脓毒症不合并肾功能障碍时持续肾替代治疗的时机探讨
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摘要
目的：
1将不合并急性肾损伤(acute kidney injury,AKI)的脓毒症、严重脓毒症和多器官功能障碍综合征(multiple organ dysfunction syndrome, MODS)患者按器官功能障碍的数目作为持续肾替代治疗(continuous renal replacement treatment, CRRT)免疫调理的起始治疗时间点,观察不同起始治疗时间对患者病情、血清炎症介质水平和预后的影响,初步明确该类患者CRRT免疫调理的最佳治疗时机和可能作用机制,为临床脓毒症的治疗提供依据。
2分析CRRT免疫调理的延迟时间对该类患者的病情、血清炎症介质水平和预后的影响,希望为CRRT免疫调理时提供一个有效、安全的时间窗。
3观察分析脓毒症患者CRRT联合血必净治疗对病情、免疫功能和预后等方面的影响,通过炎症因子水平的变化阐述其可能的作用机制,为血必净联合CRRT应用于脓毒症的治疗提供证据。
方法：
第一节脓毒症不合并AKI患者CRRT不同治疗时机对患者病情和预后的影响
选择2008年6月1日至2011年12月31日期间广州军区广州总医院重症医学科收治的不合并AKI的脓毒症、严重脓毒症和MODS患者,进行前瞻性、随机对照实验。按器官功能障碍的数目分为脓毒症组(不合并器官功能障碍,S组),严重脓毒症组(合并单一器官功能障碍,SS组)和脓毒症合并多器官功能障碍组(M组)。S组和SS组患者按简单随机原则又分为治疗组和对照组。对照组指仅接受2008年拯救脓毒症宣言(Surviving Sepsis Campaign, SSC)指南制定的标准集束化治疗；治疗组在集束化治疗的基础上联合使用CRRT治疗。脓毒症合并多器官功能障碍组根据伦理学观点不设对照组,在集束化治疗的基础上给予CRRT治疗。记录患者病情指标,包括治疗前、治疗后、治疗后第二天、治疗后第五天、治疗后第七天以及转科或死亡时的APACHE Ⅱ评分、SOFA评分和PCT水平,统计治疗前、治疗后第三天和治疗后第七天的HLA-DR/CD14+表达。记录患者确诊后到接受CRRT治疗的间隔时间和CRRT治疗的持续时间。记录预后指标包括呼吸机使用时间、ICU住院时间、总住院时间、28天生存率以及住院费用。
第二节脓毒症不合并AKI患者CRRT不同治疗时机对炎症介质水平的影响
选择2010年12月31日至2011年12月31日期间入组的病人共29例,分组和治疗方案同实验一。记录患者的病情指标、预后指标和花费,同实验一。检测治疗前、治疗后第一天、治疗后第二天、治疗后第五天的血清促炎介质(IL-1β、IL-6和TNF-α)和抗炎介质(IL-1ra和IL-10)水平。
实验三血必净联合CRRT对脓毒症患者病情和血清炎症介质的作用
选择2011年6月1日至2011年12月31日期间广州军区广州总医院重症医学科收治的脓毒症患者24例,随机分为对照组,CRRT治疗组和CRRT+血必净联合治疗组。对照组和CRRT治疗组的治疗方案同实验一,CRRT+血必净联合治疗组在CRRT治疗组的基础上加用血必净注射液。记录患者的病情指标、血清炎症介质水平、预后指标和住院费用,同实验二
结果
1CRRT不同治疗时机对患者病情和预后的影响
1.1器官功能障碍的数目对病情和预后的影响
与脓毒症无器官功能障碍患者比较,单一器官功能障碍患者的入院APACHE Ⅱ评分和SOFA评分显著增加(p<0.05),呼吸机时间显著延长(p<0.05),但死亡率无统计学差异(p=0.077)；两个器官功能障碍患者的APACHE Ⅱ评分和SOFA评分显著增加(p<0.05),呼吸机时间显著延长(p<0.05),死亡率显著升高(p=0.006)；3个器官功能障碍患者的APACHE Ⅱ评分和SOFA评分进一步升高(p<0.05),且呼吸机使用时间延长(p<0.05),死亡率虽显著增高(p<0.05),但与2个器官功能障碍患者相比无统计学差异(p=0.093)；但器官功能障碍的数目≥4时,APACHE Ⅱ评分和SOFA评分最高,死亡率达100%。HLA-DR/CD14+表达无显著变化(p>0.05)。
1.2CRRT起始治疗时机对患者病情与预后的关系
S组接受CRRT免疫调理治疗后,APACHE Ⅱ评分和SOFA评分显著下降(P＜.001), HLA-DR/CD14+表达显著增加(P<0.001)。但与对照组相比,PCT水平无显著变化(P=0.1),APACHEⅡ评分显著增高(P<0.05),各时点的SOFA评分和HLA-DR/CD14+表达亦无统计学差异(P>0.05)。预后指标如28天死亡率、呼吸机使用时间、ICU住院时间和住院花费均无统计学差异(P>0.05)。总住院时间缩短(p=0.025)。
SS组患者CRRT治疗后,APACHE Ⅱ评分、SOFA评分和PCT水平显著下降(P<0.05),HLA-DR/CD14+表达显著升高(p=0.002)。但与对照组相比,APACHE Ⅱ评分和SOFA评分均显著下降(p<0.05),各时点的PCT水平和HLA-DR/CD14+表达无统计学差异(P>0.05)。预后指标如28天死亡率、呼吸机使用时间、ICU住院时间、总住院时间和住院费用两组均无差异(P>0.05)。
M组患者CRRT治疗后APACHE Ⅱ评分和PCT水平显著降低(P=0.001),SOFA评分和HLA-DR/CD14+表达变化不明显(P>0.05)。
1.3CRRT治疗延迟时间与存活组、死亡组的相关性分析
S组患者死亡者(n=27)和存活者(n=45)的治疗延迟时间有显著差异(p=0.015)；治疗延迟ROC曲线下面积为0.944(95%CI：0.839-1.049),用于预测患者28天死亡率有显著意义(P=0.017)；治疗延迟时间为36h时判断患者预后的灵敏度为80%,特异度为93.7%。
所有接受CRRT治疗的患者(n=72)治疗延迟时间的ROC曲线下面积为0.668(95%CI：0.533-0.804),治疗延迟时间为36h时判断患者预后的灵敏度下降至40.7%,特异度升高至91.1%。
1.4CRRT治疗延迟时间对病情、预后的影响
所有接受CRRT治疗的患者(n=72)根据治疗延迟时间进行比较,治疗延迟时间<36h的患者APACHE Ⅱ评分、SOFA评分、PCT水平显著降低(p<0.05),HLA-DR/CD14+表达显著升高(p<0.05)。再与>36h开始治疗患者比较,治疗后第五天APACHE Ⅱ评分和SOFA评分显著较低(p<0.05)。<36h治疗患者呼吸机使用时间显著减少(p<0.05),28天死亡率也明显降低(p<0.05)。
1.5CRRT治疗持续时间和预后的关系
所有接受治疗患者(n=72)CRRT持续时间的ROC曲线下面积为0.763(95%CI：0.600-0.927),选择5.5天为截断点时,灵敏度为0.700,特异度为0.769,治疗持续时间超过5.5天,患者28天死亡的风险显著增加(P=0.012)。
