第二型糖尿病及其相關藥物對敗血症預後的關聯性分析

Sepsis Prognosis and Drug Use in Patients with Type II Diabetes

謝明順(Ming-Shun Hsieh)

指導教授 ： 陳保中

國立臺灣大學/公共衛生學院/職業醫學與工業衛生研究所/博士(2019年)

https://doi.org/10.6342/NTU201904379

摘要

中文摘要
研究背景：
敗血症"Sepsis"具有極高的死亡率，身體免疫系統因為嚴重的感染進入失控狀態，並引發多重器官衰竭。一旦患者進入敗血性休克"Septic shock"狀態時，死亡率更是大幅提升，並產生許多住院中及出院後的長短期併發症。
第二型糖尿病敗血症患者的住院預後一直存在著爭議，甚至有人提出第二型糖尿病對肺臟有保護的作用等論點。主要的原因在於第二型糖尿病所衍生出的併發症嚴重程度多未被納入考量。再者，由於治療第二型糖尿病及其相關共存慢性病(如高血壓)等藥物的進展，亦可能改變了原本敗血症的預後。在此研究中，我們將這個主題分成三個主要部分作探討。

研究設計與方法：
第一部分：
第二型糖尿病病患併發症嚴重程度與敗血症預後的關聯性分析：一個世代研究，合併使用健保資料庫跟醫院資料庫
在我們團隊過去的健保資料庫研究中發現，健保署多年來推動的糖尿病共照計畫(Diabetes Shared Care Program, DSCP) 可以有效地降低第二型糖尿病患者在敗血症發生時的死亡率，尤其在低社經地位及老年族群上，且亦可有效降低整體醫療成本。但直至今日，仍未有完整的世代研究(cohort study)針對第二型糖尿病患者發生敗血症時的病程做詳細的探討。
在第一部分的研究中，我們合併使用健保資料庫及多醫學中心資料庫 (取自榮總及長庚醫療體系)，完整探討第二型糖尿病病程的發展，從入院時的糖尿病併發症嚴重程度，入院前三個月內的糖化血色素值(HbA1c)到入院時於急診的第一次抽血血糖值(blood glucose)，做串聯整合。同時利用兩個資料庫對第二型糖尿病敗血症患者做全面的評析，包含糖尿病用藥，感染菌種，是否具抗藥性，呼吸衰竭、洗腎及死亡率等。
第二部分：
入院前高血壓藥物使用與敗血症預後的關聯性分析：血管張力素第I型轉化酶抑制劑(ACEIs)及血管張力素第II型受體拮抗劑(ARB)的影響(兼及敗血性休克的資料庫驗證：能否以敗血症診斷碼加上升壓劑藥物的藥物申報碼來代表患者有敗血性休克"septic shock"的產生)
本研究針對健保資料庫中，從未曾被驗證過(Validate)的"敗血性休克""Septic shock"定義做臨床上的驗證。初始假設為：在申報資料庫(Administrative database)中，如健保資料庫(NHIRD)中 ICD-9-CM 038的診斷碼加上升壓劑(inotropic agents)藥物的申報碼可以代表病患曾經進入敗血性休克"Septic shock"的病程中。目前國際上及國內皆無相關的驗證研究(validation study)，主要是因為驗證過程耗時且耗費人力。但這個驗證研究將大幅提申健保(申報)資料庫在急重症領域的應用，並造福之後眾多國、內外學者。
此外更探討病患入院前高血壓藥物的使用，如血管張力素第I型轉化酶抑制劑(ACEI)、血管張力素第II型受體拮抗劑(ARB)是否能對第二型糖尿病敗血症的患者的住院死亡率產生助益，分析過程中亦將敗血症病患依上述驗證後的結果，將其分類為敗血性休克"Septic shock"及非敗血性休克"Non-septic shock"去做後續的各項分析。

第三部分：
入院前Pioglitazone的使用與第二型糖尿病敗血症患者預後的關聯性分析
第三部分的研究將利用健保資料庫探索可能的敗血症輔助治療藥物，而此藥物必須要先有合理的藥理作用解釋及動物實驗上的佐證。本研究探討住院前Pioglitazone的使用對敗血症住院預後的關聯性分析。

