Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Comparison
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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), triggered by various pathogenic factors inside and outside the lungs, leads to diffuse lung injury and can result in respiratory failure and death, which are typical clinical critical emergencies. Severe acute pancreatitis (SAP), which has a poor clinical prognosis, is one of the most common diseases that induces ARDS. When SAP causes the body to produce a storm of inflammatory factors and even causes sepsis, clinicians will face a two-way choice between anti-inflammatory and anti-infection objectives while considering the damaged intestinal barrier and respiratory failure, which undoubtedly increases the difficulty of the diagnosis and treatment of SAP-ALI/ARDS.

  • glucocorticoid
  • severe acute pancreatitis
  • acute lung injury
  • acute respiratory distress syndrome

1. Introduction

Glucocorticoids (GCs) are “stress hormones” that affect the metabolic processes of almost every cell type. Under relaxed conditions, healthy individuals secrete about 20 mg GC/day but, under stress, secretion can reach 300 mg/day [1]. The circadian rhythm also regulates GCs production, which reaches its highest level in the blood during the early morning and drops to its lowest point at nightfall. This secretion pattern helps to regulate chemokine and inflammatory cytokine production and to moderate metabolism [2]. Each cell type has a distinct response to GCs and changes in GC structure and concentration affect the human body in different ways [3]. Meanwhile, GC function is dependent on its specific molecular structure, and GCs’ clinical efficacy is most dependent on the degree and duration of GC exposure to the GC receptor (GR). Maximal GRα saturation induced by different drug doses, start times, and mode and duration of administration ensures that GC efficacy is optimized [4]. In a randomized controlled trial of 17 ICU patients with moderate-to-severe ARDS, the administration of 20 mg/day intravenous GCs for 5 days followed by 10 mg/day from day 6 onwards downregulated inflammation, increased tissue repair, and elevated the alveolar-capillary membrane permeability index, reducing mechanical ventilation duration and overall mortality [5]. In recent decades, GCs have been increasingly used to treat several conditions, including various autoimmune diseases, rheumatoid arthritis, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), sepsis, allergic skin diseases, and the suppression of transplant graft rejection [6]. GCs have also been shown to have a therapeutic effect against coronavirus disease 2019 (COVID-19). In a 2020 study of 173 patients with severe COVID-19 pneumonia from 14 distinct respiratory high-dependency units (RHDUs), early and extended administration of low-dose methylprednisolone (MP), a synthetic GC, improved the systemic inflammatory response, increased oxygenation markers, and reduced invasive mechanical ventilation and mortality rates [7].
Severe acute pancreatitis (SAP), which mediates the secretion of several inflammatory mediators and leads to ALI/ARDS, is a common clinical disease. ALI is the most important cause of the early death of SAP patients. Xuan et al. [8] surveyed 45 hospital ICUs and found that, while routine GC use remains controversial, most physicians still chose a short-course and low-dose GC treatment early in the disease process. However, several reports of adverse side effects have been recorded. GCs are often effective at improving clinical symptoms but rarely cure the disease. Thus, before prescribing GCs, it is important to define the corresponding parameters needed to decide whether to continue treatment [9].

