Sepsis is an unsolved medical problem worldwide. Sepsis and septic shock occur in millions of people around the world each year, and one in four (and often more) of them die [
]. Sepsis is a leading cause of death among patients with severe burns, particularly when it is complicated by septic shock or multiple organ dysfunction syndrome (MODS). Once septic shock or MODS occurs, no specific and effective therapeutic measures are available, resulting in a very poor prognosis. Patients with severe burns often exhibit an intense stress response and produce large amounts of inflammatory mediators, which are prone to result in organ damage and immune dysfunction, increasing susceptibility to infections and even causing sepsis [
]. Theoretically, the early blockade or inhibition of excessive inflammatory reactions may improve a patient’s condition. However, because the cytokine network is unlikely to control the systemic inflammatory response by the simple blockade or elimination of some specific meditators, previous clinical studies on the antagonisation of some inflammatory mediators did not demonstrate an associated benefit to patients [
]. Therefore, effective therapeutic measures for sepsis remain lacking.
Blood purification can non-specifically eliminate inflammatory mediators in blood, controlling the levels of pro-inflammatory and anti-inflammatory mediators and regulating the host immune responses by means of filtration, adsorption and plasma exchange [
]. Therefore, blood purification has been applied as an organ support therapy for critically ill patients, including those with sepsis [
]. Currently, advances in blood purification render it a promising therapeutic measure for treating sepsis [
However, it remains controversial whether blood purification can improve the prognosis of patients with sepsis [
]. Our previous work has verified that continuous venovenous haemofiltration (CVVH) can improve organ function, maintain homeostasis and relieve inflammatory reactions in burn patients with sepsis but cannot improve their survival rate [
]. In clinical work, we also found 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. Microcirculatory disorders and organ functional failure in patients with septic shock, who often exhibit refractory shock, severe metabolic acidosis, hypoxemia and increased lactic acid, are difficult to reverse using blood purification. A recent multi-centre randomised controlled trial showed that HVHF was effective in reversing shock and improving organ function over a 2-week period in burn patients with septic shock and acute kidney injury (AKI), but that it was ineffective in decreasing cytokine levels and improving survival [
]. Possible reasons for this may be that the excessive inflammatory reactions that occur during sepsis or septic shock were far beyond the clearance capacity of current blood purification methods or that the patients had already experienced irreversible secondary organ injury and microcirculatory and mitochondrial dysfunction [
]. These blood purification interventions might be too late following the onset of sepsis or septic shock.
Therefore, patients may benefit from blood purification when applied at the early stage of burns rather than when MODS and sepsis occur. Theoretically, blood purification is effective during the early stage of severe burns owing to its ability to non-specifically remove a broad spectrum of inflammatory mediators, stress hormones, oxygen radicals, myoglobin, metabolites and toxins; to regulate water-electrolyte and acid-base equilibria; to clear excessive water in vivo (especially the clearance of third space liquid); and to relieve tissue oedema and improve the microcirculation in organs [
]. Studies have shown that in patients with burns with a total burn surface area (TBSA) > 40% complicated by AKI, the early application of CVVH can reduce mortality and improve the clinical symptoms of patients in cases that are complicated by shock and acute lung injury/acute respiratory distress syndrome, which may be associated with an early reduction of inflammatory mediators [
]. Therefore, we hypothesised that the early application of continuous blood purification to patients with severe burns might regulate immune function, reduce the incidence of sepsis and improve patient prognosis through the clearance of excessive inflammatory mediators.
High-volume haemofiltration (HVHF), which has evolved from renal replacement therapy (RRT), enhances the convection and adsorption on medium-molecular-weight solutes, and improves the clearance ability by increasing the input of the displacement liquid. Therefore, it is regarded as a common and effective blood purification technique for the treatment of inflammatory mediator-related diseases and may improve outcomes in systemic inflammatory response syndrome and sepsis [
]. In the present study, we explored the early application of HVHF therapy in patients with burns in a randomised prospective study, and observed the levels of several inflammatory cytokines in the blood circulation, immune phenotypes in peripheral blood immune cells, and the clinical outcomes.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [
]. Owing to excessive inflammation, early sepsis often results in a high level of inflammatory mediators in the blood, which can lead to organ injury and dysfunction [
]. In addition, the prolonged release of inflammatory mediators can cause immunocyte impairment and further immunosuppression [
], and it can even evolve into immune paralysis and increase the chance of secondary infection, ultimately causing death [
]. Therefore, early preventive measures to control excessive inflammatory mediators, alleviate inflammation and maintain immune homeostasis can reduce the incidence of sepsis and organ dysfunction, thus improving patient outcomes.