結果：
第一部分：
本研究第一部分採用健保資料庫中"全糖尿病檔(LHDB)"及"百萬歸人檔(LHID2000)"，共收集19,719名第二型糖尿病敗血症患者和等同數量的非糖尿病敗血症患者。第二型糖尿病會增加敗血症患者的住院死亡，其勝算比(OR)為1.14 (95%信區間為1.10-1.19)。死亡率的勝算比隨"糖尿病併發症的嚴重程度分數" "(aDCSI score)增加"。當aDCSI score分別為0、1、2、3、4和 ≥5分時，死亡率的勝算比分別為0.91、0.87、1.14、1.25、1.56和1.77 (P值皆< 0.001)。
第二部分則採用多醫學中心的臨床資料庫(臺北榮總、臺中榮總及林口長庚醫院)。共收集1,054名糖尿病敗血症患者，存活和死亡的糖尿病敗血症患者，其初始血糖平均值並沒有顯著差異：273.9 ± 180.3 mg/dl對比266.1 ± 200.2 mg/dl (P值= 0.095)。此外，存活的糖尿病敗血症患者，其糖化血色素(HbA1c; %)值並沒有比死亡者低：8.4 ± 2.6%對比8.0 ± 2.5% (P值= 0.078)。

第二部分：
本研究總共收集了33,213名敗血症合併高血壓藥物的使用患者(研究組)作為研究對象，並以頻率配對的方式(性別、年紀)，在資料庫中選取同樣人數的未使用降血壓藥的敗血症患者(對照組)做為對比。與比較組相比，研究組的患者發生敗血性休克的機率較高 (4.36% 對比2.31%，P值 <0.001)，且總死亡率亦較高(38.42%對比24.57%，P值 <0.001)。在敗血症性休克狀態下，入院前有使用降血壓藥物相比於未使用降血壓藥物的患者，其校正後的勝算比為0.66 (95%信賴區間為0.55-0.80)，然而這個現象並未在"非"敗血性休克的狀況下被觀察到。
與未使用降血壓藥物的人相比，在敗血症的狀況下，ACEI和ARB的使用者其住院死亡率的校正後勝算比分別為：ACEI校正後勝算比 = 0.93，95%信賴區間，0.88-0.98，ARB校正後勝算比 = 0.85，95%信賴區間，0.81-0.90)
但是，在鈣離子阻斷劑，β受體阻斷劑和利尿劑的使用者上並沒有觀察到上述現象。然而在敗血症性休克的狀態下，ACEI，ARB，鈣離子阻斷劑，β受體阻斷劑使用者的住院死亡率勝算比均下降。
聯合療效分析(Joint effect analysis)顯示，除與利尿劑聯合使用外，ACEI與其它降血壓藥物的共同使用對敗血症住院死亡率的校正後勝算比皆明顯降低。在ARB的使用者身上也觀察到了相似的結果。
為了驗證敗血症休克定義的正確性與否，我們從醫院臨床資料庫中任意挑選出100名患者，由一位重症醫師，一位急診專科醫師共同審閱病歷，依定義有97人可明確診斷為敗血性休克，另外3人則無共識 (敏感度sensitivity為97%)評分者間信度(Inter-observer agreement)為優良(κ值為0.887)

第三部分：
本研究從全糖尿病檔(LHDB)資料庫共收集了9,310名敗血症合併Pioglitazone使用的患者和46,550名依傾向分數"Propensity score"配對後擷取而來的敗血症非Pioglitazone使用患者(採1:5的比例)分別作為研究組和對照組。敗血症合併Pioglitazone使用患者其總住院和28天住院死亡率的校正後勝算比分別為0.95 (95%信賴區間為0.89-1.03)和0.98 (95%信賴區間為0.92-1.06)。
但如果使用較嚴謹的定義去規範Pioglitazone的使用(敗血症入院當日前30天內的累積使用劑量需≥7天)，則總住院和28天住院死亡率的校正後勝算比顯著降低至0.80 (95%信賴區間為0.72-0.89)和0.79 (95%信賴區間為0.70-0.88)。
然而值得一提的是，不管採用較寬鬆或嚴格的Pioglitazone使用定義，Pioglitazone使用者皆比非Pioglitazone使用者更容易發生敗血性休克。在採用寬鬆及嚴謹的Pioglitzone使用定義時，產生敗血性休克的校正後勝算比分別為1.16 (95%信賴區間為1.05-1.29)和1.19 (95%信賴區間為1.01-1.39)。

結論與建議：
第一部分：
對於第二型糖尿病敗血症患者，與糖尿病相關的併發症嚴重程度才是決定敗血症死亡率的關鍵因素，而非糖尿病本身。HbA1c或初始血糖值亦非第二型糖尿病敗血症患者預後的關鍵因子。