1.6危险因素分析
单因素回归分析发现器官衰竭数目、治疗方法、治疗前APACHE Ⅱ评分、SOFA评分、HLA-DR/CD14+表达、呼吸机使用时间、总住院时间均和死亡有显著相关关系(p<0.05),多因素分析发现器官衰竭数目(P=0.037)和呼吸机时间(OR=1.283,95%CI(1.112-1.481),P=0.001)是和死亡有显著相关关系,治疗前HLA-DR/CD14+高表达(OR=0.948,95%CI(0.914-0.983))和总住院时间短(OR=0.932,95%CI(0.888-0.977))是对预后有利的积极因素,但其OR值均非常接近于1。
2CRRT不同治疗时机对患者血清炎症介质水平的影响
2.1CRRT免疫调理时机对血清炎症介质的影响
S组患者CRRT治疗后仅IL-6水平显著下降(p<0.05)。SS组患者CRRT治疗后与对照组相比,血清IL-1p和IL-1ra水平在治疗后虽第一天显著下降(p<0.05),但第二天以后IL-1β和TNF-α持续升高(p<0.05),IL-1ra水平继续显著降低(p<0.05),而各时点的IL-6、IL-10、IL-6/IL-10、IL-10/TNF-a无明显变化(p>0.05)。对照组治疗后IL-6、IL-10水平和IL-10/TNF-a显著升高(p<0.05),治疗组相关介质水平变动不明显(p>0.05)。M组患者CRRT治疗后第二天IL-10/TNF-α开始显著增加(p<0.05)。
2.2CRRT治疗延迟对血清炎症介质水平的影响
与超过36h治疗患者相比,确诊后36h行CRRT治疗的患者IL-1β水平逐渐升高(p<0.05),前1-5天IL-6、IL-10水平均显著降低(p<0.05)。
2.3炎症介质水平和病情指标以及死亡率之间的相关性分析
治疗前和治疗后患者的APACHE Ⅱ评分和IL-10水平在第2天呈正相关(r=0.419,P=0.015；r=0.489,P=0.004),其余两两均无显著相关性(P>0.05)。
3CRRT联合血必净对脓毒症患者的疗效
3.1CRRT联合血必净对患者病情的影响
治疗后仅CRRT治疗组(ST)组和CRRT联合血必净治疗的患者(SX组)APACHE Ⅱ评分显著下降(p≤0.001)。但SX组治疗后1-5天的水平明显低于对照组(SC组)和CRRT治疗组(ST组)(p<0.05),而SOFA评分、PCT和HLA-DR/CD14+表达均没有明显变化(p>0.05)。对照组(SC)组治疗后其他指标均无明显变化(P>0.05)。
3.2和对照组比较,SX组治疗后IL-6水平、IL-10显著降低(P<0.05),IL-6/IL-10显著升高(P=0.033)。与对照组和CRRT治疗组相比IL-6水平、IL-10显著降低(P<0.05)。IL-1ra和IL-6水平在治疗后1-5天也显著减少(P<0.05)。对照组治疗后各指标均无统计学差异(P>0.05)。
3.33组患者的呼吸机使用时间和28天死亡率均没有显著差异(P>0.05)；和对照组相比,CRRT治疗组的ICU住院时间、总住院时间和住院费用显著升高(P<0.05),而CRRT+血必净组的ICU住院时间、总住院时间和住院费用没有差异(P>0.05)。
结论
1不合并AKI的脓毒症患者随着器官功能障碍数目的增加,病情越危重,预后越差,死亡率越高。器官功能障碍的数目越多和呼吸机使用时间越长是该类患者预后不良的独立危险因素。入院时HLA-DR/CD14+高表达是患者预后有利的积极因素。
2脓毒症合并单一器官功能障碍(SS组)患者行CRRT免疫调理能改善患者的病情严重程度和器官功能障碍程度,但不能改善预后和住院花费。脓毒症不合并器官功能障碍和合并多器官功能障碍患者(S组和M组)行CRRT不能改善患者病情和预后。
3脓毒症合并单一器官功能障碍(SS组)患者CRRT治疗延迟可增加该类患者的死亡率,治疗在<36h内展开的患者病情严重程度和器官功能障碍程度能显著降低,呼吸机使用时间缩短,死亡风险减少。
4不合并AKI的脓毒症患者CRRT治疗持续时间超过5.5天,死亡风险显著增加。
5脓毒症不合并器官功能障碍患者(S组)CRRT治疗后仅能降低血清IL-6水平。治疗效果有限。脓毒症合并单一器官功能障碍(SS组)患者CRRT治疗仅清除少数抗炎因子,对部分抗炎和促炎因子可能存在“削峰”效果,可能调节抗炎／促炎反应平衡。多器官功能障碍患者(M组)CRRT治疗后抗炎反应有逐渐增加的趋势。
6脓毒症确诊后<36h给予CRRT治疗可对部分抗炎和促炎因子存在“削峰”作用。
7所有脓毒症患者治疗前和治疗后第二天的IL-10水平可预判患者的病情严重程度。
总之,脓毒症患者随着器官功能障碍数目的增加,病情越危重,预后越差,死亡率越高。器官功能障碍的数目越多和呼吸机使用时间越长是该类患者预后不良的独立危险因素。入院时HLA-DR/CD14+高表达是患者预后有利的积极因素。脓毒症合并单一器官功能障碍患者确诊后36h内给予CRRT免疫调理可显著改善病情严重程度和器官功能障碍程度,降低患者死亡风险。可能的机制是CRRT治疗降低机体的促炎因子和抗炎因子水平,改善促炎／抗炎平衡,减少炎症介质对机体组织器官的损伤,减轻或逆转免疫麻痹状态。
8CRRT联合血必净治疗后可显著降低患者的病情严重程度。与对照组比较,预后无统计学差异,但与CRRT治疗组相比,患者的ICU住院时间、总住院时间和住院费用均显著降低。
9CRRT联合血必净治疗后可能是通过降低体内大部分促炎介质和抗炎介质水平(IL-6和IL-10),调节体内抗炎/促炎反应平衡而改善患者的病情。
CRRT联合血必净可安全、有效应用于脓毒症的治疗,可提高疗效,改善预后,降低患者费用。
Oject ive:
1To observe the effect of different timing of continuous renal replacement treatment (CRRT) on the severity, serum cytokine levels and outcome in the patients with sepsis, severe sepsis and MODS without any symptoms of acute renal injury (AKI) based according to the number of organ dysfunction as the initiation index of CRRT immuno-modulation, and to explicite the optimal initiation time and its possible mechanism to provide evident in the clinical treatment of sepsis.
