Acute Lung Injury in aortic dissection : new insights in anesthetic management strategies

Several classification systems have been established for AAD. Among them, Stanford and DeBakey are the most used. Aortic dissection can be divided into Stanford type A, involving the ascending aorta, and Stanford type B, confined to the descending aorta. DeBakey type I is defined as the entire aorta affected; DeBakey type II confines the ascending segment; DeBakey type III confines the descending segment. Acute aortic dissection type A is a highly lethal acute aortic syndrome, with in-hospital mortality of 15–38% [6]. In most cases, AAD pathology starts with intimal injury, leading to false lumen formation. Then, an intimal-medial flap separates the false lumen from the true lumen [7, 8]. Blood malperfusion triggers the propagation of aortic dissection, resulting in the ischemia of involved organs. Meanwhile, an excessive inflammatory response occurs, contributing to the development of oxygen impairment [9]. In Chinese adults patients undergoing ATAAD surgery, 78.5% of them who developed postoperative hypoxemia had a preoperative oxygenation impairment, which might further aggravate the prognosis [10]. However, the pathogenesis of AAD combined with ALI remains largely unknown.

A recent study suggested that inflammation and coagulation are involved in AAD combined ALI [7, 10]. Endothelial and epithelial barriers are destroyed by increased alveolar-capillary barrier permeability, which is responsible for ALI [11]. Furthermore, inflammatory and oxidative stress-related cellular and metabolic regulatory mechanisms might participate in the AAD course worsened by ALI [12, 13]. Herein, we summarized significant mechanisms involved in the progression of AAD combined with ALI.

Nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-κB) can regulate the transcription of several encoding proinflammation cytokines genes and accelerates lung dysfunction [14]. NF-κB signal pathways play a crucial role in the inflammatory response. Angiotensin-II (Ang-II) can be used to establish an animal model of AAD-complicated ALI by stimulating human pulmonary microvascular endothelial cells (PMVEC) [15]. Moreover, Ang-II can participate in the early stages of AAD complex ALI by facilitating the release of matrix metalloproteinases via NF-κB pathway downregulation [15, 16]. Ang-II-induced macrophage infiltration is also closly related to ALI at the onset of AAD [16]. Another in vitro experiment also revealed that Bindarit (Bnd), an indazole derivative, could attenuate the incidence of AAD-complicated ALI by modulating the NF-κB pathway [17].

Interleukin-22 (IL-22) is a protective inflammation factor that plays a critical role in the pathogenesis of autoimmune diseases and anti-apoptosis. Moreover, IL-22 is a member of the IL-10 family, which has protective effects on animal models with ischemia-reperfusion injury in the lung [18]. The JAK/STAT signal pathway is involved in various biological processes [19]. IL-22 can inhibit the apoptosis of PMVECs induced by Ang-II by activating the JAK2/STAT3 pathway [20]. It also has been reported that microRNA-101 can inhibit the proliferation of PMVECs by targeting the JAK2/STAT3 pathway [21].

High-mobility group box 1 (HMGB1) is a nuclear nonhistone protein crucial in initiating and maintaining inflammation [22]. The receptor for advanced glycation end products (RAGE) binds with HMGB1 and activates inflammatory factors such as NF-κB and IL-6 [23]. In AAD complicated ALI, the excessive inflammatory cascade plays a critical role, leading to damaged PMVECs and increased microvascular permeability [24]. HMGB1/RAGE signal pathway exists in various respiratory system diseases, and it might participate in the pathogenesis of AAD-complicated ALI, providing a potential therapeutic target [9].

Among AAD patients, the most dangerous risk is hypertension. Almost 75% of patients have a history of hypertension, especially poorly controlled. Other risk factors include trauma, drugs, smoking history, and genetic disorders (e.g., Marfan, Loeys-Dietz and Ehlers-Danlos syndromes) [25]. According to a study from the Berlin-Brandenburg region, hypertension, preexisting aortic dilatation, and hereditary connective tissue disease accounted for 62.7, 10 and 1.8%, respectively [3]. A multi-center case-crosser study showed that daily mean temperature lower than 24 °C and temperature drops between neighboring days are associated with increased AAD risk [26].

Obese patients are more predisposed to develop ATAAD complicated ALI [27]. Obesity can trigger chronic inflammation by activating inflammasomes in adipose tissues, promoting the production of cytokines IL-1β and IL- 18 [28]. Obese people are also predisposed to oxygen deficits, resulting in persistent hypoxia in adipose tissue [29]. Moreover, obesity is linked to lung damage due to poor lung compliance and irregular ventilation perfusion. Obesity is also one of the most significant risk factors for developing ALI[27, 29].

