In our study, OI occurred in 67 patients (32.2%) on hospital day 2.4 ± 1.5 on average, and 22 patients (32.8%) in OI group necessitated mechanical ventilation. The high incidence of OI development in AAD patients and risks of use of mechanical ventilation highlight the importance to predict this severe respiratory complication. However, limited is known about the pathogenesis, prevention and management. This study indicated that the occurrence of OI can be predictable in the patients with AAD. Elevated serum CRP levels and peak body temperature, and decreased albumin levels were independent predictor of OI development.
Inflammatory cells and cytokines have been found in participating in the pathogenesis of aortic dissection [11, 12]. The first stage of inflammatory reactions is the long-term chronic inflammation in the aorta in the patients with hypertension. Inflammation, oxidative stress and genetic predisposition play great roles in the pathogenesis of hypertension [13]. Chronic low-grade inflammation exists in the course of hypertension, triggers the progress of hypertension and contributes to vascular remodeling [9, 14, 15]. Angiotensin Ⅱ also serves an important inflammatory roles in hypertension; it can induce macrophages to differentiate into the M-1 type, secrete proinflammatory cytokines, and stimulate the attachment and migration of leukocytes [15, 16]. The second stage of inflammatory reactions is the rapid development to acute inflammation after aortic injuries [5, 6]. And it can subsequently develop to systemic inflammatory reactions syndrome (SIRS) due to uncontrolled inflammatory cascade [17]. Aortic samples from the patients with aortic dissection revealed a large amount of macrophages infiltration [18]. A large number of cytokines have also been found infiltrating the aortic wall of patients with aortic dissection, such as IL-6 and IL-17 [12]. It was reported that levels of IL-11 and interferon γ were increased in blood samples in acute thoracic aortic dissection [19]. In this present study, there was no correlation between the development of OI and hypertension grade, hypertension course, previous blood control, and antihypertensive strategy, suggesting that the impact of chronic inflammation in hypertension is limited in the development of OI. It was majorly due to the second stage of inflammatory reactions and the severity of SIRS.
Systemic inflammatory reactions play key roles in the pathogenesis of acute lung injuries and the development of OI. Recent studies found that AAD complicated with acute lung injury was highly associated with the macrophages infiltrating the pulmonary interstitial tissue and released matrix metalloproteinases 9 in response to angiotensin Ⅱ [20, 21]. Inflammatory reactions can cause fluid to leak across alveolar-capillary barrier because of increased permeability and produce enough alveolar edema to cause the clinical characteristics of refractory hypoxemia [22]. In mice model, IL-22 could significantly attenuate the incidence and severity of angiotensin Ⅱ induced acute lung injury [23]. Hence, concerns on anti-inflammatory agents and some protective cytokines will help find insights on the therapeutic strategy for acute lung injury and OI development in AAD. Very limited has been known about the pathogenesis of acute lung injury and OI development in the patients with AAD, so further studies need to be conducted.
Given the great roles of inflammatory reactions in the development of OI, inflammatory markers should be especially investigated in predicting OI development in the patients with AAD. Inflammatory markers can reflect the severity of SIRS, and in turn it may be predictors of OI development. CRP, a highly sensitive marker of systemic inflammation, is an acute-phase protein induced by pro-inflammatory cytokines, particularly IL-6 [24]. Elevated CRP was indicated in the patients with AAD [25], and it can be a prognostic factor to be independently associated with inhospital death [24, 26]. Procalcitonin has also been advocated as a diagnostic parameter in systemic inflammation and infectious diseases [27]. Recent studied showed that postoperative levels of procalcitonin could be used to predict adverse outcome in acute type-A aortic dissection [28, 29]. We first described the characteristics of procalcitonin in the patients with OI in AAD. Our study showed the negative correlation between the 2 inflammatory markers, CRP and procalcitonin, and the development of OI. The peak body temperature was significantly elevated in the patients with OI and negatively correlated with the occurrence of OI, further increasing the evidence that systemic inflammatory reactions contribute to the development of OI in the patients with AAD. Upon an inflammatory challenge, hepatic and pulmonary macrophages (and later brain endothelial cells) start to release lipid mediators, including prostaglandin E2 and cytokines [30]. Blood prostaglandin E2 enters the brain and triggers fever, and at later stages of fever, prostaglandin E2 synthesized within the blood-brain barrier maintains fever [30].
Albumin is both an important nutritional indicator and an acute-phase protein involved in inflammatory response [31]. Lower serum albumin levels were indicated in SIRS [32]. Decreased albumin levels have also been found in some cardiovascular diseases, of which inflammatory reaction participates in the pathogenesis, including heart failure and coronary heart disease [33, 34]. Its synthesis is stimulated by hormones and can be inhibited by pro-inflammatory substances, including IL-6 [35]. In inflammatory states, albumin distribution alters from intravascular to extravascular compartments due to increased microvascular permeability [36, 37]. And increased depletion of albumin further leads to the negative albumin balance [37]. We firstly introduce the value of albumin in predicting OI in the patients with AAD. We guess that decreased levels of albumin in the patients with OI are perhaps due to more severe inflammatory reactions.
Stepwise multiple linear regression analysis showed that elevated serum CRP levels, higher peak body temperature and decreased albumin levels were independent predictors of the occurrence of OI. However, the average timing of peak body temperature was later than that of the occurrence of OI, and only CRP had a good sensitivity and specificity indicated by ROC curves. Hence, the predicting value of the peak body temperature and albumin was actually limited. Our study showed that the serum CRP ≥ 9.20 mg/L might be a valuable predictor of OI development in AAD patients. CRP is a simple, widely available, and in-expensive test. So it can be widely used as a biomarker in predicting OI in the patients with AAD.
This study also found that most of AAD patients had poor blood pressure control at home. Most of them were grade 3 hypertension and nearly a half had hypertensive cardiopathy. Patients had poor awareness of blood pressure monitoring and regular antihypertensive therapy. Therefore, it highlights the importance of the education of hypertension in public, especially blood pressure monitoring and regular antihypertensive therapy in patients with hypertension.
This study has some limitations. Our study is a single-center retrospective study, and the sample size is still not large enough. We will further investigate the expression differences of some cytokines including IL-6 in future. We hope to establish a multicenter, large-sample prospective cohort study focusing on the prevention and management of OI in AAD patients.