2To analyze the effect of delay of CRRT initiation on the severity, serum cytokine levels and outcome in the patients with sepsis, severe sepsis and MODS without any symptoms of acute renal injury (AKI), so as to offer a safe and effective time window for CRRT immuno-modulation.
3To discuss the combined therapy of CRRT and Xuebijing Injections on the severity, serum cytokine levels and outcome in the patients with sepsis, and to explore its probable mechanism through the changes of serum cytokine levels, in order to support the combined therapy in the treatment of patients with sepsis.
Methods:
1In the1~(st) chapter of different timing of CRRT initiation on the severity and outcome in the patients with sepsis without AKI, all patients with sepsis, severe sepsis and MODS in ICU of Guangzhou Military Hospital of Guangzhou Command during2008.6.1~2011.12.31were included. The prospective study were performed. According to the number of organ dysfunction, the patients were randomly divided into sepsis group (without organ dysfunction, group S), severe sepsis (with one organ dysfunction, group SS) and MODS(with more than2organ dysfunction). the patients in the group S and group SS were randomly divided into treatment group and control group. The control group received standard therapy according to Surviving Sepsis Campaign2008. the treatment group received standard therapy plus CRRT. The APACHE II scores、 SOFA scores and serum PCT levels were recorded before treatment, after treatment, day2, day5, day7and when discharge from hospital. HLA-DR/CD14+expressions were evaluated before treatment, day3and day7. the delay and duration of CRRT was recorded, as well as ventilation duration, ICU stay, total length of stay, mortality rate and cost.
2In the2~(nd) chapter of the different timing of CRRT initiation on the cytokine levels and outcome in the patients with sepsis without AKI,29cases of patients with sepsis, severe sepsis and MODS in ICU of Guangzhou Military Hospital of Guangzhou Command during2010.12.31~2011.12.31were included and divided into same group standard as the1~(st) chapter. The parameters were recorded like the1~(st) chapter and serum cytokine levels like IL-1β, IL-6, TNF-α, IL-lra and IL-10before treatment, after treatment, day2and day5.
3In the3rd chapter of the combined effect of CRRT and Xuebijing injection on the treatment of patients with sepsis,24cases of patients with sepsis in ICU of Guangzhou Military Hospital of Guangzhou Command during2011.6.1~2011.12.31were included and randomly divided into control group, CRRT group and combined group with CRRT and Xuebijing injection. The control group and CRRT group received same treatment like in the1~(st) chapter. The combined group received standard therapy plus CRRT treatment plus Xuebjing injection. The detecting indexes were the same as the2~(nd) chapter. Same parameters were collected as in the2~(nd) chapter.
Results:
1the effect of different timing of CRRT initiation on the severity and outcome of patients with sepsis without AKI
1.1the effect of organ dysfunction number on the severity and outcome of patients with sepsis without AKI
compared with sepsis patients without any organ dysfunction, significantly increased APACHE Ⅱ scores and SOFA scores(p<0.05)., extended use of ventilation(p<0.05). were found in the patients with only1organ dysfunction, but there is no difference in the mortality rate between the above two groups (p=0.077). Much higher APACHE Ⅱ scores and SOFA scores, longer use of ventilation and raised mortality rate were represent in the patients with2organ dysfunction, when the dysfunction organ number increased to3, significantly higher APACHE Ⅱ scores and SOFA scores (p=0.006), longer use of ventilation (p<0.05) were observed but with no difference in the mortality rate compared with patients with2organ dysfunction(p=0.093). When organ dysfunction number increased to more than4, the APACHE Ⅱ scores and SOFA scores reached their peaks, and mortality rate surge to100%. The expression of HLA-DR/CD14+changed little(p>0.05).
1.2the effect of initiation timing of CRRT on the severity and outcome of patients with sepsis without AKI
In sepsis group without organ dysfunction (group S), the APACHE Ⅱ scores and SOFA scores were significantly decreased in the treatment group (P<0.001), and the expression of HLA-DR/CD14+increased (P<0.001). Compared with control group, the PCT level changed little (p=0.1), the APACHE Ⅱ scores increased substantially(P<0.05), the SOFA scores and the expression of HLA-DR/CD14+were similar at different time point (P>0.05),, as well as other outcome parameters like mortality rate, ventilation duration, ICU stay and cost.(P>0.05), and the total length of stay is much shorter (p=0.025).