Furthermore, the interaction between genetics and the nongenetic-environment is involved in the progression of ALI [30]. Recently, the prevalence of coronavirus disease 19 (COVID-19) has challenged the healthcare system. COVID-19 can bind to the lung pneumocyte type II cells, triggering hyper-inflammation and oxidative stress, subsequently inducing ALI development of [31]. Moreover, a detailed analysis showed that metabolic disturbances caused by type II diabetes mellitus (T2DM) might accelerate ALI incidence through platelet activation, coagulation disorders, endothelial dysfunction, and insulin resistance [31, 32]. Recently, a retrospective study suggested that CPB duration ≥ 257.5 min, left atrium diameter ≥ 35.5 mm, hemoglobin ≤ 139.5 g/l, LVPWT (left ventricular posterior wall thickness) ≥ 10.5 mm, NEUT (neutrophilic granulocyte percentage) ≥ 0.824 might also increase the risk of ALI after ATAAD surgery [33].

It is crucial for AAD patients to quickly confirm the diagnosis, clarify the classification, and locate the intimal injury site. ATAAD can be misdiagnosed as myocardial infarction, acute coronary syndrome, or cardiac arrest of unknown reasons in emergency department [3]. It is essential to separate the diagnosis of acute aortic dissection from other diseases since treatment differences might lead to disastrous consequences [11]. Among misdiagnosed patients, 81% were determined to have type A aortic dissection [34]. Those walking into the hospital or providing an obscure history might meet increased risks of misdiagnosis[35]. Up to 80% of patients who diagnosed with AAD had received an emergency diagnosis previously [36]. According to a retrospective study, the initial misdiagnosis of AAD was 31% in emergency department [36]. The primary diagnostic imaging method currently used is contrast-enhanced CT angiography. Magnetic resonance imaging (MRI) is well-suited for diagnosing aortic diseases [11]. However, it is limited due to longer acquisition times than CT and the difficulty in long-term monitoring for patients with unstable circulation [37]. In patients with ATAAD complicated ALI, comprehensive evaluation and early diagnosis of ALI have predictive value. According to Berlin’s gold standard definition, the clinical definition of acute respiratory distress syndrome (ARDS) mainly relies on the acute onset, chest imaging of bilateral opacities, and PaO₂/FiO₂ ≤ 200 mmHg with positive end-expiratory pressure or continuous positive airway pressure ≥ 5 cmH₂O; ALI was introduced using the same criteria but with less-severe hypoxemia (i.e., PaO₂/FiO₂ ≤ 300 mmHg) [38]. Additionally, to diagnose AAD complicated with ALI, we should exclude pulmonary edema caused by cardiac failure, fluid overload, or other extrapulmonary factors. The degree of bilateral lung opacities is used in the radiographic assessment of lung edema (RALE) score [39]. The score is obtained by summing the chest X-ray analysis score according to density and consolidation. When the RALE score is ≥ 16, 36.3% of patients develop dyspnea and hypoxemia, defined as ALI [40]. In recent years, lung ultrasound has gained popularity for its portability and real-time and noninvasive characteristics. A lung ultrasound score (LUS) has been gradually applied in predicting the severity and prognosis of AAD-complicated ALI. Lung ultrasound is used to evaluate the lung areas, including bilateral, lateral, upper, and lower posterior chest walls, to provide a point score based on the severity of lung tissues: lung consolidation = 3 points, severely reduced lung ventilation area = 2 points; moderately reduced lung ventilation area = 1 point; normal ventilation area = 0 points. The cutoff values for the LUS score in ALI patients are 18.6 points [41, 42]. As PaO2/FiO2 changes occur after the lung ventilation area change, the LUS can well reflect lung changes and evaluate ALI severity.

Considering the high mortality rate, a study suggested that the time from symptom onset to surgery in patients with ATAAD should not exceed 10 h [6]. When combined with ALI, preoperative oxygen impairment might occur, increasing the incidence of postoperative acute respiratory distress syndrome [17]. Therefore, surgeons and anesthesiologists must schedule a detailed preoperative evaluation. Considering postoperative pulmonary complications, there is still a debate on surgery time. In our center, we choose early operation because AAD can aggravate the inflammatory cascade.

For patients with ATAAD, initial management aims to control blood pressure and pain, which can limit the false lumen propagation [47]. Blood pressure control can lower shear strain on the arterial wall and increase organ tissue perfusion. The recommended systolic blood pressure is 100–120 or 70–90 mmHg for typical arterial blood pressure, with a heart rate of 60–80 beats per minute [25]. Beta-blocker is recommended as the first-line drug that can simultaneously reduce blood pressure and heart rate to minimize aortic shear stress [6, 48]. Among them, propranolol, metoprolol, labetolol, and esmolol are generally preferred to control initial blood pressure, and calcium channel blockers such as verapamil or diltiazem, are more suitable for asthma or bradycardia patients [49]. Additionally, recent reports have shown that Beta-blocker has an anti-inflammatory effect, which can alleviate lung oxygen impairment in ATAAD-complicated ALI [48]. Other studies have shown that beta-agonist can accelerate the resolution of pulmonary edema by regulating type I and type II cells but increase the mortality rate [38]. Opiate is currently underway for pain management in AAD in clinical practice to reduce the sympathetic release of catecholamines [50].