第二部分：
入院前的ACEI及ARB使用均可明顯降低住院死亡率的風險(不論是否在住院過程中產生敗血性休克)。另外亦驗證了使用敗血症的出(住)院診斷碼加上升壓劑的藥物申報碼，可以明確的定義"敗血性休克"的發生。

第三部分：
在這項研究中，Pioglitazone的使用對於敗血症的總住院死亡率和28天住院死亡率並沒有出現顯著的保護作用，除非在敗血症住院之前有高劑量的使用。但值得一提的是，Pioglitazone在本研究中發現會明顯引致患者併發敗血性休克，此機制仍有待進一步的研究。

總結：
本研究的對科學及人類主要的貢獻：
其一、同時併用"醫院資料庫"及"健保資料庫"，完整剖析了多年來一直爭論不休的議題：第二型糖尿病與敗血症預後的關聯性。說明真正的決定因子在於病人因糖尿病所引致的併發症嚴重程度，而非僅僅糖尿病本身。
其二、跨越十數年來一直無人的能由申報資料庫(administrative database)中作出敗血性休克"septic shock"定義的鴻溝，由兩位醫師的作了三個多月的苦功，逐本翻閱醫師及護理紀錄，用健保資料庫制定了全新敗血性休克的定義。將廣泛嘉惠未來國、內外的相關學者。
其三、先行測試各項高血壓藥物，如ACEI、ARB及糖尿病藥物Pioglitazone對敗血症預後的修飾作用。

關鍵字

血管張力素第I型轉化?抑制劑(ACEIs) ； 血管張力素第II型受體拮抗劑(ARB) ； ?格列酮(Pioglitazone) ； 降血壓藥物(antihypertensive drug) ； 敗血症(Sepsis) ； 敗血性休克(Septic shock) ； 健保資料庫(NHIRD) ； 第二型糖尿病 ； 過氧化物?體增殖物活化受體-γ (PPARγ) ； ?唑烷二酮(Thiazolidinedione, TZD) ； 糖尿病併發症嚴重程度指數分數(DCSI score) ； 醫院資料庫(HBD) ； 嚴重敗血症(Severe sepsis) ； 驗證(Validation)

並列摘要

Background:
Sepsis prognosis in type II diabetic patients remains controversial when severity of diabetes is not taken into consideration. Furthermore, the preadmission anti-diabetic and ant-hypertensive drugs may also change the sepsis trajectory. In this current study, we divided into three parts to discuss the above topics.

Aims: There are three studies as follows:

1. Hospital Outcomes and Cumulative Burden from Complications in Type 2 Diabetic Sepsis Patients: A Cohort Study Using Administrative and Hospital-based Databases.

Materials and Methods:
The first part of this study was mainly conducted using a nationwide database, which included 1.6 million type 2 diabetic patients. The diabetic complication burden was evaluated using the adapted Diabetes Complications Severity Index score (aDCSI score). In the second part, we used laboratory data from a distinct hospital-based database to make comparisons using regression analyses.
Results:
The nationwide study included 19,719 type 2 diabetic sepsis patients and an equal number of nondiabetic sepsis patients. The diabetic sepsis patients had an increased odds ratio (OR) of 1.14 (95% confidence interval 1.1–1.19) for hospital mortality. The OR for mortality increased as the complication burden increased [aDCSI scores of 0, 1, 2, 3, 4, and ≥5 with ORs of 0.91, 0.87, 1.14, 1.25, 1.56, and 1.77 for mortality, respectively (all P < 0.001)]. The hospital-based database included 1054 diabetic sepsis patients. Initial blood glucose levels did not differ significantly between the surviving and deceased diabetic sepsis patients: 273.9 ± 180.3 versus 266.1 ± 200.2 mg/dl (P = 0.095). Moreover, the surviving diabetic sepsis patients did not have lower glycated hemoglobin (HbA1c; %) values than the deceased patients: 8.4 ± 2.6 versus 8.0 ± 2.5 (P = 0.078).
Conclusions:
For type 2 diabetic sepsis patients, the diabetes-related complication burden was the major determinant of hospital mortality rather than diabetes per se, HbA1c level, or initial blood glucose level.

