利用目標導向療法最適化復甦後症候群的神經學預後

A Goal-directed Approach to Optimize Neurological Prognosis of Post-cardiac Arrest Syndrome

王志宏(Chih-Hung Wang)

指導教授 ： 陳文鍾 ； 劉興華

國立臺灣大學/醫學院/臨床醫學研究所/博士(2018年)

https://doi.org/10.6342/NTU201800919

摘要

雖然心跳停止患者進行急救後的存活率或是神經學預後，經過心肺復甦術的教育推廣，略有提升，但是仍不甚理想。尤其在台灣，經過心肺復甦後，能夠恢復獨立或是半獨立生活能力的病人少之又少。因此，改善復甦後病人的神經學預後對於台灣而言，是至為重要的議題。對於復甦後症候群的重視，由2010年，美國心臟學會的心肺復甦術指引開始特闢章節專述可見一班。針對復甦症候群中最重要的缺氧性神經傷害，根據基礎動物實驗，以及臨床觀察研究的結果，優化腦部氧氣運送以及能量利用進而改善神經學預後應是一可行的治療方法。主要目標生理參數包括平均動脈壓，動脈血氧和二氧化碳分壓，血色素濃度以及血糖濃度。研究可分為三個部分，第一部分是系統性回顧以及薈萃分析；第二部分是臨床回溯性世代分析；最後是動物實驗。分述如下：
首先，在系統性回顧以及薈萃分析方面，作者主要探討高氧（動脈氧分壓大於300 mmHg）對於心肺復甦後病人死亡率和神經學功能恢復的影響。透過Pubmed以及Embase搜尋，結果發現至2013年為止，共有2982篇文獻符合關鍵字設定的需求；經過篩選後，有14篇研究被納入系統性分析；其中，有10篇文獻的研究結果可以經統計進行薈萃分析。薈萃分析結果指出，高氧與增加的院內死亡率顯著相關（odds ratio [OR]：1.40; 95% confidence interval [CI], 1.02–1.93; I2, 69.27%）；但是高氧與神經學預後沒有統計上顯著相關（OR, 1.62; 95% CI, 0.87–3.02; I2, 55.61%）。然而，因為過高的異質性，以及子群分析和敏感性分析結果的不一致，薈萃分析的結果需要被審慎判讀。
其次，在臨床回溯性世代分析方面，本研究以2006-2014年間在台大醫院發生院內心跳停止的病人為基礎，從中篩選適合的病人進入分析。其納入條件為：（1）年齡大於18歲；（2）確認無脈搏且進行心肺復甦術超過兩分鐘以上；（3）沒有不進行心肺復甦術之醫囑：（4）達成持續性恢復自主循環（亦即恢復自主循環超過20分鐘以上，中間無須進行心肺復甦術）。排除條件為：（1）病人為重度創傷病患；（2）病人在達成持續性恢復自主循環後24小時內沒有任何本研究欲探討的五大生理指標的紀錄，包括平均動脈壓，動脈氧分壓和二氧化碳分壓，血色素濃度以及血糖濃度。除了記錄一般的年齡，性別，共病症外，本研究會根據Utstein template紀錄與心肺復甦術相關的變項，恢復自主循環後的介入性治療，以及達成持續性恢復自主循環後24小時內五大生理指標的第一次，最高和最低的紀錄值。主要結果變數為出院時恢復良好的神經學功能預後。神經學功能是用Cerebral Performance Category來評估；當Cerebral Performance Category分數落在1分或是2分時，病人的神經學功能恢復良好，可以獨立自主或是半獨立自理生活。本研究使用多變數回歸分析來評估自變數與獨立變數間的關係，並且使用generalized additive models plot來辨識五大生理指標的最適範圍。
臨床回溯性世代分析結果顯示：（1）平均動脈壓超過85 mmHg與病人良好的神經學功能預後顯著相關（OR 4.12, 95% CI 1.47-14.39, p = 0.01）。對於沒有高血壓的病人，復甦後平均動脈壓落在85與115 mmHg間時，病人恢復良好神經學功能的機會較高（OR 8.80, 95% CI 3.13–28.55, p < 0.001）；對於有高血壓病史的病人，復甦後平均動脈壓超過88 mmHg，病人恢復良好神經學功能的機會較高（OR 4.04, 95% CI 1.41–13.03, p = 0.01）；（2）動脈氧分壓落在70與240 mmHg間時，病人恢復良好神經學功能的機會較高（OR 1.96, 95% CI 1.08–3.64, p = 0.01），相對地，動脈二氧化碳分壓愈高，病人神經學預後愈差（OR 0.98, 95% CI 0.95–0.99, p = 0.01）；（3）血色素濃度與周邊血氧飽和度的乘積愈高，病人恢復良好神經學功能的機會愈高（OR 1.003, 95% CI 1.002–1.004）。急救指南建議的周邊血氧飽和度範圍為94-98%，根據此一建議，本研究可以計算得到相對應的最低的血色素濃度範圍為8.6 至9.0 g/dL。（4）對於糖尿病患者，平均血糖濃度落在183與307 mg/dL間時，病人恢復良好神經學功能的機會較高（OR 2.71, 95% CI 1.18–6.20, p = 0.02），平均血糖濃度落在147與317 mg/dL間時，病人存活出院的機會較高（OR 2.38, 95% CI 1.26-4.53, p = 0.008）；對於非糖尿病患者，平均血糖濃度落在143與268 mg/dL間時，病人存活出院的機會較高（OR 2.93, 95% CI 1.62-5.40, p < 0.001）。
最後，利用Wistar rat建立窒息引發心跳停止的動物模型，以norepinephrine調控血壓，並使用OxyFlo導管觀測腦部血流改變對於大鼠神經學預後的影響。其結果顯示，在控制組方面，如同前人研究，OxyFlo測得的腦部血流在心跳恢復後約10-15鐘左右達到最高，接著下降，並於約20-30分鐘左右達到心跳停止前腦部血流量六成左右的低點，並持續到觀測結束。而於實驗組，經norepinephrine調高血壓後，腦部血流量可隨之上升，暗示腦部血流自我調節機制的失能。針對臨床結果，滴注norepinephrine四小時組在神經學預後方面，相較於控制組，有較好的傾向，但因實驗動物隻數不足，未達統計上顯著。

