Severe systemic inflammatory response syndrome in patients following Total aortic arch replacement with deep hypothermic circulatory arrest

Postoperative systemic inflammatory response syndrome (SIRS), discussed in some specific cardiovascular interventions such as transcatheter or open aortic valve repair [1‐3], has received limited attention yet. Nevertheless, studies on the prevalence of inflammatory responses following open total aortic replacement (TAR) using 4-branch graft are lacking. Inflammation following TAR can be incurred by operative trauma, blood exposed to cardiopulmonary bypass (CPB), infection and hypothermia, although the combination of TAR and DHCA to treat aortic pathology with selective cerebral perfusion is technically preferable.

SIRS, a whole-body inflammation, has remained a primary clinical problem to be addressed despite significant improvement of strategies in diagnostics and therapy. As SIRS progresses, the incidence of morbidity, such as multi-organ failure and even mortality, will increase in cardiac [4, 5] and noncardiac settings [6, 7]. The inflammatory response has detrimental effects on cardiac function, and it arouses respiratory problems, hemostasis dysfunction, and kidney or liver injury. However, SIRS as a consequence of multiple coexisting factors has been controversial due to its high prevalence but low specificity for infection [8]. It is currently recognized that severe SIRS (sSIRS) is a more practical term for inflammation and has high accuracy to predict prognosis [2, 9].

We hypothesize that sSIRS following TAR with DHCA appears often because of the complex and risky surgical procedure and contact with CPB. This retrospective study carried out at our institute is intended to explore the incidence, independent predictors, and clinical outcomes of sSIRS in patients following TAR with DHCA.

This cohort study was approved by the Ethics Committees of Fuwai Hospital. Informed consent from the participants was waived for the retrospective nature. All details of design, conception and conduct are listed in the following parts.

To the best of our knowledge, this is the first study to investigate the prevalence of severe inflammation following TAR with DHCA. The incidence of sSIRS was 31.4% following TAR regardless of routine methylprednisolone prophylaxis, which obviously contributed to the postoperative development of major adverse events.

The inflammatory response after cardiac surgery has been widely recognized [4, 14, 15]; however, few studies have focused on its occurrence following repair of aortic pathology, especially its severity. SIRS, defined when the patient met two or more criteria, is seen in 96.2% of patients after cardiac surgery, without any discriminatory value for predicting clinical outcomes [6]. A previous study carried out among patients undergoing elective abdominal aneurysm repair demonstrated that SIRS development was as high as 89% [16]. Recently, Lindman and colleagues [2] introduced the application of severe SIRS, which developed in 11% of patients undergoing surgical aortic valve replacement but 6% of patients treated with transcatheter aortic valve replacement; sSIRS itself was also strongly associated with a greater risk of six-month mortality. It is the conception of severe SIRS rather than conventional SIRS criteria that is more appropriate to depict the relationship between the inflammatory response and its clinical outcomes.

The patients undergoing arch repair for aortic pathology had an average age of 40 yr at our institute, younger than those of other investigations, where patients aged 53.9 to 70.1 yr [17‐21]. The incidence of emergent status was as greater, at 55.8%, than in previous settings. At two institutes in Japan, the emergency rates were 26.1% [17] and 25.1% [18], respectively, according to recent publications in the field of TAR using a 4-branched graft. The definition of an emergent procedure at our institution was within 24 h prior to surgery, while the precise time was not given in those two single-center experiences.

In this study, we demonstrated the clear association of age with sSIRS development. Our logistic regression showed that advancing age was correlated with a lower risk of sSIRS in patients following TAR with DHCA. Elderly individuals presented delayed initiative and even poor maintenance with regard to the immune system after encountering inflammatory stressors [22]. It is a fact that age-related immunosenescence, consisting of dysregulation of immune cells (such as incompetency to generate pro-inflammatory cytokines and compromising capacity of phagocytizing) and reduced level of C-reactive protein upon interleukin-6 stimulation is a common scenario in elderly patients [23‐25]. This kind of nonintensive inflammation reaction uniquely linked to advancing age has strong evidence in clinical work. There was striking evidence that the risk of SIRS at any time within 24 h after cardiac surgery is uniquely attenuated in patients aged 72 yr or older [4]. It is hypothesized that the phenotypic and genomic variation and patients’ susceptibility had good perioperative predictability of the individual inclination to develop inflammatory syndromes. Systematic inflammatory responses were also not intensive and diminished in patients aged over 80 yr who had community-acquired pneumonia and reduced levels of C-reactive protein and cytokines after admission [26]. A precise scheme for anti-inflammation should be put into practice in our clinical settings, although the patients’ age varies greatly. The therapeutic approach, such as intraoperative dexamethasone, gave no benefit to patients aged over 80 yr undergoing cardiac repair [27].