Both inflammation and coagulation are involved in ATAAD-complicated ALI. Coagulation disorder is usually associated with low coagulation factors and high D-Dimer in ATAAD patients. Moreover, secondary fibrinolysis caused by ATAAD can worsen ALI [10]. Therefore, better control of abnormal coagulation is essential. Preoperative hypoxemia might occur in most ATAAD-complicated ALI patients. The optimal oxygenation target in patients with ALI patients is unclear. However, oxygen toxicity has attracted increasing attention. A randomized clinical trial has suggested that conservative oxygen therapy, maintaining PaO2 between 70 and 100 mmhg or arterial oxyhemoglobin saturation between 94% and 98%, can improve the prognosis [51]. For patients with PaO₂/FiO₂ < 200 mmhg, keeping PaO₂ 55–80 mmHg or SpO₂ 88-95% and pH ≥ 7.25 might lead to improved outcomes [38].

Assessment of pulmonary risk is essential for AAD-complicated ALI patients. A series of predicting risk indexes for evaluating postoperative respiratory failure have been made based on emergency surgery, a history of smoking, and chronic obstructive pulmonary disease [52]. Arterial blood analysis can predict pre-anesthesia hypoxemia and provide timely treatment. Point of Care Ultrasound (POCUS) of the lung is also indicated to evaluate preoperative pulmonary disease, which can be used as clinical treatment. Pulmonary ultrasound can be implemented bedside, real-time, presenting substantial advantages in diagnosing ALI and providing references for clinicians to make decisions [42].

ALI management remains conservative and lacks established target therapies. Currently, treatments for improving the pathophysiology of ALI have attracted significant attention. Herein, we discuss drug and non-drug therapies.

Since inflammation plays an important role in AAD-complicated ALI, we first discuss anti-inflammatory treatment. Nitric oxide (NO) is a vasodilator, especially for pulmonary hypertension patients. It can enhance arterial oxygen, regulate inflammatory-induced microvascular injury in the lung, and decrease the need for ventilation. A recent study showed that NO could reduce pulmonary and systemic neutrophils and pre-inflammatory factors in lung injury in a rodent ARDS model [87]. Dexmedetomidine (DEX) is a selective α2-adrenergic receptor agonist clinically used for sedation and analgesia. DEX has antioxidant, anti-apoptosis, and anti-inflammatory properties [88]. Studies have shown that DEX can activate the protein kinase C/heme oxygenase-1 pathway and decrease LPS-induced ALI [89]. In a prospective clinical trial, Xenon, an ideal anesthetic with hemodynamic stability and anti-inflammatory effects, eased lung injury in cardiac surgery [90]. In their study, pulmonary static inflation with 50% Xenon during CPB can triggered anti-inflammatory responses and suppressed pro-inflammatory and oxidative effects. In another sepsis-induced ALI model, the antioxidant idebenone (IDE) alleviated inflammatory response by reducing free radicals and lipid peroxidation [91]. Escitalopram is clinically used as an antidepressant drug and can inhibit lung inflammation through the SIK2/HDAC4/NF-kB pathway [92]. Molecular hydrogen is the lightest chemical element. Its application for ALI is mainly based on anti-inflammatory, antioxidative, autophagy, and cell death effects [93]. Pterostilbene (PTE) is a polyphenol. Pretreatment with PTE can reduce the inflammatory response in an LPS-induced ALI rat model by activating nuclear receptor subfamily 4 group A member (NR4A1) [94]. However, more prospective studies are encouraged to prove their effectiveness in clinical practice.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is another essential tool to treat ALI. VV-ECMO has been increasingly used in ALI patients, especially for those whose conventional ventilation management fails to supply adequate oxygen exchange [97]. Additionally, postoperative ventilation might lead to secondary lung injury. For AAD-complicated ALI, alveolar overdistension and high transpulmonary pressure can result in trauma, which might also aggravate lung injury. VV-ECMO can mitigate lung injury caused by ventilation, even lung-protection ventilation [98]. Optimized ventilation for patients with ECMO remains controversial. For example, an acute respiratory distress syndrome (ARDS) model requiring ECMO was established to investigate a moderate PEEP to reduce lung injury. They suggested that a 10 cmH₂O PEEP can minimize lung injury, improve gas exchange, and not affect hemodynamic stability [99]. However, it needs more clinical studies to certify its benefits.

Extracorporeal carbon dioxide removal (ECCO₂R) can improve acidosis via CO2 clearing. ECCO₂R combined with ultra-lung protective ventilation, driving pressure, titrating PEEP, or optimizing mechanical power might have more lung protective effects. A prospective study found that using ECCO₂R and ultra-protective ventilation could mitigate respiratory acidosis in moderate ARDS patients [100]. However, contraindications for systemic anticoagulation and bleeding disorders are crucial in cardiac surgery patients. Hence, the overall benefits and harms should be addressed in the future.