| Objective: Severe Sepsis is one of the main causes of death in critically ill patients. Although the prevailing theories of sepsis are uncontrolled systemic inflammatory response, the anti-inflammatory therapies were disappointed. Thus there may be other downstream cytokines or effects participating in the pathophysiology of severe sepsis. Recently, HMGB1 was discovered to be a new late-acting mediator of severe sepsis, targeting treatment towards HMGB1 offers a wider therapeutic window. As our understanding of the pathophysiology of sepsis continues to evolve, we have gained a greater appreciation for the profound effects that severe sepsis and similar states of overwhelming stress have on host innate and adaptive immunity. Impaired leukocyte function in sepsis has important clinical consequences, as high mortality rates have been observed in patients who display evidence of sepsis-induced immune dysregulation. Continuous blood purification (CBP) is one of the possible interventions in severe septic patients, especially the high volume hemofiltration (HVHF). But the mechanisms need to be further studied. In this study we observed the changes of oxygenation, circulation, metabolism, plasma levels of HMGB1 and IL-6, peripheral blood PMN apoptosis and subgroups of T cells during HVHF. The purpose of this study was to explore the role of HMGB1 in the pathophysiology of sepsis, the immune state of severe septic patients and the effects of HVHF.Methods:Fifteen severe septic patients receiving HVHF entered this study. Changes of temperature (T), heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), C-reactive protein (CRP), alveolo-arterial oxygen partial pressure difference [(A-a)DO2], blood urea nitrogen (BUN), serum creatinine (SCr), buffuer excess (BE), PaO2, FiO2, blood routine, and electrolyte analysis were recorded at the following time points: pre-HVHF(T0), 24 (T1), 48 (T2) and 72h (T3) of HVHF in order to calculate Oxygenation Index (OI = PaO2/FiO2), acute physiology and chronic health evaluation (APACHEâ…¡) and sepsis-related organ failure assessment (SOFA). Simutaneously, peripheral venous blood and ultrafiltrate (UF) sample were collected. HMGB1, IL-6 levels in plasma and ultrafiltrate were measured by enzyme linked immunosorbent assay (ELISA). Neutrophils were isolated and apoptosis was detected by flowcytometry (FCM). Subgroups of T cells (the expression of CD4+ T cells, CD8+ T cells and CD4+/CD8+) were also detected by FCM. Ten healthy volunteers were selected as basic control.Results: 1 Comparisons between severe septic patients and healthy volunteers:Compared with healthy volunteers, the plasma HMGB1, IL-6 levels were significantly higher in severe septic patients before HVHF (P<0.01); neutrophil apoptosis, the expression of CD4+ T cells and CD8+ T cells were significantly decresed (P<0.05 or P<0.01); No significant difference was found in CD4+/CD8+ between healthy volunteers and severe septic patients (P>0.05).2 Changes of HMGB1, IL-6 levels in severe septic patients pre- and post-HVHFAll patients showed a significant decline in plasma IL-6 level during HVHF. There were significant differences between T0 and other three time points (P<0.05).Plasma HMGB1 level went to peak at T1 time point, which was later than that of IL-6. It decreased slowly after T2 time point. There were no significant differences between T0 and other three time points (P>0.05).Compared with T0, plasma HMGB1 level was significantly decreased at T3 time point in survival patients (P<0.05). There were no significant differences between T0 and other three time points in dead patients (P>0.05). HMGB1 and IL-6 could be detected in the ultrafiltrate.3 Changes of subgroup of peripheral blood Tcells and neutrophil apoptosis during HVHFCompared with T0, neutrophil apoptosis and the expressions of CD4+ T cells were significantly increased at T3 time point (p<0.05). There were no significant differences of CD8+ T cells and CD4+/CD8+ between between T0 and other three time points (P>0.05).4 Changes of haemodynamics, temperature and oxygenation of severe septic patients during HVHFThe haemodynamics of all patients were stable, and the doses of dopamine and norepinephrine which were used in 11 of 15 patients were reduced gradually. There was a progressively decrease in T, HR and P (A-a) O2 (P<0.05 or P<0.01). There was a significant increase in OI during HVHF (P<0.05).5 Changes of metabolism of severe septic patients pre- and post-HVHFBUN and SCr levels of patients with severe septic patients were significantly decreased (P <0.05), while the values of pH and BE were gradually increased (P <0.05).6 Changes of CRP of severe septic patients during HVHFCRP level was decreased significantly after HVHF (P<0.05).7 Changes of APACHE II and SOFA score during HVHFAPACHE II score was decreased with significant difference during HVHF (P<0.05). Similarly, SOFA score was decreased, however, no statistical difference was observed between T0 and other three time points (P>0.05).8 Clinical outcomesFive patients died and ten patients were survived in ICU. The actual mortality was 33.33%, while the predicted mortality according to APACHE II score was 51.88 %.Conclusions1 We found immunosuppression and delayed neutrophil apoptosis in severe sepsic patients. The level of HMGB1 was higher in severe sepsic patients. Persistently high HMGB1 level contributed to poor prognosis.2 HVHF could effectively remove HMGB1 through convection transport, thus weaken the peak concentration of HMGB1 and accelerate neutrophil apoptosis.3 HVHF might improve T lymphocyte function, adjust immune state and promote the re-establishment of immune system homeostasis.4 HVHF could stabilize haemodynamics, improve renal function and oxygenation, correct metabolic acidosis and retain homeostasis of severe septic patients.5 HVHF could reduce mortality and improve prognosis of severe septic patients. |
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