In severe sepsis group, the APACHE Ⅱ scores, SOFA scores and PCT levels were reduced significantly in the treatment group (P<0.05), the expression of HLA-DR/CD14+was also increased (p=0.002). Compared with control group, the APACHE Ⅱ scores, SOFA scores were decreased significantly. PCT levels and expression of HLA-DR/CD14+were similar, as well as like mortality rate, ventilation duration, ICU stay, total length of stay and cost.(P>0.05)
In MODS group, the APACHE Ⅱ scores and PCT levels was much lower after CRRT treatment(p=0.001), while the SOFA scores and expression of HLA-DR/CD14+changed little(p>0.05)
1.3the Roc analysis of initiation delay with outcome
The initiation delay was much shorter in the survival patient of SS group, and AUC of initiation delay is0.944(95%CI:0.839-1.049), the sensitivity was80%, the specificity was93.7%if36h of initiation delay is chosen.
Besides, AUC of initiation delay in all CRRT group was0.668(95%CI:0.533-0.804), the sensitivity was80%, the specificity was93.7%if36h of initiation delay is chosen.
1.4the effect of initiation delay on the severity and outcome
for all patients received CRRT treatment (n=72), much lower the APACHE Ⅱ scores, SOFA scores and PCT levels, raised expression of HLA-DR/CD14+were observed in the patients with the initiation delay<36h(p<0.05). compared with patient with the initiation delay>36h, the APACHE Ⅱ scores and SOFA scores were significantly lower at day5(p<0.05). besides, shorter ventilation duration and decreased mortality was found in the patients with the initiation delay<36h(p<0.05).
1.5the relationship between the duration of CRRT and outcome
the AUC of CRRT duration in all CRRT patients was0.763(95%CI:0.600~0.927). The sensitivity was70%, the specificity was76.9%if5.5d of duration is chosen. If CRRT lasted more than5.5d, the risk is significantly increased (p=0.012).
1.6risk factor analysis
urivariate regression analyse suggest that the dysfunction organ numbers, the treatment methods, the APACHE II scores, SOFA scores and PCT levels, expression of HLA-DR/CD14+, ventilation duration, total length of stay were related to death(p<0.05). multivariate regression analysis showed the dysfunction organ number and ventilation duration were independent risk factors. High expression of HLA-DR/CD14+and short total length of stay were protective factors.
2the effect of different initiation timing on the serum cytokine levels
2.1the effect of different initiation timing on the serum cytokine levels
Only serum IL-6levels decreased significantly after CRRT treatment in the group S. compared with control group, the serum IL-13and IL-lra decreased right after treatment, the serum IL-13and TNF-α levels continued to increase since day2, and serum IL-lra levels kept reducing. The other cytokines like IL-6, IL-10, IL-6/IL-10and IL-10/TNF-α changed little when compared with other2groups, the serum IL-6levels, IL-10level and IL-10/TNF-α increased significantly in the control group, while these cytokine levels changed little in the treatment group. The IL-10/TNF-α ratio increased since day2after CRRT treatment in group M.
2.2the effect of CRRT delay on the cytokine levels
Compared with patients with CRRT delay>36h, gradually increased IL-1β and decreased IL-6and IL-10levels from day Pday5was present in the patients with CRRT delay<36h.
2.3the relationship between the serum cytokine levels with severity markers and outcome
only the APACHE II scores before treatment and at day2were closed related to serum IL-6levels (r=0.419, P=0.015; r=0.489, P=0.004, respectivly)
3the combined effect of CRRT and Xuebijing on the patients with sepsis
3.1only APACHE Ⅱ scores decreased in the CRRT treatment group and combined group after treatment (p≤0.001), while was lowest in the combined group form day1~day5compared with control group and CRRT group(p<0.05). other parameters changed little in the two groups(p>0.05). no obvious changes of cytokine levels were seen in the control group(p>0.05).
3.2compared with control group, the IL-6and IL-10levels significantly decreased in the combined group(p<0.05), and the ratio of IL-6/IL-10was significantly higher (P=0.033). compared with the control group and CRRT group, the serum IL-6and IL-10levels was the lowest in the combined group (P<0.05). the serum IL-1ra and IL-6levels significantly decreased from day1~day5(P<0.05). the serum cytokine levels changed little in the control group (P>0.05)
3.3the ventilation time and28-day mortality rate is similar in the3groups (P>0.05). there were no difference in the ICU stay, total length of stay and cost between control group and combined group (P>0.05), however, they are much higher in the CRRT group (P<0.05) Conelusion:
1As the number of organ dysfunction increases, the severity raises and the outcome is worse in the septic patients without AKI. The number of organ dysfunction and ventilation duration is independent risk factor. High expression of HLA-DR/CD14+is a protective factor.
2CRRT immuno-modulation can improve the severity and organ functions in the septic patients with one organ dysfunction, without any effect on the outcome and cost. CRRT can not improve the severity and outcome in the septic patients and MODS patients.
3CRRT initiation delay can increase the risk factors in the septic patients with one organ dysfunction,, and the patients with delay<36h was present with much improved organ dysfunction and severity, shortened ventilation duration and death risk.
4The CRRT duration>5.5d can increase the risk in septic patient without AKI.
5Only the serum IL-6levels decreased in the septic patients, and the treatment effect is limited. CRRT inununo-modulation can remove part of anti-inflammatory cytokines, and may have some effect like "eliminating the peaks" and regulating the balance of anti-inflammatory/inflammatory response. CRRT deteriorate the anti-inflammatory response in MODS patients.
6The CRRT initiation delay<36h can eliminate the peaks of part of anti-inflammatory and inflammatory cytokines.
7The serum IL-10levels at day1and day2can predict the. severity of patients with sepsis.
Therefore, as the number of organ dysfunction increases, the severity raises and the outcome is worse in the septic patients without AKI. The number of organ dysfunction and ventilation duration is independent risk factor. High expression of HLA-DR/CD14+is a protective factor. CRRT initiation delay<36when one organ dysfunction occurred can improve the severity and organ dysfunction, decreased the mortality rate through the possible mechanism of reducing the inflammatory and anti-inflammatory cytokine levels and improving their balance to reduce tissue and organ injury and to relieve or reverse the immunoparalysis.
8Combined therapy of CRRT and Xuebijing Injection can significantly reduce the severity of sepsis patients, and decreased the ICU stay, total length of stay and cost from CRRT treatment.
9Removing most cytokine levels like IL-6and IL-10and regulate their balance could be the possible mechanism for CRRT and Xuebijing injections to improve the patients condition.
