Research Progress of Neonatal Acute Respiratory Distress Syndrome

for ARDS in Berlin, Germany. The Berlin definition addresses many of the limitations of the definition of AECC and believes that ARDS is a unique pathophysiological process. It can be described by time, imaging changes and severity, and ARDS can be divided into mild, moderate and severe according to 2 2 / Pao Fio ratio [5]. This was followed by a multicenter clinical study conducted by the European Society of Pedatric and Neonatal Intensive Care (ESPNIC) to verify the effectiveness of the Berlin standard in children aged 1 to 18 months [6]. According to the AECC and the Berlin definition, Barreira et al. [7] conducted a multicenter study of children aged from 1 month to 15 years in PICU. The results showed that the mortality rate and ventilator use days of children with severe ARDS were significantly higher than those with mild to moderate ARDS. It is considered that compared with the definition of AECC, the Berlin definition is more effective in predicting mortality and leaving ventilator and can better distinguish the severity of ARDS in children. Abstract Neonatal Acute Respiratory Distress Syndrome (ARDS) is one of the most common critical diseases in neonatal period. In recent years, with the rapid development of perinatal medicine, the survival rate of children with ARDS has increased significantly, but the mortality rate is still high. At present, there is no specific treatment for the disease, mainly according to its pathophysiological changes to take comprehensive symptomatic treatment measures, including respiratory support, extracorporeal membrane oxygenation therapy, PS replacement, nutritional support and liquid management. In this paper, the diagnostic criteria, pathogenesis and treatment strategies of neonatal ARDS were reviewed in order to provide some theoretical basis for the diagnosis and treatment of neonatal ARDS in the future.


Introduction
Acute respiratory distress syndrome (ARDS) is one of the most common respiratory acute and critical diseases in newborns. It refers to the acute inflammatory reaction of the lung caused by various pathogenic factors inside and outside the lung. It is characterized by progressive dyspnea, intractable hypoxia and decreased lung compliance [1]. With the vigorous development of neonatal intensive care unit, the survival rate of newborns, especially premature infants, has increased year by year, and the incidence of ARDS has also increased significantly, but the mortality rate is still high [2]. In view of the fact that the treatment of neonatal ARDS is only limited to the comprehensive treatment based on the corresponding respiratory support therapy, it is the focus of every neonatal pediatrician to understand the pathogenesis and diagnostic criteria of ARDS and actively take reasonable treatment measures.

Evolution of Ards Definition
Since Ashbaugh et al [3] first put forward the concept of ARDS in the 1960s, pediatricians have realized that children's ARDS is different from adult ARDS. The 1994 American-European Consensus Conference(AECC) defined Acute Lung Injury (ALI) as 2 2 / 300 Pao Fio mmHg ≤ , ARDS as 2 2 / 200 Pao Fio mmHg ≤ , and later referred to "Acute" as the double meaning of "acute" rather than "adult or acute", in order to accurately reflect the fact that this syndrome can occur in both adults and children, the diagnostic criteria of ARDS have been widely used in adults and children [4]. In 2012, the European Critical Care Association presided over the revision of the new diagnostic criteria for ARDS in Berlin, Germany. The Berlin definition addresses many of the limitations of the definition of AECC and believes that ARDS is a unique pathophysiological process. It can be described by time, imaging changes and severity, and ARDS can be divided into mild, moderate and severe according to 2 2 / Pao Fio ratio [5]. This was followed by a multicenter clinical study conducted by the European Society of Pedatric and Neonatal Intensive Care (ESPNIC) to verify the effectiveness of the Berlin standard in children aged 1 to 18 months [6]. According to the AECC and the Berlin definition, Barreira et al. [7] conducted a multicenter study of children aged from 1 month to 15 years in PICU. The results showed that the mortality rate and ventilator use days of children with severe ARDS were significantly higher than those with mild to moderate ARDS. It is considered that compared with the definition of AECC, the Berlin definition is more effective in predicting mortality and leaving ventilator and can better distinguish the severity of ARDS in children. To clarify the pathogenic factors, etiology and pathophysiology, put forward suggestions for treatment, and determine the focus of research. The PALICC standard states that pARDS includes children of all ages from newborn to adolescence and is unique in pathophysiology, etiology and high-risk factors [9]. PALICC standard not only reduces the mortality of ARDS in children and adults, but also provides a strong guarantee for improving the quality of life of patients [10]. Although the PALICC standard has achieved a major breakthrough in the age of the ARDS standard, it specifically excludes Perinatal specific diseases such as acute hypoxia in newborns and secondary severe lung injuries such as meconium aspiration syndrome and congenital disseminated pneumonia. The clinical characteristics of neonatal ARDS have not been pointed out [11]. On the basis of the existing research on ARDS, the international multi-center and multi-disciplinary assistance group established the diagnostic criteria of neonatal ARDS for the first time in 2017, that is, the Montreux criteria [12]. At present, the Montreux criteria is the first ARDS diagnostic standard for newborns in the world. It  Table 1).

