Early Application Of Continuous High-volume Hemofiltration Can Reduce Sepsis Of Patients With Severe Burns

Background:Sepsis is one of the leading causes of death among severe burn patients,in particular when complicated by septic shock or multiple organ dysfunction syndrome?MODS?.Once septic shock or MODS happens,there is no specific and effective therapeutic measure,resulting a very poor prognosis.Although currently there are standard guidelines for the diagnosis and treatment of sepsis,for example,early bundle therapy for sepsis,which has led to improvements in survival of patients with sepsis,but the mortality remains high.Sepsis is one of the hottest spot in burn injury research,even in world medical research.Excessive inflammatory response is an important cause of organ injuries in the body's immune response to infection.Previous clinical trials of antagonistic therapy for some specific inflammatory mediators have failed,indicating that there is a close relationship between the network effect of inflammatory mediators and sepsis.And there is still a lack of effective therapeutic measures for excessive levels of inflammatory mediators caused by sepsis.Continuous veno-venous haemofiltration?CVVH?is capable of non-specifically eliminating the inflammatory mediator in blood.As a common method of blood purification,CVVH has been gradually applied in the treatment of inflammatory mediators-related diseases including sepsis.Our previous work has verified that CVVH could improve the organ functions,maintain homeostasis and relieve inflammatory reactions of burn patients with sepsis,but could not improve their survival rate.It seems that the effect of using blood purification as a salvage therapy on burn patients with septic shock and MODS was not as good as expected.We assume that excessive inflammatory response,or the proinflammatory/anti-inflammatory imbalance,or immune disorders of septic patients,are difficult to be reversed using current conventional treatment in intensive care unit?ICU?and blood purification,resulting the poor prognosis in sepsis.Therefore,we suggest that prevention of sepsis may be more important than treatment of sepsis.Severe burn patients often exhibit intense stress response and produce massive inflammatory mediators in the early stage after injury,which are prone to develop organ damages and immune dysfunction,increasing their susceptibility to infections and leading sepsis.We hypothesized that early application of continuous blood purification in severe burned patients might regulate immune function,reduce the incidence of sepsis and improve the prognosis through clearance of the excessive inflammatory mediators.The modality of high-volume hemofiltration?HVHF?is equivalent to a high dose of CVVH.HVHF enhances the convection and adsorption on medium-and small-molecular-weight solutes,and improves the clearance abilities through increasing the input of displacement liquid.In the present study,HVHF was applied in the severe burn patients,and the adsorption and removal of macromolecular solute were enhanced by increasing the replacement frequency of filter.We observed the levels of some inflammatory cytokines in blood circulation,immune phenotypes in peripheral blood immune cells,and clinical outcomes of the severe burn patients treated with HVHF therapy or conventional therapy in a randomized prospective study.Objective:We observed whether early application of HVHF may be beneficial to reduce sepsis and improve prognosis of patients with severe burns.Method:Adult patients with burns?50%total body surface area?TBSA?,of which the sum of deep partial-thickness and full-thickness burn area?30%TBSA,arrived to our burn research institute in 72h after burn injury.They were enrolled for a randomized prospective study and randomly divided into the control group?41 cases?and HVHF group?41 cases?.The patients in the control group received standard management of major burn patients,while the patients in HVHF group,additionally,were received HVHF treatment within 3 days after burn,prescribing a dose of 65 ml/kg.h for consecutive 3 days.Patients discharged from hospital before the end of the study were followed for 3 months.The primary endpoints were incidence of sepsis and 90-day mortality.Secondary endpoints were 28-day and 60-day mortality,incidence of septic shock,duration of mechanical ventilation and vasopressor treatment,and length of stay in ICU.Adverse events were also recorded.The measures of both groups outlined below were recorded at days 1,3,5,7,14,21 and 28 post-burn:laboratory data including white blood cell?WBC?count,platelet?PLT?count,C-reactive protein?CRP?,procalcitonin?PCT?,kalium?K⁺?,natrium?Na⁺?,blood glucose?GLU?,aspartate transaminase?AST?,alanine transaminase?ALT?,total bilirubin?TBIL?,blood urea nitrogen?BUN?,serum creatinine?Cr?of venous blood,and oxygen partial