Extracorporeal blood purification can remove a broad spectrum of inflammatory mediators and bacterial toxins in a non-selective way through filtration and adsorption and has been proposed to improve the prognosis of patients with sepsis [
]. Several theories have been proposed to explain the potential benefits of blood purification in sepsis. First, the “peak concentration hypothesis” [
] suggests that blood purification therapy can lower the overall level of water-soluble mediators at the pro-inflammatory stage and, owing to the peak-shaving effects, can decrease the incidence of MOF syndrome and reduce mortality. Second, the “threshold immunomodulation hypothesis” [
] explains that some cytokines equilibrate between the blood and tissue compartments. Therefore, blood purification clears mediators in the blood directly, and the mediators in the interstitium and tissues will then be indirectly reduced owing to the concentration gradient. When a certain threshold value is reached, inflammatory cascade reactions are blocked and organ injuries are attenuated. Third, the “mediator delivery hypothesis” [
] proposes that HVHF can reinforce the lymphatic flow in mediator-rich tissues and displace inflammatory mediators to the blood compartment, from whence they are gradually removed. The fourth hypothesis considers the effect of regulating and maintaining immunological homeostasis [
]. A previous study demonstrated that HVHF reverses sepsis-related immunoparalysis in a porcine model of pancreatitis and increases the expression of major histocompatibility complex II and CD14 in monocytes, thereby alleviating oxidative stress and improving the phagocytic ability of polymorphonuclear leukocytes, even reducing bacterial translocation and endotoxaemia [
]. Ronco [
] also proposed that HVHF and coupled plasma filtration adsorption regulate the immunological functions of sepsis.
However, treating sepsis by blood purification remains controversial. Some studies have found that blood purification, including the use of polymyxin B haemoperfusion [
], cannot lower the level of blood inflammatory mediators and does not improve the survival rate of patients with sepsis [
]. The Surviving Sepsis Campaign guidelines panel has noted that there is inadequate research evidence in favour of or against the use of blood purification to treat patients with sepsis, and the clinical benefit of blood purification requires further clarification [
]. However, some beneficial effects have been found in patients with severe burns. Chung et al. revealed that HVHF reversed shock and improved organ function in burn patients with septic shock and AKI [
]. Early and aggressive CVVH decreased mortality in patients with burns and critically ill patients [
]. In addition, therapeutic plasma exchange may be effective as a salvage intervention for refractory burn shock [
]. These inconsistent results may be explained by the different pathophysiological features between patients with severe burns and general ICU patients. In general, the evidence suggests that blood purification is beneficial for patients with severe burns.
In this study, we observed that HVHF in the early stage of severe burn reduced the incidence of sepsis and septic shock in patients with burns ≥ 50% TBSA. Notably, it additionally improved the survival of patients with burns ≥ 80% TBSA. In our centre, we assess the severity of burns based largely on the burn depth, burn size and burn-related complications. Because it remains severely challenging to save patients with burns ≥ 80% TBSA, these burns are classified as extremely severe. No differences were found in the duration of mechanical ventilation and ICU days between the two groups. This may have occurred because more critically ill patients survived, prolonging the two variables in the HVHF group. For example, the two surviving patients with 95% TBSA (deep partial thickness burn 32% TBSA, full-thickness burn 65%TBSA) and 95%TBSA (all full-thickness burns) extended their ICU stays to 75 and 78 days, respectively. A PP analysis was performed and also showed that HVHF treatment was effective in reducing the incidence of sepsis and 90-day mortality of the patients with severe burns. No severe adverse events were observed during HVHF treatment. Early application of HVHF may be a key treatment technology for treating severe burns.