1将不合并急性肾损伤(acute kidney injury,AKI)的脓毒症、严重脓毒症和多器官功能障碍综合征(multiple organ dysfunction syndrome, MODS)患者按器官功能障碍的数目作为持续肾替代治疗(continuous renal replacement treatment, CRRT)免疫调理的起始治疗时间点,观察不同起始治疗时间对患者病情、血清炎症介质水平和预后的影响,初步明确该类患者CRRT免疫调理的最佳治疗时机和可能作用机制,为临床脓毒症的治疗提供依据。
2分析CRRT免疫调理的延迟时间对该类患者的病情、血清炎症介质水平和预后的影响,希望为CRRT免疫调理时提供一个有效、安全的时间窗。
3观察分析脓毒症患者CRRT联合血必净治疗对病情、免疫功能和预后等方面的影响,通过炎症因子水平的变化阐述其可能的作用机制,为血必净联合CRRT应用于脓毒症的治疗提供证据。
方法：
第一节脓毒症不合并AKI患者CRRT不同治疗时机对患者病情和预后的影响
选择2008年6月1日至2011年12月31日期间广州军区广州总医院重症医学科收治的不合并AKI的脓毒症、严重脓毒症和MODS患者,进行前瞻性、随机对照实验。按器官功能障碍的数目分为脓毒症组(不合并器官功能障碍,S组),严重脓毒症组(合并单一器官功能障碍,SS组)和脓毒症合并多器官功能障碍组(M组)。S组和SS组患者按简单随机原则又分为治疗组和对照组。对照组指仅接受2008年拯救脓毒症宣言(Surviving Sepsis Campaign, SSC)指南制定的标准集束化治疗；治疗组在集束化治疗的基础上联合使用CRRT治疗。脓毒症合并多器官功能障碍组根据伦理学观点不设对照组,在集束化治疗的基础上给予CRRT治疗。记录患者病情指标,包括治疗前、治疗后、治疗后第二天、治疗后第五天、治疗后第七天以及转科或死亡时的APACHE Ⅱ评分、SOFA评分和PCT水平,统计治疗前、治疗后第三天和治疗后第七天的HLA-DR/CD14+表达。记录患者确诊后到接受CRRT治疗的间隔时间和CRRT治疗的持续时间。记录预后指标包括呼吸机使用时间、ICU住院时间、总住院时间、28天生存率以及住院费用。
第二节脓毒症不合并AKI患者CRRT不同治疗时机对炎症介质水平的影响
选择2010年12月31日至2011年12月31日期间入组的病人共29例,分组和治疗方案同实验一。记录患者的病情指标、预后指标和花费,同实验一。检测治疗前、治疗后第一天、治疗后第二天、治疗后第五天的血清促炎介质(IL-1β、IL-6和TNF-α)和抗炎介质(IL-1ra和IL-10)水平。
实验三血必净联合CRRT对脓毒症患者病情和血清炎症介质的作用
选择2011年6月1日至2011年12月31日期间广州军区广州总医院重症医学科收治的脓毒症患者24例,随机分为对照组,CRRT治疗组和CRRT+血必净联合治疗组。对照组和CRRT治疗组的治疗方案同实验一,CRRT+血必净联合治疗组在CRRT治疗组的基础上加用血必净注射液。记录患者的病情指标、血清炎症介质水平、预后指标和住院费用,同实验二
结果
1CRRT不同治疗时机对患者病情和预后的影响
1.1器官功能障碍的数目对病情和预后的影响
与脓毒症无器官功能障碍患者比较,单一器官功能障碍患者的入院APACHE Ⅱ评分和SOFA评分显著增加(p<0.05),呼吸机时间显著延长(p<0.05),但死亡率无统计学差异(p=0.077)；两个器官功能障碍患者的APACHE Ⅱ评分和SOFA评分显著增加(p<0.05),呼吸机时间显著延长(p<0.05),死亡率显著升高(p=0.006)；3个器官功能障碍患者的APACHE Ⅱ评分和SOFA评分进一步升高(p<0.05),且呼吸机使用时间延长(p<0.05),死亡率虽显著增高(p<0.05),但与2个器官功能障碍患者相比无统计学差异(p=0.093)；但器官功能障碍的数目≥4时,APACHE Ⅱ评分和SOFA评分最高,死亡率达100%。HLA-DR/CD14+表达无显著变化(p>0.05)。
1.2CRRT起始治疗时机对患者病情与预后的关系
S组接受CRRT免疫调理治疗后,APACHE Ⅱ评分和SOFA评分显著下降(P＜.001), HLA-DR/CD14+表达显著增加(P<0.001)。但与对照组相比,PCT水平无显著变化(P=0.1),APACHEⅡ评分显著增高(P<0.05),各时点的SOFA评分和HLA-DR/CD14+表达亦无统计学差异(P>0.05)。预后指标如28天死亡率、呼吸机使用时间、ICU住院时间和住院花费均无统计学差异(P>0.05)。总住院时间缩短(p=0.025)。
SS组患者CRRT治疗后,APACHE Ⅱ评分、SOFA评分和PCT水平显著下降(P<0.05),HLA-DR/CD14+表达显著升高(p=0.002)。但与对照组相比,APACHE Ⅱ评分和SOFA评分均显著下降(p<0.05),各时点的PCT水平和HLA-DR/CD14+表达无统计学差异(P>0.05)。预后指标如28天死亡率、呼吸机使用时间、ICU住院时间、总住院时间和住院费用两组均无差异(P>0.05)。
M组患者CRRT治疗后APACHE Ⅱ评分和PCT水平显著降低(P=0.001),SOFA评分和HLA-DR/CD14+表达变化不明显(P>0.05)。
1.3CRRT治疗延迟时间与存活组、死亡组的相关性分析
S组患者死亡者(n=27)和存活者(n=45)的治疗延迟时间有显著差异(p=0.015)；治疗延迟ROC曲线下面积为0.944(95%CI：0.839-1.049),用于预测患者28天死亡率有显著意义(P=0.017)；治疗延迟时间为36h时判断患者预后的灵敏度为80%,特异度为93.7%。
所有接受CRRT治疗的患者(n=72)治疗延迟时间的ROC曲线下面积为0.668(95%CI：0.533-0.804),治疗延迟时间为36h时判断患者预后的灵敏度下降至40.7%,特异度升高至91.1%。
1.4CRRT治疗延迟时间对病情、预后的影响
所有接受CRRT治疗的患者(n=72)根据治疗延迟时间进行比较,治疗延迟时间<36h的患者APACHE Ⅱ评分、SOFA评分、PCT水平显著降低(p<0.05),HLA-DR/CD14+表达显著升高(p<0.05)。再与>36h开始治疗患者比较,治疗后第五天APACHE Ⅱ评分和SOFA评分显著较低(p<0.05)。<36h治疗患者呼吸机使用时间显著减少(p<0.05),28天死亡率也明显降低(p<0.05)。
1.5CRRT治疗持续时间和预后的关系
所有接受治疗患者(n=72)CRRT持续时间的ROC曲线下面积为0.763(95%CI：0.600-0.927),选择5.5天为截断点时,灵敏度为0.700,特异度为0.769,治疗持续时间超过5.5天,患者28天死亡的风险显著增加(P=0.012)。