pressure?PaO₂?,lactate?Lac?of artery blood were recorded,and the ratio of PaO₂ to the fraction of inspiration O₂?PaO₂/FiO₂?was calculated.The APACHE II and SOFA scores were recorded also.The plasma cytokine levels?tumour necrosis factor[TNF]-?,interleukin[IL]-1?,IL-6,IL-8,IL-10?were measured using enzyme-linked immunosorbent assay?ELISA?kits.The human leukocyte antigen-DR?HLA-DR?expression on CD14⁺peripheral blood monocytes,proportion of CD4⁺CD25⁺Foxp3⁺reg?latory T cells?Tregs?,as well as the counts of CD3⁺,CD4⁺and CD8⁺T lymphocytes were observed at days 1,3,7,14,21 and 28 post-burn.Data were analyzed according to the intention-to-treat?ITT?principle.A per-protocol?PP?analysis was also performed to further verify the effects of HVHF treatment.Between two groups,variables were examined by Mann-Whitney U test and chi-square test?or Fisher's exact test?,repeated measures data were analysed using a linear mixed-effects model.Results:1.Eighty-two patients were enrolled in this study.Five patients in each group abandoned therapy and were discharged from hospital during the study,one of whom was in the HVHF group and received therapy for only 1 day.2.The patients in the HVHF group had a significantly lower incidence of sepsis?26.8%vs.51.2%?and septic shock?14.6%vs.43.9%?,as well as a shorter duration of vasopressor treatment?1.0 d vs.4.0 d?,than those in the control group?P<0.05?.No significant difference was found in 28-,60-and 90-day mortality,duration of mechanical ventilation and ICU days?P>0.05?.However,in the subset of patients with burns more than 80%TBSA,the primary endpoints:incidence of sepsis?37.5%vs.71.4%?and 90-day mortality?29.4%vs.66.7%?,both showed significant decreases in the HVHF group compared with the control group?P<0.05?.The same benefits were present in the secondary endpoints:incidence of septic shock?18.6%vs.61.9%?and duration of vasopressor treatment?1.5 d vs.8.0 d??P<0.05?.No significant difference was found in 28-,60-day mortality,duration of mechanical ventilation and ICU days in both groups?P>0.05?.Additionally,similar results were comfirmed by the PP analysis.3.Over the 28-day observation period,compared with the control group,the data for PaO₂/FiO₂ were significantly higher in the HVHF group?P<0.001?.Compared between both groups at single observation time point,PaO₂/FiO₂ were significantly higher in HVHF group at day 7 post-burn?P=0.003?.The level of PCT in the HVHF group was significantly lower than that in the control group over time?P=0.005?,but no significant difference was found at single ovservation day?P>0.05?.No significant difference was found in the WBC and PLT counts or in the concentrations of K⁺,Na⁺,GLU,AST,ALT,TBIL,CRP,Cr,BUN and Lac?P>0.05?.4.The APACHE II score and SOFA score of the patients in the HVHF group showed a continuous decreasing trend and were significantly lower than those of the patients in the control group over time?P<0.05?.Compared with those of control group,the APACHE II score at day 21 post-burn,while SOFA score at days 14,21 post-burn in the HVHF group were significantly lower?P<0.05?.5.In the HVHF group,significant lower levels were found in plasma cytokines,including TNF-??IL-1??IL-6?IL-8,than those in the control group over time?P<0.05?.In addition,at different observation time points from day 3 to day 28 post-burn,each indicator was significant lower than those in the control group?P<0.05?.No significant difference was observed in IL-10 between both groups?P>0.05?.6.Compared with healthy adults,patients in both groups had HLA-DR expression on the CD14⁺monocytes that decreased to the lowest level at day 3 post-burn?P<0.001?.The HLA-DR expression on the CD14⁺monocytes were significantly higher than those in the control group over time?P<0.01?,and similar difference was found from day14 to day 28post-burn?P<0.05?.7.Compared with healthy adults,the proportion of CD4⁺CD25⁺Foxp3⁺Tregs increased to the highest level at day 3 post-burn?P<0.001?,and then gradually decreased from day 7 to day 28 post-burn in the two groups.Compared with the control group,the patients in the HVHF group had a significantly lower proportion over time?P<0.05?.And similar difference was found from day 7 to day 21 post-burn?P<0.05?.8.From day 1 after burn,the counts of CD3⁺,CD4⁺and CD8⁺T lymphocytes in both groups were significantly lower than those in healthy adults?P<0.05?.No difference was found between the two groups over time?P>0.05?.9.Transitory active bleeding of incisions was found in four patients in the HVHF group.No severe adverse events associated with HVHF occurredConclusion:Early application of HVHF benefits patients with severe burns,decreasing the incidence of sepsis,especially for those with a greater burn area??80%TBSA?,also decreasing mortality.This effect may be attributed to its early clearance of inflammatory mediators and the resulting recovery of the patient's immune status.