- 學位論文
重症休克病患的體液復甦序貫式網絡統合分析以及臨床資料分析
Fluid resuscitation for critically ill patients–Sequential Network meta-analysis and Clinical data analysis
摘要
背景： 各類輸液在體液復甦時可能帶來不同的副作用。不同病人族群的臨床試驗結果發現各類輸液的優缺點有不一致的結論。在敗血症病人族群中，乳酸林格試液較生理食鹽水能降低死亡率，但此差異可否推論到術後病人、外傷病人則沒有定論，且不同輸液對於各器官的影響缺乏整體的綜合比較。敗血症病人中有很大部分有慢性腎病變、肝病變、肺病變等，不同輸液是否會造成有共病症、慢性器官病變病患的副作用，是值得且需要詳細探討，才能給予臨床實際治療時最好的建議。 方法： 此論文第一部分利用系統性文獻搜尋與網絡統合分析去比較各類輸液於敗血症、手術、外傷病人的差異(PROSPERO website, registration number: CRD42018115641)。搜尋資料庫包含PubMed、EMBASE及Cochrane CENTRAL，並利用相關發表文章的參考文獻進行收集。收錄分析的隨機分派研究需主要針對急重症需要體液復甦的病患，給予的治療需是乳酸林格式液(lactated Ringer’s)、生理食鹽水(Saline)、白蛋白(albumin)、乙烴澱粉輸液(hydroxyethyl starch)及明膠輸液(gelatin)其中兩種的比較。系統性文獻評讀利用Risk of Bias工具2.0版本，並藉由CINeMA (Confidence in Network Meta-Analysis)工具統整證據等級；網絡統合分析利用隨機效應模型。 論文第二部分則是前瞻性世代研究，利用一間台灣醫學中心加護病房資料進行分析，該醫學中心針對敗血症病患進行標準評估與照護，進而可取得各類慢性病病患對於不同輸液的詳細反應生理及血液生化數據。再利用Cox回歸模型(Cox regression model)控制干擾因子比較死亡率、利用competing risk model排除死亡個案後比較住院天數，線性混合模型(Linear mixed model)比較各類重複測量數據。 結果： 第一部分的統合分析共有53個隨機分派研究(26351位病患)，共評估7類輸液。敗血症與手術病人中，相較於接受生理食鹽水(Saline)與乙烴澱粉輸液(hydroxyethyl starch)，接受乳酸林格式液(lactated Ringer’s)與白蛋白(albumin)的病患存活率較佳、急性腎病變較少、輸血量較少。特別是敗血症的病患中，乳酸林格式液(lactated Ringer’s)較生理食鹽水(Saline)能顯著下降死亡率( 0.84; 95% CI 0.74 to 0.95)。然而外傷病人中，各類輸液差異較不明顯，但於外傷性腦損傷病人中，生理食鹽水(Saline)與乙烴澱粉輸液(hydroxyethyl starch)卻反而較乳酸林格式液(lactated Ringer’s)與白蛋白(albumin)明顯下降死亡率，特別是生理食鹽水(Saline)相較於白蛋白(albumin)能顯著增加存活率(Odd ratios, 0.55; 95% CI 0.35 to 0.87)。 第二部分的世代研究納938位病人，乳酸林格式液(lactated Ringer’s)較生理食鹽水(saline)降低死亡率(adjusted hazard ratio, 0.59; 95% CI 0.43-0.81)且住院天數較短(subdistribution hazard ratio, 1.39; 95% C.I. 1.15-1.67)，而此差異於慢性肺病變的病人較明顯，於慢性腎病變、慢性肝病變中較不顯著。 結論： 第一部分的統合分析發現在敗血症病人中，乳酸林格式液(lactated Ringer’s)、白蛋白(albmin)較生理食鹽水(saline)、乙烴澱粉輸液(hydroxyethyl starch)降低死亡率，但在外傷性腦損傷的病人，反而生理食鹽水(Saline)與乙烴澱粉輸液(hydroxyethyl starch)較乳酸林格式液(lactated Ringer’s)與白蛋白(albumin)明顯下降死亡率。第二部分的世代研究發現乳酸林格式液(lactated Ringer’s)較生理食鹽水(Saline)的死亡率下降，只在慢性肺病變顯著，在於慢性腎病變、慢性肝病變中較不顯著。因此，病患類別、病患是否有哪些共病症，在輸液選擇上是非常重要的。
並列摘要
Background： Crystalloids and colloids, used for volume resuscitation, are associated with adverse effects. Clinical trial findings on the adverse effects of various fluid types are conflicting in patients with different conditions. Most sepsis patients had chronic kidney disease, chronic liver disease, chronic pulmonary disease and diabetes mellitus, and whether those solutions lead to adverse effects in those patients with organ failure is still unclear. Methods： The first part of this thesis is to use systemic review and network meta-analysis to compare the effects of different fluid types in the treatment of sepsis, surgical and trauma patients. Electronic databases (PubMed, EMBASE, and Cochrane CENTRAL) and reference lists of relevant articles were searched from their inception until January 2020. Clinical trials on critically ill adults requiring the following types of fluid resuscitation were included: balanced crystalloid, saline, iso-oncotic albumin, hyperoncotic albumin, low molecular weight hydroxyethyl starch (L-HES), high molecular weight HES, and gelatin. Network meta-analyses were conducted using random-effects