The Preliminary Clinical Study Of Timing Of Continuous Renal Replacement Treatment On The Treatment Of Septic Patients Without Acute Renal Injury

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 during2008.6.1²011.12.31were 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 during2010.12.31²011.12.31were 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 during2011.6.1²011.12.31were 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 AKI1.1the effect of organ dysfunction number on the severity and outcome of patients with sepsis without AKIcompared with sepsis patients without any organ dysfunction, significantly increased APACHE â…¡ 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 â…¡ 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 â…¡ 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 â…¡ 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 AKIIn sepsis group without organ dysfunction (group S), the APACHE â…¡ 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 â…¡ 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 â…¡ 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 â…¡ 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 â…¡ 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 outcomeThe 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 outcomefor all patients received CRRT treatment (n=72), much lower the APACHE â…¡ 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 â…¡ 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 outcomethe AUC of CRRT duration in all CRRT patients was0.763(95%CI:0.600⁰.927). 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 analysisurivariate 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 levels2.1the effect of different initiation timing on the serum cytokine levelsOnly 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 levelsCompared 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 outcomeonly 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 sepsis3.1only APACHE â…¡ 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.