1.6危险因素分析
单因素回归分析发现器官衰竭数目、治疗方法、治疗前APACHE Ⅱ评分、SOFA评分、HLA-DR/CD14+表达、呼吸机使用时间、总住院时间均和死亡有显著相关关系(p<0.05),多因素分析发现器官衰竭数目(P=0.037)和呼吸机时间(OR=1.283,95%CI(1.112-1.481),P=0.001)是和死亡有显著相关关系,治疗前HLA-DR/CD14+高表达(OR=0.948,95%CI(0.914-0.983))和总住院时间短(OR=0.932,95%CI(0.888-0.977))是对预后有利的积极因素,但其OR值均非常接近于1。
2CRRT不同治疗时机对患者血清炎症介质水平的影响
2.1CRRT免疫调理时机对血清炎症介质的影响
S组患者CRRT治疗后仅IL-6水平显著下降(p<0.05)。SS组患者CRRT治疗后与对照组相比,血清IL-1p和IL-1ra水平在治疗后虽第一天显著下降(p<0.05),但第二天以后IL-1β和TNF-α持续升高(p<0.05),IL-1ra水平继续显著降低(p<0.05),而各时点的IL-6、IL-10、IL-6/IL-10、IL-10/TNF-a无明显变化(p>0.05)。对照组治疗后IL-6、IL-10水平和IL-10/TNF-a显著升高(p<0.05),治疗组相关介质水平变动不明显(p>0.05)。M组患者CRRT治疗后第二天IL-10/TNF-α开始显著增加(p<0.05)。
2.2CRRT治疗延迟对血清炎症介质水平的影响
与超过36h治疗患者相比,确诊后36h行CRRT治疗的患者IL-1β水平逐渐升高(p<0.05),前1-5天IL-6、IL-10水平均显著降低(p<0.05)。
2.3炎症介质水平和病情指标以及死亡率之间的相关性分析
治疗前和治疗后患者的APACHE Ⅱ评分和IL-10水平在第2天呈正相关(r=0.419,P=0.015；r=0.489,P=0.004),其余两两均无显著相关性(P>0.05)。
3CRRT联合血必净对脓毒症患者的疗效
3.1CRRT联合血必净对患者病情的影响
治疗后仅CRRT治疗组(ST)组和CRRT联合血必净治疗的患者(SX组)APACHE Ⅱ评分显著下降(p≤0.001)。但SX组治疗后1-5天的水平明显低于对照组(SC组)和CRRT治疗组(ST组)(p<0.05),而SOFA评分、PCT和HLA-DR/CD14+表达均没有明显变化(p>0.05)。对照组(SC)组治疗后其他指标均无明显变化(P>0.05)。
3.2和对照组比较,SX组治疗后IL-6水平、IL-10显著降低(P<0.05),IL-6/IL-10显著升高(P=0.033)。与对照组和CRRT治疗组相比IL-6水平、IL-10显著降低(P<0.05)。IL-1ra和IL-6水平在治疗后1-5天也显著减少(P<0.05)。对照组治疗后各指标均无统计学差异(P>0.05)。
3.33组患者的呼吸机使用时间和28天死亡率均没有显著差异(P>0.05)；和对照组相比,CRRT治疗组的ICU住院时间、总住院时间和住院费用显著升高(P<0.05),而CRRT+血必净组的ICU住院时间、总住院时间和住院费用没有差异(P>0.05)。
结论
1不合并AKI的脓毒症患者随着器官功能障碍数目的增加,病情越危重,预后越差,死亡率越高。器官功能障碍的数目越多和呼吸机使用时间越长是该类患者预后不良的独立危险因素。入院时HLA-DR/CD14+高表达是患者预后有利的积极因素。
2脓毒症合并单一器官功能障碍(SS组)患者行CRRT免疫调理能改善患者的病情严重程度和器官功能障碍程度,但不能改善预后和住院花费。脓毒症不合并器官功能障碍和合并多器官功能障碍患者(S组和M组)行CRRT不能改善患者病情和预后。
3脓毒症合并单一器官功能障碍(SS组)患者CRRT治疗延迟可增加该类患者的死亡率,治疗在<36h内展开的患者病情严重程度和器官功能障碍程度能显著降低,呼吸机使用时间缩短,死亡风险减少。
4不合并AKI的脓毒症患者CRRT治疗持续时间超过5.5天,死亡风险显著增加。
5脓毒症不合并器官功能障碍患者(S组)CRRT治疗后仅能降低血清IL-6水平。治疗效果有限。脓毒症合并单一器官功能障碍(SS组)患者CRRT治疗仅清除少数抗炎因子,对部分抗炎和促炎因子可能存在“削峰”效果,可能调节抗炎／促炎反应平衡。多器官功能障碍患者(M组)CRRT治疗后抗炎反应有逐渐增加的趋势。
6脓毒症确诊后<36h给予CRRT治疗可对部分抗炎和促炎因子存在“削峰”作用。
7所有脓毒症患者治疗前和治疗后第二天的IL-10水平可预判患者的病情严重程度。
总之,脓毒症患者随着器官功能障碍数目的增加,病情越危重,预后越差,死亡率越高。器官功能障碍的数目越多和呼吸机使用时间越长是该类患者预后不良的独立危险因素。入院时HLA-DR/CD14+高表达是患者预后有利的积极因素。脓毒症合并单一器官功能障碍患者确诊后36h内给予CRRT免疫调理可显著改善病情严重程度和器官功能障碍程度,降低患者死亡风险。可能的机制是CRRT治疗降低机体的促炎因子和抗炎因子水平,改善促炎／抗炎平衡,减少炎症介质对机体组织器官的损伤,减轻或逆转免疫麻痹状态。
8CRRT联合血必净治疗后可显著降低患者的病情严重程度。与对照组比较,预后无统计学差异,但与CRRT治疗组相比,患者的ICU住院时间、总住院时间和住院费用均显著降低。
9CRRT联合血必净治疗后可能是通过降低体内大部分促炎介质和抗炎介质水平(IL-6和IL-10),调节体内抗炎/促炎反应平衡而改善患者的病情。
CRRT联合血必净可安全、有效应用于脓毒症的治疗,可提高疗效,改善预后,降低患者费用。
Oject ive:
1To observe the effect of different timing of continuous renal replacement treatment (CRRT) on the severity, serum cytokine levels and outcome in the patients with sepsis, severe sepsis and MODS without any symptoms of acute renal injury (AKI) based according to the number of organ dysfunction as the initiation index of CRRT immuno-modulation, and to explicite the optimal initiation time and its possible mechanism to provide evident in the clinical treatment of sepsis.
