肋膜腔連續性藥物輸注於胸腔疾病的治療研究

Studies on Continuous Intrapleural Drugs Instillation for Thoracic Diseases

黃培銘(Pei-Ming Huang)

指導教授 ： 陳炯年

共同指導教授 ： 張逸良

國立臺灣大學/醫學院/臨床醫學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.01267

摘要

肋膜腔屬於一個特殊的循環動力環境，在以往有許多文獻經由肋膜腔給予藥物來治療氣胸、膿胸、或者是惡性肋膜腔的積水問題，我們進一步運用連續性肋膜腔藥物輸注的方式，來治療急性呼吸窘迫症，以及手術後發生的乳糜胸，還有血胸的治療。這些疾病是目前醫學上積極研究的課題，並且本文研究的成效較以往的治療方式來的有效，是值得積極推廣的治療方式。

壹、肋膜腔內注射類固醇於食道癌術後的急性呼吸衰竭及急性呼吸窘迫症合併多重器官衰竭的研究
食道癌是近來醫學研究的重要課題，基本上食道癌的病人由於營養不良及手術的範圍較廣，經由手術處理後的照顧需求高，對於食道癌手術後最常見的肺部併發症的治療，主要分為保守性(胸部呼吸運動、化痰藥物)以及侵入性(支氣管鏡對呼吸道抽痰或氣管造口)。然而，綜觀目前對於真正危急的急性呼吸窘迫症的治療卻有限。因此，我們利用連續性肋膜腔類固醇輸注的治療模式，針對食道癌術後及急性呼吸窘迫症合併多重器官衰竭的病人做進一步治療的研究分析。
第一部份研究結果及結論如下：
結果：
在前驅性的兩位食道癌術後個案中，在傳統性的治療後(包括適當的抗生素使用、及營養補充)，其病情仍持續惡化，之後經由肋膜腔內注射類固醇，其呼吸功能均能由原本需要100%氧氣濃度供應，而能調降氧氣濃度，進而得到良好呼吸功能改善。另外在30位連續病人使用葉克膜支持下符合嚴重急性呼吸窘迫症合併多重器官衰竭的研究中，在肋膜腔內注射類固醇這組，3日後的胸部X光浸潤情形(p=0.008)以及五天後的PaO2/FiO2(p=0.028)可以見到比起對照的傳統靜脈注射類固醇組獲得改善。28天死亡率(p = 0.017)及60天死亡率(p = 0.003)及存活率 (p = 0.003) 在肋膜腔內注射類固醇這組也顯著改善。
結論：
由肋膜腔內注射類固醇可以很容易及有效的治療嚴重急性呼吸窘迫症合併多重器官衰竭，尤其是在傳統治療無效時更應該考慮。這個技術使病人面臨最短的加護中心照顧，並且能夠快速地改善呼吸功能。假使病患的術後肺浸潤很顯著時，或可能有急性呼吸窘迫症時，此種治療措施就可開始進行。

貳、肋膜腔連續性米諾環素輸注於術後所引起的難治療性乳糜胸的運用
乳糜胸是由不同原因導致乳糜胸導管或其分支的破裂或阻塞，而引起乳樣的乳糜堆積在肋膜腔所產生的稀有但嚴重的疾病，它可產生呼吸衰竭、體液的不平衡和營養不良等症狀。雖然曾有許多治療方式被提出，但是對於確切的治療方式上仍缺乏共同的一致性。此研究，延續第一部份研究的精神，我們使用連續性的肋膜腔米諾環素灌注的方式來治療乳糜胸，這有別於以往傳統只是單次間斷性的灌注方式來的更加有效。
此部份實驗結果及結論如下：
結果：
以連續性米諾環素肋膜腔灌洗的方式(在1000cc生理鹽水中加入800毫克的2%的利多卡因氫氯化物，和800毫克的米諾環素，設定流速為每個小時100cc)成功的治療了3位乳糜胸的患者，這有別於以往傳統只是單次間斷性的方式，來的更加有效且未有施打期間疼痛的情況發生。
結論：
乳糜胸是手術後少見但難以處理的併發症，以連續性米諾環素肋膜腔灌洗的方式，既有效且安全。

參、肋膜腔連續性腎上腺素輸注於血胸治療上的運用
血胸被認為是一種臨床難題，其外科處理的策略很少在醫學文獻中有提及相關細節，特別與使用葉克膜治療上發生的血胸，文獻上所提供的治療更是稀少。我們發展肋膜腔腎上腺素灌注方式，以其刺激血管收縮，以進一步提高止血效果，這種方式也可運用在其他疾病引起的血胸治療中。
此部份實驗結果及結論如下：
結果 ：
以連續肋膜腔腎上腺素灌洗的方式用於與葉克膜相關的大量血胸的治療。所有患者的血胸皆為單邊，隨著矯正凝血，兩名患者於肋膜腔引流減壓後出血受到控制。此外，有四個病人在經由胸管肋膜腔腎上腺素灌注後，雖然未經手術也能達到止血，另外八名患者需要手術來治療。此外，肋膜腔腎上腺素灌注方式只造成這些患者收縮壓些微的增加(10 mmHg)。
結論：
在血胸進行確切的手術治療前，建議可先使用腎上腺素灌洗肋膜腔。然而，一些血胸狀況（如患者大血管破裂、臟器破裂、或手術後大量血胸）則是需要即時且明確的手術介入。因此，如果出血沒有停止或者經腎上腺素灌注後無減少的跡象，則不宜繼續使用肋膜腎上腺素灌注。

肆、總結：
本研究結果以連續性肋膜腔藥物灌洗來治療急性呼吸窘迫症、手術後發生的乳糜胸，以及血胸的治療，這是一種簡單、安全且確切的治療方式。然而，還需要在未來的研究中收集更多的研究個案，以證明這方面的研究成果。

關鍵字

肋膜腔輸注 ； 急性呼吸窘迫症 ； 乳糜胸 ； 血胸

並列摘要

The pleural cavity has unique dynamic drainage pathways. Intrapleural instillation was previously used to treat several diseases, such as pneumothorax, empyema, and malignant pleural effusion. We attempted to establish a new therapeutic method with continuous intrapleural instillation for diseases that are difficult to treat, such as acute respiratory distress syndrome, post-operative chylothorax, and hemothorax. This study yielded favorable results, and therefore, can be used as an effective treatment modality.