This study showed that either dexmedetomidine or ulinastatin could diminish the likelihood of postoperative development of sSIRS. Dexmedetomidine, a highly selective α₂-adrenergic agonist and universal option for sedation, has been revealed to be effective in reducing cytokine release associated with the nuclear factor kappa B activation inhibition mechanism in cardiac surgery with CPB [28, 29]. However, whether dexmedetomidine is of prophylactic benefit in a population with sSIRS has been obscure, and more clinical trials are imperative in the future. Ulinastatin, extracted from humane urine, acts as a unique anti-inflammatory agent with a mechanism that includes the inhibition of neutrophil elastase and of various other proteases. Clinical trials have provided robust evidence that its administration in cardiac surgery with CPB could attenuate postoperative typical inflammatory biomarker release, such as interleukin, tumor necrosis factor-α, and other cytokines [30‐32]. Consequently, the organ-protective property of ulinastatin has been reported, primarily in correlation with attenuating acute kidney injury, pulmonary compromise and hemodynamic instability [30, 33].

Patients diagnosed with sSIRS were found to have a greater likelihood of suffering any adverse complications after the TAR procedure. In-hospital outcomes were not promising in the sSIRS cohort: they had extended duration of weaning from mechanical ventilation, as well as prolonged duration of ICU length of stay and postoperative hospital stay. In a population with transcatheter aortic valve implantation, sSIRS has also raised the risk of certain adverse events: mortality, stroke, infection, bleeding, myocardial infarction and acute kidney injury [3]. It is implied that sSIRS also has predictive ability for the length of stay after admission to the ICU [9].

Undergoing an emergent procedure could have enhanced the chance of experiencing major adverse events in patients following TAR in our investigation. One of the potential reasons would be that the population requiring emergency treatment was indeed in an exacerbated status prior to surgery and had greater risks to develop sequentially worse outcomes after the implementation of total arch repair. However, another possibility, which cannot be ruled out, is that preoperative temporary treatments for patients were insufficient within the limited duration under study, so that they did not reach an optimized status and then had a higher incidence of major adverse events after discharge from the operating room.

No further analysis of neurological defects following TAR, such as stroke or paraplegia until hospital discharge, was carried out in this cohort study owning to their lower incidence (2.1, 3.4%, respectively). Previous investigations provided robust evidence that stroke primarily occurred in patients with concomitant coronary artery bypass grafting, cerebrovascular defect history, or new-set atrial fibrillation [34, 35]. Surgical techniques, including hypothermic circulatory arrest times, selective antegrade cerebral temperature [36, 37], unilateral or bilateral cerebral perfusion [38] and treatment for distal aortic arch aneurysm [19], also significantly contribute to stroke development. There is a classic view in clinics that coronary artery disease is an alternative to atherosclerosis, feasibly extending to the bloodstream and maximizing the risk of thrombosis of the neurologic system. Paraplegia, a serious complication of spinal injury, can be primarily predicted by stented elephant trunk implantation. Extended stent graft implanted into the descending aorta could harm the intercostal arteries, and then collateral blood supplying to the spinal cord extremely deteriorates [20]. Therefore, cerebral spinal fluid drainage, and reduced hypothermic circulatory arrest to 25 °C, and stent-graft lengths less than 10 cm are practical techniques to prevent spinal cord injury [18, 20].

This study has several limitations. First, heterogeneity existed owning to its retrospective and single-centered nature. Second, the identification of SIRS and even its severity following TAR may not be accurate because it was only judged by patients’ vital signs instead of strong evidence from serial biomarkers measurements, including serum C-reactive protein and interleukins. The number of leukocytes and the ratio of lymphocytes/macrophages cannot be obtained routinely, major contributors to the imperfection of this work. Third, it was proposed that meeting three criteria of SIRS within 24 h after cardiac surgery or at least two criteria for 6 h would be more valid in predicting clinical outcomes [6]. However, the time for severe SIRS in our research was extended until 48 h postoperatively. The validity of sSIRS for organ dysfunction, ICU length of stay and hospital stay should be explored further. Forth, evidence of preoperative malperfusion cannot be obtained, which resulted in bias. Finally, all participants with aortic dissection undergoing repair had a history of acute status. Further investigations should be aimed at elucidating the relationship between sSIRS onset and acute, subacute or chronic dissection pathology.

sSIRS is as common as 31.4% in patients following total arch replacement with the DHCA technique. There was an inverse association between age over 60 yr and sSIRS onset. Higher baseline serum creatinine, concurrent coronary disease and prolonged CPB time aggressively contribute to a greater possibility of postoperative sSIRS, while the preferred administration of ulinastatin and dexmedetomidine can attenuate it. sSIRS has significant predictive value for postoperative major clinical adverse events, which can also be increased by severe hyperglycemia, concomitant kidney failure prior to repair, emergent procedure and extended duration of CPB.