Pathogensis of Ards
Although the pathogenesis of ARDS has not been fully understood, current studies have shown that systemic inflammation is a key link in the occurrence and development of ARDS, severe inflammation leads to changes in vascular permeability, resulting in acute pulmonary edema [13][14][15]. After primary injuries such as infection, trauma and chemical factors affect alveolar epithelial cells and vascular endothelial cells, the boundary between alveolar epithelial cells and vascular endothelial cells is destroyed, and pulmonary capillary barrier dysfunction leads to increased permeability. Promote inflammatory cells to enter the alveolar cavity and pulmonary capillaries, protein-rich liquid quickly enter the lung tissue to cause acute pulmonary edema [16][17]. The results showed that the activity of type Ⅱ secretory phospholipase A2 (sPLA2) was increased in both adults and children with ARDS. SPLA2 could promote inflammation and decompose surfactant phospholipids directly by hydrolyzing Dipalm Oil-Phosphate Diol-Cholinesterase (DDPC). At the same time, oxidative hydrolysis activated by inflammatory reaction can increase the degradation of PS, both of which can cause secondary deficiency of PS, resulting in hyaline membrane formation and alveolar collapse [18]. Therefore, pulmonary inflammation caused by inflammatory diseases, which leads to abnormal PS, is an important reason for the occurrence of ARDS.
Neonatal period is a unique stage which is different from adults and children. It not only has high mortality, but also has particularity in the inducement and pathological characteristics of ARDS. Neonatal ARDS can be triggered by direct injury of the lung parenchyma (that is, direct or primary ARDS), such as Meconium Aspiration Syndrome (MAS), pneumonia, or extrapulmonary processes (that is, indirect or secondary ARDS), such as septicemia, necrotizing enterocolitis, Perinatal asphyxia and so on. In addition, some studies have found that the incidence of neonatal ARDS is also related to preterm delivery, caesarean section, diabetic mother, placenta previa and acidosis. It can be seen that the pathogenesis of neonatal ARDS is complex. How to treat ARDS from the aspect of pathophysiology is worthy of more in-depth study ( Figure 1). Crs=respiratory system compliance. Rrs=respiratory system resistance.

Treatment of Primary Diseases
A variety of internal and external factors such as meconium aspiration syndrome, pneumonia, perinatal asphyxia, septicemia, neonatal necrotizing enterocolitis and so on can cause neonatal ARDS. Therefore, it is the primary task of prevention and treatment of ARDS to take corresponding treatment measures for the primary disease in the early stage and curb the systemic uncontrolled inflammatory reaction induced by it.

Respiratory Support
Mechanical Ventilation (MV) is an important treatment for ARDS, but inappropriate mechanical ventilation can cause lung injury in children [19][20].

