The study is the first to focus on the protective effect of hemoperfusion therapy on ATAAD surgery with characteristics of severe inflammatory response and poor prognosis. Our results revealed that adding a HA-380 cartridge to conventional CPB circuit could not only reduce the high levels of IL-6 and CRP but also decrease the accidence of AKI and severe ARDS postoperatively. While the length of postoperative ICU stay was similar between the groups, patients in HP group seemed to require less treatment intensity. Adding hemoperfusion in CPB was well tolerated and safe, with no device related adverse events occurring.
ATAAD is a life-threatening medical emergency with high morbidity and mortality rates [22]. The most efficient way to save fatal consequences is emergent operation and most of the survival benefits come from advances in surgery recently [14]. Ascending and total arch replacement along with aortic-valve replacement or repair, combined with stent elephant trunk implantation into the true lumen of the distal aorta (Sun’s operation) is an accepted surgical management of ATAAD, and has resulted in a decrease of the in-hospital mortality to 4.7%[17, 22]. The study reported the surgical mortality was 3.31%. Both ATAAD itself and surgical procedure are non-infectious stimuli for systemic inflammation and that is characterized by elevated plasma concentrations of complement, secretion of pro-inflammatory cytokines and ultimately tissue and multisystem organ destruction [23, 24]. Characterized by prolonged CPB time, lower body temperature and larger amount of blood loss, an ATAAD surgery has more severe inflammatory response [25]. IL-6 exhibits expression in all major cell types which is an important member of the cytokine family, and regulates hematopoiesis, immune homeostasis, and various metabolic processes [26]. The level of IL-6 elevated on admission, increased several times postoperative immediately and decreased in the following days indicating that both dissection itself and surgery stimulates inflammatory responses and the latter being more serious in this study. The single peak of serum IL-6 indicated that cytokine adsorption could attenuate the inflammatory response during ATAAD surgery.
Extracorporeal cytokine adsorption, known as hemoadsorption, using materials with high adsorptive capacity applied to a number of disorders [1].The HA-380 cartridge is a novel hemoadsorption device that contains neutral macroporous beads, and is capable of removing 10 to 60 kDa molecules from blood including various cytokines [3]. IL-6 has been identified as a diagnostic tool, and frequently as a potential clinical target of hemoperfusion treatment [27]. Another inflammation biomarker CRP, an acute-phase protein regulated by pro-inflammatory cytokines, were higher in aortic dissection and independently associated with worse short-term mortality and poor prognosis[28, 29]. Although the clinical benefts was uncertain in sepsis, a Chinese study showed that applying hemoperfusion therapy during CPB had significantly lower levels of IL-6, IL-8, and IL-10 and improve recovery after cardiac surgery[5]. In this study, the lower IL-6 and CRP level postoperatively were found in HP group compared to conventional group. And so a benefits of relevant clinical outcomes as AKI and severe ARDS were found in HP group. But another study showed hemoperfusion was not associated with inflammatory cytokines decrease nor with outcome improvement [9]. Different from ATAAD surgery, the study populations had a shorter CPB time and no requirement of deep hypothermic circulatory arrest might be associated with low inflammatory response.
Applying hemoperfusion therapy can both clear inflammatory cytokines and benefit in kidney function in this study. The pathophysiology of cardiac surgery associated AKI is very complex, one is hemolysis from the prolonged duration of CPB[30–32].The incidence of AKI (40/115, 34.8%) was higher than selected cardiac surgery without aortic arch repair[25]. There was also no difference in branch vessel and renal artery involvement between 2 groups for renal artery dissection is an important risk factor for AKI. Obviously, HP group had a lower incidence of AKI. The HA-380 cartridge can partly adsorb myoglobin (18 kDa) and plasma-free hemoglobin (60 kDa)[3, 33, 34] just as lower myoglobin level in HP group. A greater increase of plasma-free hemoglobin during cardiac surgery was observed and associated with higher incidence of AKI, and the use of a CytoSorb hemoperfusion cartridge could significant reduce hemoglobin at the end of CPB [11, 35]. Thus, the renal protective effects of hemoperfusion include not only by inflammatory cytokines removal but also by free haemoglobin and myoglobin clearance[3].
A systemic inflammatory state induced by ATAAD and surgery is also associated with ARDS[36, 37]. The incidence of severe ARDS was 26.5% (31/117) in our study that the incidence was higher but the mortality was lower than previous report[36, 37]. HA-380 cartridge resulted in a lower incidence of ARDS and the lung-protective effect of hemoperfusion had been reported before[38]. There was no impact on ventilator support time, or the incidence of re-intubation, and also no difference in delirium, stroke, paraplegia, and other postoperative outcomes. The reason might be that ATAAD is a catastrophic condition and surgical repair is a complex operation. The postoperative support and overall outcomes are influenced by associated complications such as malperfusion syndrome, mesenteric ischemia, cerebral infarction, and low cardiac output syndrome [17] which cannot be rescued by hemoperfusion therapy.
An in vitro study of the biocompatibility and cytotoxicity of Jafron cartridge showed there was no increase of monocytes, necrosis, or apoptosis and cytotoxicities[3]. No extra anticoagulation required for heparinization during CPB period. Our results also showed no significant blood loss and more platelets transfusion in HP groups.
One strength of the study is that the first report to evaluate effective of hemoperfusion therapy during emergent surgery of an ATAAD. We strictly selected patients with symptom onset to operating room less than 72 hours and receiving total arch replacement based on the understanding that this emergency situation and arch operation had more severe inflammatory response and worse prognosis. Single peak inflammatory response of surgery and no extra anticoagulation requirement were the other consideration. This work indicates the potential for enhancing the hemoperfusion therapy in complex cardiac surgery.
The study is not without limitations, most of which is the retrospective study. Our study depended on clinical data with potential confounders for patients were not randomized and the interventions were compared to that of a historical cohort group. From September 2021 to February 2022, the second half of the study period, adding HA-380 cartridge in CPB was the unique variable of ATAAD management comparing to previous 6 months. All patients at the study period who did meet the eligibility criteria were totally enrolled in the analysis in order to avoid selection bias and provide comparable data. Another limitation is a single center study. Reported survival rates for ATAAD surgery vary widely among different centers[39]. Both high volume center, standardized protocol and experienced surgeons confirmed a net positive impact on ATAAD outcomes. The Xiamen Cardiovascular Hospital is the center of 4-hours life-saving circle and chest pain center of Southeast China, nearly 200 ATAAD patients per year were hospitalized. Although we have routine surgical produce and medical treatment with unified mode in our hospital with the surgery mortality less than 5%, it is obvious that multiple homogeneous centers must show superior performance than single center study. The third is that methylprednisolone was prophylactically administered to patients, and it can greatly decrease the level of the inflammatory response. There are still inconclusive in routine use of steroids in ATAAD operation although steroids might be harm in other CPB operation [40, 41]. Additionally, although the HP group had lower inflammatory mediators and better clinical outcomes, does not determine they have a causation relationship. Finally, cytokine levels and lab results such as plasma-free hemoglobin, IL-1, IL-10, TNF, and macrophage migration inhibitory factor did not measure. Nevertheless, adding hemoperfusion therapy in CPB circuit offers an easy and safe method to improve organ functions post ATAAD surgery.