2To analyze the effect of delay of CRRT initiation on the severity, serum cytokine levels and outcome in the patients with sepsis, severe sepsis and MODS without any symptoms of acute renal injury (AKI), so as to offer a safe and effective time window for CRRT immuno-modulation.
3To discuss the combined therapy of CRRT and Xuebijing Injections on the severity, serum cytokine levels and outcome in the patients with sepsis, and to explore its probable mechanism through the changes of serum cytokine levels, in order to support the combined therapy in the treatment of patients with sepsis.
Methods:
1In the1~(st) chapter of different timing of CRRT initiation on the severity and outcome in the patients with sepsis without AKI, all patients with sepsis, severe sepsis and MODS in ICU of Guangzhou Military Hospital of Guangzhou Command during2008.6.1~2011.12.31were included. The prospective study were performed. According to the number of organ dysfunction, the patients were randomly divided into sepsis group (without organ dysfunction, group S), severe sepsis (with one organ dysfunction, group SS) and MODS(with more than2organ dysfunction). the patients in the group S and group SS were randomly divided into treatment group and control group. The control group received standard therapy according to Surviving Sepsis Campaign2008. the treatment group received standard therapy plus CRRT. The APACHE II scores、 SOFA scores and serum PCT levels were recorded before treatment, after treatment, day2, day5, day7and when discharge from hospital. HLA-DR/CD14+expressions were evaluated before treatment, day3and day7. the delay and duration of CRRT was recorded, as well as ventilation duration, ICU stay, total length of stay, mortality rate and cost.
2In the2~(nd) chapter of the different timing of CRRT initiation on the cytokine levels and outcome in the patients with sepsis without AKI,29cases of patients with sepsis, severe sepsis and MODS in ICU of Guangzhou Military Hospital of Guangzhou Command during2010.12.31~2011.12.31were included and divided into same group standard as the1~(st) chapter. The parameters were recorded like the1~(st) chapter and serum cytokine levels like IL-1β, IL-6, TNF-α, IL-lra and IL-10before treatment, after treatment, day2and day5.
3In the3rd chapter of the combined effect of CRRT and Xuebijing injection on the treatment of patients with sepsis,24cases of patients with sepsis in ICU of Guangzhou Military Hospital of Guangzhou Command during2011.6.1~2011.12.31were included and randomly divided into control group, CRRT group and combined group with CRRT and Xuebijing injection. The control group and CRRT group received same treatment like in the1~(st) chapter. The combined group received standard therapy plus CRRT treatment plus Xuebjing injection. The detecting indexes were the same as the2~(nd) chapter. Same parameters were collected as in the2~(nd) chapter.
Results:
1the effect of different timing of CRRT initiation on the severity and outcome of patients with sepsis without AKI
1.1the effect of organ dysfunction number on the severity and outcome of patients with sepsis without AKI
compared with sepsis patients without any organ dysfunction, significantly increased APACHE Ⅱ scores and SOFA scores(p<0.05)., extended use of ventilation(p<0.05). were found in the patients with only1organ dysfunction, but there is no difference in the mortality rate between the above two groups (p=0.077). Much higher APACHE Ⅱ scores and SOFA scores, longer use of ventilation and raised mortality rate were represent in the patients with2organ dysfunction, when the dysfunction organ number increased to3, significantly higher APACHE Ⅱ scores and SOFA scores (p=0.006), longer use of ventilation (p<0.05) were observed but with no difference in the mortality rate compared with patients with2organ dysfunction(p=0.093). When organ dysfunction number increased to more than4, the APACHE Ⅱ scores and SOFA scores reached their peaks, and mortality rate surge to100%. The expression of HLA-DR/CD14+changed little(p>0.05).
1.2the effect of initiation timing of CRRT on the severity and outcome of patients with sepsis without AKI
In sepsis group without organ dysfunction (group S), the APACHE Ⅱ scores and SOFA scores were significantly decreased in the treatment group (P<0.001), and the expression of HLA-DR/CD14+increased (P<0.001). Compared with control group, the PCT level changed little (p=0.1), the APACHE Ⅱ scores increased substantially(P<0.05), the SOFA scores and the expression of HLA-DR/CD14+were similar at different time point (P>0.05),, as well as other outcome parameters like mortality rate, ventilation duration, ICU stay and cost.(P>0.05), and the total length of stay is much shorter (p=0.025).