2. GCs Mechanism in SAP-SIRS-ALI Treatment

22.1. Core Pathology of SAP-SIRS-ALI

2.1. Core Pathology of SAP-SIRS-ALI

Acute pancreatitis (AP) is a potential complication of abdominal surgery. Serious AP can lead to ALI/ARDS and is a common reason for AP-associated mortality. Currently, no treatment exists to slow progression. As a result of population growth, environmental changes (including changes in dietary patterns and increasing obesity and smoking rates), and improvements in diagnostic techniques, the annual global incidence of AP is increasing. In 2019, there were 34 cases of AP (95% CI: 23–49) per 100,000 in the general population and 1.16 deaths (95% CI: 0.85–1.58) per 100,000 in the general population [52][10]. This common and complex disease is also putting a major burden on national health care costs. AP-related admission costs in the United States were USD 2.2 billion in 2003 (95% CI: 2.0–2.3 billion), with a mean cost per hospital day of USD 1670 (95% CI: 1620–1720), and an average cost per hospital stay of >USD 10,000. These findings underscore the importance of identifying cost-effective treatment strategies and illustrate that the early identification and prevention of disease progression can significantly reduce hospital costs [53][11]. The mechanisms involved in the pathological process of SAP causing ALI/ARDS have been outlined by ourthe research team in a previous review. Damage to acinar cells is triggered by abnormal activation of pancreatic trypsin induced by various etiologies including glandular pathological changes such as calcium overload of alveolar cells and the disruption of pancreatic microcirculation. This promotes the destruction of mechanical, chemical, biological, and immune barriers in the intestine. Accompanied by inflammatory cell necrosis and the high production of inflammatory mediators such as IL-1β and TNF-α, this inflammatory storm increases local inflammation to SIRS, indicating that AP has begun the early stage of multi-organ dysfunction syndrome (MODS). After extensive damage to alveolar epithelial cells, capillary endothelial cells, and the blood–brain barrier caused by elevated inflammatory cell numbers and cytokine production, ALI/ARDS begins to develop [54][12]. The 1992 American College of Chest Physicians/Society of Critical Care Medicine (SCCM) Consensus Conference Committee defines this as an uncontrolled host response to infectious or non-infectious injury [55,56][13][14]. Excessive cytokine production disrupts the balance of pro- and anti-inflammatory cytokines and signals the development of SIRS. The inflammatory mediators involved in this pathological process include tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), intercellular adhesion molecule-1 (ICAM-1), platelet-activating factor (PAF), CD40L, complement component C5a, substance P, hydrogen sulfide (H2S), and chemokines [57,58,59,60,61][15][16][17][18][19]. SIRS is a double-edged sword for the body. While fighting pathogens or the body’s own necrotic tissue, SIRS can have many harmful effects including altered immune status, organ dysfunction, and a disruption in the procoagulant/anticoagulant balance [62][20]. There are two mortality peaks associated with SAP (Figure 71). The initial peak occurs 1–2 weeks following the onset of symptoms. MODS, which is induced by SIRS, is the most common cause of death at this time point, accounting for 60–80% of all fatalities. The second peak occurs approximately 2 months after onset. Most of these deaths are caused by sepsis and other infections, and the length of SIRS is directly associated with the severity of SAP and its prognosis [63][21]. Hietaranta et al. [55][13] showed that the risk of systemic complications increases as the severity of SIRS rises.
Ijms 24 12138 g007 550
Figure 71. Death Spikes of SAP. The figure shows the distribution of deaths in SAP patients. The first peak of death occurred in the first week or so after SAP, and respiratory failure caused by ALI/ARDS complicated by SIRS was the most common. The second death peak was due to sepsis secondary to MODS caused by pancreatic necrosis infection. It is usually located in the third and fourth weeks.
During the early stages of SAP, pro-inflammatory processes destroy pathogens and dead tissue but may also cause irreversible damage to the host. At the same time, the compensatory anti-inflammatory response syndrome (CARS) works to limit damage to host tissue without interfering in pathogen clearance [64][22]. CARS was proposed in 1996 by Bone [65][23], who served as the chair of the ACCP/SCCM Consensus Conference. In contrast to SIRS, CARS restores balance from the inflammatory state through systemic inactivation of the immune system. It is important to note that CARS and SIRS can occur concurrently [64][22]. Gunjaca et al. [66][24] showed that SIRS and CARS are pathogenic states associated with the early acute inflammation response to AP and their intensities are correlated. Thise study used the SIRS/CARS model to measure AP severity. There are several possible ways in which this immunological response may occur. When SAP is initiated, there is a high production of pro-inflammatory mediators and a low production of anti-inflammatory mediators. During the early stages of the disease, mixed anti-inflammatory response syndrome (MARS) occurs and high amounts of pro- and anti-inflammatory mediators are produced. In the end stage, CARS, associated with high levels of anti-inflammatory mediators and few or no pro-inflammatory mediators, occurs [67][25]. Thus, maintaining the balance between pro- and anti-inflammatory cytokines early in SAP and alleviating any tissue and organ damage is critical to preventing MODS and reducing mortality [68,69][26][27].

3.2. Research Progress of GC in SAP-SIRS-ALI

2.2. Research Progress of GC in SAP-SIRS-ALI

GCs are the most used drug for the treatment of ALI/ARDS caused by SAP and can effectively reduce patient mortality. After binding to GR and moving into the nucleus, GCs play a significant role in promoting an anti-inflammatory response, reducing oxygen-free radical damage, and improving microcirculation [70][28]. Kimura et al. [71][29] found that, following adrenalectomy, AP rats were more sensitive to acinar cell apoptosis due to reduced endogenous cortisol production. These animals had greater pancreatic edema, higher amylase levels, more potent inflammatory responses, and higher rates of mortality. These effects were significantly reduced following exogenous GC administration [72][30]. These studies provide evidence that GCs reduce the onset of AP [73][31].

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