Patients with extensive burns presented manifestations of prolonged and intense inflammatory responses [
]. We found that some inflammatory cytokines in the blood increased immediately after the burns, and this may be related to early stress reactions. The highest levels of most inflammatory cytokines appeared from days 7 to 21 post-burn and may have been closely associated with the dissolving of eschar, wound infection or sepsis occurring in the patients. The early excessive inflammatory response is mainly caused by the burn wound and has the primary role in the initiation of organ injury. Thus, early blood purification treatment combined with effective wound management, including debridement to remove necrotic tissue, wound closure by skin grafting, and skin substitute covering, might stop the cascading inflammatory response, and this may be beneficial in improving patient prognosis. In the HVHF group, the lower levels of most inflammatory cytokines in the circulation contributed to alleviating the inflammatory reactions and may have subsequently improved PaO
and organ function (represented by SOFA score).
The decreases in inflammatory cytokine levels after HVHF found in this study may have occurred in two ways: The first is the direct effect of haemofiltration and adsorption, and the second is the massive removal of harmful substances, such as stress hormones, oxygen free radicals, inflammatory mediators and metabolites, which may indirectly reduce inflammatory cytokine production. In this study, the cytokine levels were not reduced in a small number of patients after HVHF treatment, possibly owing to the severe infection and immune response status of these patients, who exhibited uncontrolled cytokine production from blood infections or other infectious foci beyond the clearance capacity of haemofiltration.
In addition to early changes in inflammatory mediators, changes in immune status may also be closely related to sepsis. Many studies have shown that the immunosuppression of sepsis and severe trauma is associated with lymphocyte apoptosis or immune cell dysfunction [
]. Immune imbalance and a lack or delay of the anti-inflammatory response may be an important cause of burn sepsis [
]. In addition to clearing inflammatory mediators, blood purification plays a role in the regulation of immune status [
]. HLA-DR expression on CD14
monocytes reflects the antigen-presenting ability of monocytes and is considered a reliable marker for evaluating the immune function of critically ill patients [
]. Furthermore, the activation and expansion of CD4
T cells contributes to the development of immunosuppression and sepsis after severe burns [
]. In this study, we found that HVHF treatment promoted the recovery of HLA-DR expression on CD14
monocytes and the counts of CD3, CD4 and CD8 T lymphocytes in patients with burns. Moreover, early HVHF treatment inhibits the excessive increase of Tregs. These findings indicate that secondary immune deficiency occurs in patients with severe burns and that early HVHF treatment may facilitate the recovery of immune function owing to the clearance of cytokines, consequently reducing the incidence of sepsis and sepsis-related mortality. However, further studies are needed to confirm these results.
Our previous studies showed that the use of CVVH in treating burn sepsis did not improve patient survival [
]. Over the past 5 years, our ideas related to the application of blood purification have undergone some changes: (1) from CVVH with a standard renal dose of 35 ml/kg/h to HVHF at a dose of 65 ml/kg/h, (2) from renal replacement therapy or treating sepsis to the prevention of sepsis and organ dysfunction at an early stage after burns, (3) from the use of systemic heparin or LMWH anticoagulation treatments to regional citrate anticoagulation, and (4) from intermittent therapy to continuous treatment. In the present study, we observed that early continuous HVHF benefited patients with severe burns owing to early clearance of inflammatory mediators, recovery of immune status and protection of the internal environment and organ function.
However, this study had some limitations. Firstly, these preliminary findings are from our single burn centre. A multicentre study is needed to verify these results. Secondly, although all the enrolled patients received interventions within 3 days post-burn, some of the patients might have received different treatments before being admitted to our centre, which may have had some influence on the results. Thirdly, the definition of sepsis used in our study was based on the 2012 guidelines for the treatment of burn infection, which may have had some subtle differences from the criteria used in general ICU patents. In addition, in the present study, numerous aspects, including the optimal mode, dose, timing, duration and frequency of HVHF in the early stage after severe burn, remain to be studied.