Intrapleural steroid instillation for acute lung injury after esophagectomy or multiple organ failure with acute respiratory distress syndrome
Currently, esophageal cancer therapy is an important area in medicine. In general, esophageal surgery is a complex pathophysiological process, and post-operative management plays an important role owing to the complexity of the procedure and patient malnutrition. The available therapies for pulmonary complications of esophagectomy include conservative treatments such as chest physiotherapy and mucolytic agents and invasive procedures such as bronchial toilet and tracheostomy. However, current therapies do not improve the survival rate in patients with severe acute respiratory failure (ARF). On the basis of the findings of this study, we aim to establish a new therapeutic technique with continuous intrapleural instillation for treatment of ARF after esophagectomy and acute respiratory distress syndrome combined with multiple organ failure.
The result and conclusion of the first part of study was as the followings:
Results
In the first two patients with esophageal cancer who underwent esophagectomy, we recommended intrapleural steroid instillation for ARF when the condition of the patients deteriorated despite treatment with other modalities, such as intravenous antibiotic administration and nutrition support. Improved clinical outcomes and pulmonary function were observed in both patients, and their oxygen demand also decreased from 100% concentration.
In the 30 consecutive extracorporeal membrane oxygenation adults who met the criteria of severe acute respiratory distress syndrome in combination with multiple organ dysfunction syndrome, the infiltrative shadows on plain chest radiographs were markedly improved on the third day of intrapleural treatment (p = 0.008) and significantly higher PaO2/FiO2 ratios than those treated with conventional method for 5 days (p = 0.028).
Conclusion
Intrapleural steroid instillation seems to be an easily and useful implemented treatment modality for patients with acute respiratory distress syndrome and multiple organ dysfunction syndrome that allows efficient recovery of lung function at a relatively low cost, especially when initiated early in the course of the disease.

Continuous intrapleural instillation with minocycline administration for refractory postoperative chylothorax
Chylothorax, characterized by accumulation of milky chyle in the pleural space due to disturbance of flow in the thoracic duct or its tributaries, is a rare and serious complication of thoracic surgery. The complication can lead to respiratory insufficiency, fluid imbalance, and nutrition deficiency. Although multiple approaches have been reported for the treatment of chyle leakage, there is lack of a clear consensus on its optimal management technique. We described a novel technique of continuous irrigation to enhance the pleurodesis effect of conventional intermittent minocycline infusion.
The result and conclusion of the second part of study was as the followings:
Results
Herein, we report cases of 3 patients with chylothorax in whom pleurodesis was successfully performed via continuous intrapleural irrigation with minocycline (800mg of minocycline and 800mg of 2% lidocaine hydrochloride in 1000ml of normal saline, set 100ml per hour) instead of the conventional intermittent pleurodesis. The main disadvantage of minocycline is post-instillation chest pain, which can be relieved by intrapleural lidocaine as the pretreatment and this technique of continuous low dose administration.
Conclusion
Post-operative chylothorax is rare and can lead to serious consequences. Continuous intrapleural irrigation with minocycline was a convenient and effective alternative to open surgical or thoracoscopic drainage in these cases.

Continuous intrapleural instillation with epinephrine administration for hemothorax
Although hemothorax has been recognized as a clinical entity for centuries, the surgical strategies for its management, especially when complicating ECMO, were rarely mentioned in detail in the medical literature. We also developed intrapleural epinephrine irrigation for hemothorax, which stimulates vascular contraction and further improves hemostasis. It can be further applied to hemothorax related to other disease.
The result and conclusion of the third part of study was as the followings:
Results
All hemothoraces were unilateral. With coagulopathic correction, control of bleeding was obtained in two patients after decompression of the pleural cavity, four patients after pleural epinephrine irrigation, and eight of 14 patients required surgical intervention for blood clot evacuation. Four extracorporeal membrane oxygenation patients with hemothorax had hemostasis without surgery after pleural epinephrine irrigation through the chest tube. Pleural epinephrine irrigation caused a mild increase of systolic blood pressure in these patients.
Conclusion
Furthermore, before definitive surgical treatment for hemothorax, we recommend that pleural lavaged streams of epinephrine should be used firstly. However, some hemothoraces (in patients with great vessel rupture, organ rupture, or massive postoperative hemothorax) require indispensably immediate, definitive surgical intervention. So the pleural epinephrine irrigation would not be used continuously if bleeding did not stop or decrease.

Summary
Continuous intrapleural instillation is a simple, safe, and definitive technique that can be used to treat several thoracic diseases such as acute respiratory distress syndrome, post-operative chylothorax, and hemothorax. However, future studies are warranted to demonstrate the efficacy and survival benefits of this technique.

並列關鍵字

Intrapleural instillation ； Acute respiratory distress syndrome ； Chylothorax ； Hemothorax

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