In Vitro Life Support Technology
In recent years, with the gradual increase in the incidence of refractory ARDS, the application of Extracorporeal Membrane Oxygenation (ECMO) in ARDS has gradually increased. At present, about 3000 children worldwide receive ECMO treatment each year [48][49]. ECMO mainly improves oxygenation and carbon dioxide removal through cardiopulmonary bypass, thus partially or completely replacing cardiopulmonary function to maintain blood supply and oxygen supply to major organs, which can not only buy time for pulmonary function recovery, it can also reduce the risk of ventilator-associated lung injury and improve hypoxia.
Therefore, ECMO is the most advanced support technology at present, and it has become the only effective treatment for children with ARDS when conventional treatment is ineffective [50][51][52][53][54][55]. A cohort study of multicenter randomized controlled data in the United States showed that children treated with ECMO did not have a better prognosis than children with severe ARDS who did not receive ECMO support [56]. Therefore, how to accurately grasp the indications of the application of ECOM still needs a strictly implemented randomized controlled clinical trial to provide a clear answer to this long-term problem.

Ps Replacement Therapy
Pulmonary Surfactant (PS) is a phospholipid formed and stored by type II alveolar epithelial cells. It can not only reduce alveolar surface tension to prevent alveolar collapse at the end of breath, but also increase pulmonary compliance. At the same time, it also has anti-inflammatory and antibacterial effects [57][58][59]. Because most newborns have primary or secondary PS deficiency in ARDS, the mortality of neonatal ARDS has been reduced by 50% since the emergence of exogenous PS replacement therapy [60]. The results of Wang LP et al. [61] showed that early application of PS combined with mechanical ventilation could significantly improve pulmonary oxygenation and compliance and inhibit inflammation in children with ARDS. A multicenter randomized controlled trial confirmed that intratracheal infusion of PS not only improved oxygenation in patients with ARDS, but also significantly reduced mortality [4].

And studies have shown that improvements in surfactant occur only
in patients with direct lung injury (pneumonia, inhalation or near drowning). To verify this conclusion, Willson et al. [62] conducted a multicenter randomized controlled study in 6 different countries in children with ALI/ARDS caused by direct lung injury. The results showed that intratracheal infusion of PS did not improve oxygenation. Therefore, exogenous PS is not recommended for children with ALI/ARDS. Therefore, the optimal use time, dosage and curative effect of PS in neonatal ARDS still need to be further explored. Therefore, nutritional support as an important means of ARDS treatment has been widely used in clinical practice. A multicenter study of 500 children with PICU showed that children who ate more than 66 percent of the prescribed calories had a significantly lower mortality rate than those who received less than 33 percent of the prescribed calories [65]. Further studies by Wong JJ et al. [66] have shown that consuming enough protein can improve clinical

Other Treatment
Ambroxol hydrochloride not only has the characteristics of promoting mucus excretion and dissolving secretions, but also has antioxidant and anti-inflammatory effects, and can promote the production of pulmonary surfactant [74]. A Meta-analysis showed Sao increased only 7 days after high dose ambroxol (> 15mg/kg or 1000mg/d) treatment in patients with ALI/ARDS, which may be related to the antioxidant and antiinflammatory properties of ambroxol [75]. Inhaled nitric oxide (iNO) in the treatment of ARDS is one of the most widely studied interventions in the past two decades. Although iNO treatment can improve oxygenation, there is still no study to prove whether there is a decrease in mortality [76]. A study of 161 children with ARDS showed that inhaling carbon monoxide could reduce the duration of mechanical ventilation, but there was no significant difference in mortality between the two groups [77]. Therefore, at present, iNO is not recommended for routine use in patients with ARDS, but it can be used in the rescue treatment of patients with severe intractable hypoxia [78]. Other treatments, such as liquid ventilation, volume target ventilation, Mesenchymal Stem Cell (MSC) and so on, still need further research and clinical trials to confirm [79][80].

Conclusion
Although great progress has been made in antenatal prevention and postnatal treatment of neonatal ARDS in recent years, there is still no single treatment that can significantly improve the survival of newborns. In view of the high mortality of neonatal ARDS and its specificity in etiology, pathophysiology and so on, the large sample multicenter prospective study on neonatal ARDS diagnosis and treatment is worth looking forward to.