In severe sepsis group, the APACHE Ⅱ scores, SOFA scores and PCT levels were reduced significantly in the treatment group (P<0.05), the expression of HLA-DR/CD14+was also increased (p=0.002). Compared with control group, the APACHE Ⅱ scores, SOFA scores were decreased significantly. PCT levels and expression of HLA-DR/CD14+were similar, as well as like mortality rate, ventilation duration, ICU stay, total length of stay and cost.(P>0.05)
In MODS group, the APACHE Ⅱ scores and PCT levels was much lower after CRRT treatment(p=0.001), while the SOFA scores and expression of HLA-DR/CD14+changed little(p>0.05)
1.3the Roc analysis of initiation delay with outcome
The initiation delay was much shorter in the survival patient of SS group, and AUC of initiation delay is0.944(95%CI:0.839-1.049), the sensitivity was80%, the specificity was93.7%if36h of initiation delay is chosen.
Besides, AUC of initiation delay in all CRRT group was0.668(95%CI:0.533-0.804), the sensitivity was80%, the specificity was93.7%if36h of initiation delay is chosen.
1.4the effect of initiation delay on the severity and outcome
for all patients received CRRT treatment (n=72), much lower the APACHE Ⅱ scores, SOFA scores and PCT levels, raised expression of HLA-DR/CD14+were observed in the patients with the initiation delay<36h(p<0.05). compared with patient with the initiation delay>36h, the APACHE Ⅱ scores and SOFA scores were significantly lower at day5(p<0.05). besides, shorter ventilation duration and decreased mortality was found in the patients with the initiation delay<36h(p<0.05).
1.5the relationship between the duration of CRRT and outcome
the AUC of CRRT duration in all CRRT patients was0.763(95%CI:0.600~0.927). The sensitivity was70%, the specificity was76.9%if5.5d of duration is chosen. If CRRT lasted more than5.5d, the risk is significantly increased (p=0.012).
1.6risk factor analysis
urivariate regression analyse suggest that the dysfunction organ numbers, the treatment methods, the APACHE II scores, SOFA scores and PCT levels, expression of HLA-DR/CD14+, ventilation duration, total length of stay were related to death(p<0.05). multivariate regression analysis showed the dysfunction organ number and ventilation duration were independent risk factors. High expression of HLA-DR/CD14+and short total length of stay were protective factors.
2the effect of different initiation timing on the serum cytokine levels
2.1the effect of different initiation timing on the serum cytokine levels
Only serum IL-6levels decreased significantly after CRRT treatment in the group S. compared with control group, the serum IL-13and IL-lra decreased right after treatment, the serum IL-13and TNF-α levels continued to increase since day2, and serum IL-lra levels kept reducing. The other cytokines like IL-6, IL-10, IL-6/IL-10and IL-10/TNF-α changed little when compared with other2groups, the serum IL-6levels, IL-10level and IL-10/TNF-α increased significantly in the control group, while these cytokine levels changed little in the treatment group. The IL-10/TNF-α ratio increased since day2after CRRT treatment in group M.
2.2the effect of CRRT delay on the cytokine levels
Compared with patients with CRRT delay>36h, gradually increased IL-1β and decreased IL-6and IL-10levels from day Pday5was present in the patients with CRRT delay<36h.
2.3the relationship between the serum cytokine levels with severity markers and outcome
only the APACHE II scores before treatment and at day2were closed related to serum IL-6levels (r=0.419, P=0.015; r=0.489, P=0.004, respectivly)
3the combined effect of CRRT and Xuebijing on the patients with sepsis
3.1only APACHE Ⅱ scores decreased in the CRRT treatment group and combined group after treatment (p≤0.001), while was lowest in the combined group form day1~day5compared with control group and CRRT group(p<0.05). other parameters changed little in the two groups(p>0.05). no obvious changes of cytokine levels were seen in the control group(p>0.05).
3.2compared with control group, the IL-6and IL-10levels significantly decreased in the combined group(p<0.05), and the ratio of IL-6/IL-10was significantly higher (P=0.033). compared with the control group and CRRT group, the serum IL-6and IL-10levels was the lowest in the combined group (P<0.05). the serum IL-1ra and IL-6levels significantly decreased from day1~day5(P<0.05). the serum cytokine levels changed little in the control group (P>0.05)
3.3the ventilation time and28-day mortality rate is similar in the3groups (P>0.05). there were no difference in the ICU stay, total length of stay and cost between control group and combined group (P>0.05), however, they are much higher in the CRRT group (P<0.05) Conelusion:
1As the number of organ dysfunction increases, the severity raises and the outcome is worse in the septic patients without AKI. The number of organ dysfunction and ventilation duration is independent risk factor. High expression of HLA-DR/CD14+is a protective factor.
2CRRT immuno-modulation can improve the severity and organ functions in the septic patients with one organ dysfunction, without any effect on the outcome and cost. CRRT can not improve the severity and outcome in the septic patients and MODS patients.
3CRRT initiation delay can increase the risk factors in the septic patients with one organ dysfunction,, and the patients with delay<36h was present with much improved organ dysfunction and severity, shortened ventilation duration and death risk.
4The CRRT duration>5.5d can increase the risk in septic patient without AKI.
5Only the serum IL-6levels decreased in the septic patients, and the treatment effect is limited. CRRT inununo-modulation can remove part of anti-inflammatory cytokines, and may have some effect like "eliminating the peaks" and regulating the balance of anti-inflammatory/inflammatory response. CRRT deteriorate the anti-inflammatory response in MODS patients.
6The CRRT initiation delay<36h can eliminate the peaks of part of anti-inflammatory and inflammatory cytokines.
7The serum IL-10levels at day1and day2can predict the. severity of patients with sepsis.
Therefore, as the number of organ dysfunction increases, the severity raises and the outcome is worse in the septic patients without AKI. The number of organ dysfunction and ventilation duration is independent risk factor. High expression of HLA-DR/CD14+is a protective factor. CRRT initiation delay<36when one organ dysfunction occurred can improve the severity and organ dysfunction, decreased the mortality rate through the possible mechanism of reducing the inflammatory and anti-inflammatory cytokine levels and improving their balance to reduce tissue and organ injury and to relieve or reverse the immunoparalysis.
8Combined therapy of CRRT and Xuebijing Injection can significantly reduce the severity of sepsis patients, and decreased the ICU stay, total length of stay and cost from CRRT treatment.
9Removing most cytokine levels like IL-6and IL-10and regulate their balance could be the possible mechanism for CRRT and Xuebijing injections to improve the patients condition.
引文
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