關鍵字

心跳停止 ； 復甦後症候群 ； 血壓 ； 動脈氧分壓 ； 動脈二氧化碳分壓 ； 血色素值 ； 血糖值

並列摘要

According to previous animal and human studies, optimization of cerebral oxygen delivery and energy use may be a promising treatment for post-cardiac arrest syndrome. The candidate physiologic parameters used to achieve this goal include mean arterial pressure (MAP), partial pressure of oxygen/ carbon dioxide, hemoglobin level, and blood glucose (BG) level. We examined these candidate physiologic parameters through three different approaches.
First, in the systematic review and meta-analysis, we searched PubMed and Embase from the inception through October 2013. We defined hyperoxia as a PaO2 higher than 300 mm Hg. In the literature search, 14 studies were identified from 2,982 references. Meta-analysis indicated that hyperoxia appeared to be correlated with increased in-hospital mortality (OR, 1.40; 95% CI, 1.02–1.93; I2, 69.27%; 8 studies) but not worsened neurological outcome (OR, 1.62; 95% CI, 0.87–3.02; I2, 55.61%; 2 studies).
Second, we performed the retrospective cohort study at National Taiwan University Hospital (NTUH). We screened patients who suffered IHCA at NTUH between 2006 and 2014. We included patients who met the following criteria: (1) age 18 years or older, (2) documented absence of pulse with performance of chest compression for at least 2 min, (3) no documentation of a do-not-resuscitate order, and (4) achievement of sustained return of spontaneous circulation (ROSC) (i.e., ROSC ≥ 20 min without resumption of chest compression). The primary outcome was favourable neurological outcome at hospital discharge. Multivariable logistic regression analyses were sued to examine the associations between independent variables and outcomes. We used generalized additive models (GAMs) to identify the optimal ranges for the five main physiologic parameters.
The results were as follows: (1) MAP above 85 mm Hg was found to correlate with a favorable neurological outcome (odds ratio [OR] 4.12, 95% confidence interval [CI] 1.47-14.39). For patients without arterial hypertension, the optimal MAP was between 85 and 115 mm Hg (OR 8.80, 95% CI 3.13–28.55); for patients with arterial hypertension, the threshold MAP for achieving a favorable neurological outcome was above 88 mmHg (OR 4.04, 95% CI 1.41–13.03. (2) PaO2 between 70 and 240 mmHg (OR 1.96, 95% CI 1.08–3.64) and PaCO2 levels (OR 0.98, 95% CI 0.95–0.99) were positively and inversely associated with favorable neurological outcome, respectively. (3) The product of hemoglobin × peripheral hemoglobin oxygen saturation (SpO2) was correlated with a favorable neurological outcome (odds ratio 1.003, 95% confidence interval 1.002-1.004). According to recommended SpO2 by resuscitation guidelines [94% to 98%], we calculated the corresponding range of minimum required hemoglobin concentration to be 8.6 to 9.0 g/dL for a favorable neurological outcome. (4) For diabetic patients, a mean BG level between 183 and 307 mg/dL was significantly associated with favourable neurological outcome (OR 2.71, 95% CI 1.18-6.20); a mean BG level between 147 and 317 mg/dL was significantly associated with survival to hospital discharge (OR: 2.38, 95% CI: 1.26-4.53). For non-diabetic patients, a mean BG level between 143 and 268 mg/dL was significantly associated with survival to hospital discharge (OR 2.93, 95% CI 1.62-5.40).
Finally, we used Wistar rats to establish the animal model of asphyxia-induced cardiac arrest. We used norepinephrine to manipulate MAP and observe the influence of OxyFlo-measured brain flow on clinical outcomes. The result showed that in the control group, the cerebral blood flow peaked at 10-15 mins following ROSC and then decreased to nadir at 20-30 mins following ROSC. In the experimental groups, when MAP was increased by norepinephrine infusion, the cerebral blood flow also increased accordingly, suggesting the dysfunction of cerebral auto-regulation mechanism. Clinically, the neurological outcomes in the experimental group receiving norepinephrine infusion for 4 hours tended to be better than the control group.

並列關鍵字

Cardiac arrest ； Post-cardiac arrest syndrome ； Blood pressure ； Partial pressure of arterial oxygen ； Partial pressure of arterial carbon dioxide ； Hemoglobin ； Blood glucose

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