2. Preadmission Antihypertensive Drug Use and Sepsis Outcome: Impact of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs). (Validation of septic shock)

Materials and Methods:
This study was conducted using the unique database of a sepsis cohort from the National Health Insurance Research Database in Taiwan. Frequency matching for age and sex between preadmission antihypertensive drug users (study cohort) and nonusers (comparison cohort) was conducted. The primary outcome was total hospital mortality. Logistic regression analyses were performed to calculate the odds ratios (ORs) of important variables. Further joint effect analyses were carried out to examine the impacts of different combinations of antihypertensive drugs.
Results:
A total of 33,213 sepsis antihypertensive drug use patients were retrieved as the study cohort, and an equal number of matched sepsis patients who did not use antihypertensive drugs were identified as the comparison cohort. The study cohort had a higher incidence rate of being diagnosed with septic shock compared with the comparison cohort (4.36%–2.31%, P < 0.001) and a higher rate of total hospital mortality (38.42%–24.57%, P < 0.001). In the septic shock condition, preadmission antihypertensive drug use was associated with a decreased adjusted OR (OR = 0.66, 95% confidence interval [CI], 0.55–0.80) for total hospital mortality, which was not observed for the nonseptic shock condition. Compared with antihypertensive drug nonusers, both ACEI and ARB users had decreased adjusted ORs for total hospital mortality in sepsis (adjusted OR = 0.93, 95% CI, 0.88–0.98 and adjusted OR = 0.85, 95% CI, 0.81–0.90); however, CCB, beta-blocker, and diuretic users did not. In the septic shock condition, ACEI, ARB, CCB, and beta-blocker users all had decreased ORs for total hospital mortality. Joint effect analysis showed ACEI use, except in combination with diuretics, to be associated with a decreased adjusted OR for total hospital mortality in sepsis. Similar results were observed for ARB users. (For validation, among the chosen 100 patients, the diagnosis of septic shock was confirmed for 97 and unconfirmed for 3 (sensitivity, 97.0%). Interobserver agreement was excellent (κ=0.887).)
Conclusions:
Preadmission ACEI or ARB use is associated with a decreased risk of total hospital mortality, regardless of a nonshock or septic shock condition.

3. Pioglitazone Use and Sepsis Outcomes in Type 2 Diabetic Patients: a Nationwide, Propensity Score-Matched Study.

Materials and Methods:
This study was conducted using a unique diabetes database including 1.6 million diabetic patients. From 1999 to 2013, a total of 145,327 type 2 diabetic patients, first admitted for sepsis, were enrolled. Propensity score matching was conducted to avoid selection bias between the pioglitazone users and nonusers. The main outcomes were 28-day and total hospital mortality. Multivariate logistic regression analyses were conducted to calculate the odds ratios (ORs) of pioglitazone use in sepsis.
Results:
A total of 9,310 sepsis pioglitazone users and 46,550 propensity score-matched nonusers (1:5) were retrieved as the study and comparison cohort, respectively. Pioglitazone use was associated with an adjusted OR (aOR) of 0.95 (95% confidence interval, CI, 0.89-1.03) and 0.98 (95% CI, 0.92-1.06) for total and 28-day hospital mortality, respectively. However, if pioglitazone use was redefined using a narrower criterion (cumulative use ≥7 days within 30 days prior to the index date of admission), the aOR significantly decreased to 0.80 (95% CI, 0.72-0.89) and 0.79 (95% CI, 0.70-0.88) for total and 28-day hospital mortality, respectively. However, septic shock was more frequently found in pioglitazone users than nonusers using either the wider (aOR = 1.16; 95% CI, 1.05-1.29) or narrower (aOR = 1.19; 95% CI, 1.01-1.39) definition.
Conclusions:
In this study, pioglitazone use demonstrated a nonsignificant protective effect against total and 28-day hospital mortality in sepsis, except under the condition of recent, intensive use prior to sepsis. However, care should be taken to avoid septic shock development with pioglitazone use, and the mechanism remains to be further investigated.

並列關鍵字

Angiotensin-converting enzyme inhibitors (ACEIs) ； Angiotensin II receptor blockers (ARBs) ； Antihypertensive drug ； Diabetes complication severity index score (DCSI score) ； Diabetes mellitus ； Hospital-based database (HBD) ； National Health Insurance Research Database (NHIRD) ； Peroxisome proliferator-activated receptor-gamma (PPARγ) ； Pioglitazone ； Sepsis ； Severe sepsis ； Septic shock ； Thiazolidinedione (TZD) ； Validation

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