model to calculate odds ratio (OR) and mean difference. Risk of Bias tool 2.0 was used to assess bias. CINeMA (Confidence in Network Meta-Analysis) web application was used to rate the confidence in synthetic evidence. Second part of this thesis is a prospective cohort study, conducted in a medical intensive care unit (ICU) in central Taiwan. We applied the standard sepsis evaluation protocol and identified heart, lung, liver, kidney, and endocrine comorbidities. We also evaluated resuscitation responses including central venous pressure, central venous oxygen saturation, and serum lactate level simultaneously. Propensity-score matching and Cox regression were used to compare patients’ mortality. The competing risk model compared the lengths of hospital stays with the subdistribution hazard ratio (SHR). Results： In the first part, fifty-eight trials (n=26,351 patients) comparing seven fluid types were included in our network meta-analysis. Among patients with sepsis and surgery, lactated Ringer’s and albumin achieved better survival, fewer acute kidney injury, and smaller blood transfusion volumes than saline and L-HES. In those with sepsis, lactated Ringer’s significantly reduced mortality than saline (OR, 0.84; 95% CI 0.74 to 0.95) and L-HES (OR, 0.81; 95% CI 0.69 to 0.95) and reduced acute kidney injury than L-HES (OR, 0.80; 95% CI 0.65 to 0.99). However, it required the greatest resuscitation volume among all fluid types, especially in trauma patients. In patients with traumatic brain injury, saline and L-HES achieved lower mortality than albumin and lactated Ringer’s; especially saline was significantly superior to iso-oncotic albumin (OR, 0.55; 95% CI 0.35 to 0.87). In the second part, the cohort study included 938 patients in the analysis. The lactated Ringers group had a lower mortality rate (adjusted hazard ratio, 0.59; 95% CI 0.43-0.81) and shorter lengths of hospital stay (SHR, 1.39; 95% C.I. 1.15-1.67) than the saline group; the differences were greater in patients with chronic pulmonary disease and small and nonsignificant in those with chronic kidney disease, moderate to severe liver disease and cerebral vascular disease. The resuscitation efficacy was the same between fluid types, but serum lactate levels were significantly higher in the lactated Ringers group than in the saline group (0.12 mg/dL/hour; 95% C.I.: 0.03, 0.21), especially in chronic liver disease patients. Compared to the saline group, the lactated Ringers group achieved target glucose level earlier in both diabetes and non-diabetes patients. Conclusions： Our network meta-analysis found that lactated Ringer’s and albumin decreased mortality more than L-HES and saline in sepsis patients; however, saline or L-HES, was better than iso-oncotic albumin or lactated Ringer’s in traumatic brain injury patients. In the cohort study, Lactate Ringer’s solution provides greater benefits to patients with chronic pulmonary disease than to those with chronic kidney disease, or with moderate to severe liver disease. Comorbidities are important in choosing resuscitation fluid types.