluid resuscitation, as reported in the clinical literature. In the first section of this dissertation, we conclude that the microcirculatory blood flow in the intestinal mucosa is most vulnerable to hemorrhagic shock. Furthermore, both colloidal and hypertonic solutions can restore the intestinal microcirculatory blood flow during hemorrhagic shock. However, fluid resuscitation with colloidal solutions may result in significant ischemic-reperfusion injury, which is indicated by the production of a large number of renal reactive oxygen species. The accurate determination of the time for administering an intravenous infusion is clinically challenging. At present, the most precise indicators of the time for administering fluid infusion may be dynamic fluid responsiveness parameters. These indicators reflect the interaction between the heart and lungs during mechanical ventilation. The lower the blood volume, the greater the variations in hemodynamic parameters during the respiratory cycle are. Therefore, when the dynamic fluid responsiveness parameters are higher than their threshold values, a fluid challenge is likely to considerably increase the cardiac output (this phenomenon is called “fluid responsiveness”), thereby improving the circulation. However, the threshold values of the dynamic fluid responsiveness parameters are based on patients with normal vascular tones. Certain patient groups are characterized by an abnormal vascular tone, for instance, patients with live cirrhosis have reduced vascular resistance because vasodilation-inducing substances cannot be metabolized as a result of end-stage liver disease. In the second section of this dissertation, we describe an investigation on the accuracy of three dynamic fluid responsiveness parameters, namely pulse pressure variation, stroke volume variation, and the plethysmographic variability index, in patients with liver cirrhosis. We found that although these three indicators were less accurate for predicting fluid responsiveness in common surgical patients, they were sufficiently precise to predict fluid responsiveness in patients with liver cirrhosis. Therefore, clinicians can determine the correct time for fluid administration to patients with liver cirrhosis using these indicators. In the final section of this dissertation, we clarify how to determine the correct amount of intravenous fluid for infusion, particularly with regard to vital organs. If a vital organ does not have the risk of ischemia and although intravenous infusion can improve cardiac output, excessive fluid infusion may lead to tissue edema and injury. For brain surgery, such a clinical judgment is challenging because the brain tissue has high metabolic and perfusion demands, particularly during surgery. However, excessive fluid infusion may also result in brain edema, poor outcomes, and neuronal injury. Dynamic fluid responsiveness parameters are characterized with a “gray zone.” In this interval, the lower and upper limit cutoffs respectively represent a high specificity and high sensitivityof fluid responsiveness. In an intraoperative fluid strategy targeting the upper cutoff of the gray zone, the fluid challenge highly specifically increases cardiac output without the risk of tissue edema, but the sensitivity is low; hence, a restrictive fluid balance may exist. By contrast, in a fluid strategy targeting the lower cutoff of the gray zone, a higher intraoperative cardiac output may be achieved after the fluid challenge, but the risk of tissue edema simultaneously increases. With regard to brain surgery, we investigated whether different amounts of fluid infused during intraoperative fluid challenges favored the upper or lower cutoffs in the gray zone. The results revealed that patients receiving a fluid strategy targeting the lower cutoff of the gray zone had a shorter intensive care unit stay, fewer postoperative neurological events, a superior discharge functional status, less intraoperative lactate accumulation, and lower postoperative serum neuronal injury protein expression than did patients receiving a fluid strategy targeting the upper cutoff of the gray zone. We confirmed that for patients undergoing brain surgery, the intraoperative fluid strategy should aim to maintain and increase cardiac output as much as possible. The importance of intravenous fluid therapy to surgical conditions is being increasingly emphasized in modern medicine. In summary, we investigated the pathological microcirculatory changes in multiple splanchnic organs during hemorrhagic shock in a rat model and confirmed the therapeutic effects of hypertonic saline and colloidal solutions on the restoration of intestinal mucosal microcirculatory blood flow. In addition, in vivo induction of renal reactive oxygen species by colloid solutions is reported for the first time, and this phenomenon may be associated with acute kidney injury in critically ill patients after fluid resuscitation with colloidal solutions. For further clinical applications, we observed that dynamic fluid responsiveness parameters enable clinicians to accurately determine the timing of fluid infusion not only for general surgical patients but also for patients with liver cirrhosis with altered vascular tones. Finally, we confirmed that an intraoperative fluid strategy targeting the elevation of cardiac output may be more beneficial than a restrictive strategy to patients undergoing brain tumor resection surgery. As long as the fluid therapy is based on the concept of administering the correct type of fluid at the correct time and in the correct amount, opportunities to further improve the clinical care of surgical patients are numerous. Our research begins from this perspective, and we would like to further investigate fluid therapy. Key words: splanchnic microcirculation、colloid solution、hypertonic solution、oxidative stress、liver cirrhosis、dynamic fluid responsiveness parameter、brain surgery腹部臟器微循環膠體溶液高張溶液氧化壓力肝硬化動態輸液反應性指標腦部手術splanchnic microcirculationcolloid solutionhypertonic solutionoxidative stressliver cirrhosisdynamic fluid responsiveness parameterbrain surgery