Stimuli from various sources (including cold, pain, infection, trauma, and hypotension) that exceed a certain threshold will activate the stress response of the body, resulting in activation of the hypothalamus-pituitary adrenal (HPA) axis, release of adrenocorticotrophic hormone (ACTH), and increased blood levels of cortisol. This is an important guarantee for the body to adapt and resist diseases, maintain the homeostasis of the internal environment and normal function of all systems and organs. Even mild adrenocortical insufficiency (A I) will lead to rapid death of the stressed host. However, it has been reported that the incidence of relative adrenal insufficiency (RA I) is 30% in critically ill patients and even 50% to 60% in patients with severe infections and infectious shock, and the death rate of untreated RA I patients is significantly higher. Qiu Zhanjun, Department of Emergency Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine 1. Physiological effects of glucocorticoids Glucocorticoids are important active mediators of life support and essential components of the body’s stress response. Under physiological conditions, glucocorticoids have the function of maintaining stable circulatory function. In severe infections and infectious shock, glucocorticoid release increases, which further induces Na K ATPase activity in cardiomyocytes, increases transcription and expression of adrenergic receptor genes, inhibits induciblnitric oxide synthase (iNOS) activity and reduces excessive production of nitric oxide (NO), and promotes recovery and stabilization of circulatory function. At the same time, glucocorticoids are also one of the important “glucose-raising” hormones in the body, which can increase energy supply and meet metabolic needs by effectively raising blood glucose levels and increasing the transport of sugar to tissue cells when the body is severely deprived of metabolic substrates. Anti-inflammatory and immunosuppressive effects are the fundamental properties of glucocorticoids. By acting on nuclear transcription factor kB (NF-kB), glucocorticoids inhibit the synthesis of various cytokines such as interleukin 1β (IL- 1β), IL 2, IL 3, IL 6, tumor necrosis factor (TNF)γ interferon (IFN-γ) and inflammatory mediators such as bradykinin, serotonin and histamine, reduce the production of arachidonic acid and platelet-activating factor by the activation of endothelial phospholipid system, and decrease the endotoxin-induced granulocyte chemotaxis and It also reduces endotoxin-induced granulocyte chemotaxis and adhesion, and to some extent enhances the activity of certain anti-inflammatory mediators such as IL-1 receptor antagonists, TNF receptor fusion protein, and IL-10. This anti-inflammatory and immunosuppressive effect limits the general activation of early inflammatory cells, blocks the “waterfall” chain reaction of inflammation, and effectively reduces the damage of the “double-edged sword” of inflammatory mediators in the expanded stress response of the body, making the body much more tolerant to stress. The HPA axis is one of the central axes of the human endocrine system, which synthesizes and releases dozens of active substances such as hormones, cytokines, neurotransmitters and neuromodulators, and is the basic guarantee for the normal functioning of the body. In healthy people, the blood cortisol level ranges from 138.0 to 662.4 nmol/L. However, under the effect of strong stress factors such as severe infections and infectious shock, the body reacts strongly and the functional state of the HPA axis is significantly altered, and the metabolism and utilization of corticosteroids are seriously affected. This “parallel change” in inflammatory mediators and blood cortisol levels and the inability of target organs to fully utilize available glucocorticoids is referred to as “starvation in plenty”, or RA I. RA I is a state in which the body compensates for the effects of severe infection and infectious shock. RA I is a passive manifestation of inadequate compensation in severe infections and infectious shock, which is very different from the mechanism of A I, its diagnosis and therapeutic significance. 2.1 Mechanism of RA I production: There is a complex feedback mechanism in the closed loop formed by the neuroendocrine-immune system network. In response to stimulatory signals, the body produces a variety of inflammatory mediators, such as IL 1-α, IL 1-β, IL-6 and TNF-α, which activate the HPA axis and promote the release of ACTH and glucocorticoids on the one hand, and exhibit inhibitory effects on the function of the HPA axis on the other. For example, the slow increase of IL 6 can slow down the release of ACTH; TNF Α can not only inhibit the pituitary response to CRH, but also reduce the promotion of ACTH and angiotensin on glucocorticoid synthesis. At the same time, there is increasing evidence that inflammatory mediators can affect the expression and function of hormone receptors, induce transcription activated protein (TAP 1) and NF?B overexpression, and lead to corticosteroid receptor resistance (CRR) phenomenon. Studies have shown that IL-1, IL-2, IL-6 and TNF can reduce the sensitivity of hormone receptors; IL-2 and IL-4 can greatly reduce the affinity of hormone receptors.2. 2 Diagnosis of RA I: In severe infections and infectious shock, the complex interactions between inflammatory mediators and the HPA axis and hormone receptors make it clinically difficult to determine the “normal” hormone levels that satisfy the body’s stress response. “The search for an accurate and feasible evaluation method has become a critical problem for RA I diagnosis. Since the cellular function of glucocorticoids cannot be effectively evaluated, the ACTH stimulation test is currently the most widely used clinical test to determine the stimulation of adrenocortical function. The traditional method is to record the basal blood cortisol concentration and then push ACTH 250 g intravenously, and observe the blood cortisol level before and 30 and 60 m in after the administration. However, we believe that the direct application of the above test criteria to critically ill patients may have the following problems: ① In conventional tests, the stimulation dose of ACTH is more than 100 times the normal human maximum stress level, which may lead to a significant increase in the underdiagnosis rate in the subject population. Therefore, it has been suggested to reduce the ACTH stimulation dose to 1~2ug, which is called low dose (LD)-ACTH stimulation test, and some clinical trials have confirmed that LD-ACTH stimulation test has better sensitivity compared with the former. In severe infections and infectious shock, the host stress response is so strong that the threshold value of 496.18 nmol/L does not reflect the balance of supply and demand in the pathological state of the organism. It has also been suggested that 690.10 nmol/L as the minimum threshold for cortisol concentration in critically ill patients with severe infections and infectious shock may be more useful for clinical work. In severe infections and infectious shock, the decreased metabolic capacity of the liver, reduced plasma binding proteins and impaired metabolism and utilization of glucocorticoids due to CRRT make the correlation between △max and the body’s hormone levels disappear, which is not sufficient to diagnose the presence of RA I. Finally, the ACTH stimulation test only reflects the functional status of the adrenal cortex, but in patients with severe infections and infectious shock with impaired HPA axis function, we focus more on the overall functional level of the HPA axis, which is lacking in the test itself. 2.3 Clinical significance of RA I: Severe infections and infectious shock are a developmental stage of the host stress response, and RA I is a response to the pathophysiological and neuroendocrine immune response of the body during this special stage. The clinical application of glucocorticoids in severe infections and infectious shock is of great significance in improving the prognosis of patients. The use of glucocorticosteroids in severe infections and infectious shock has been a topic of debate for nearly half a century. As early as the 1950s, the use of glucocorticoids was reported to improve the prognosis of patients with severe systemic infections. Based on the results of animal studies and early clinical studies by Schumer et al, in the late 1970s and early 1980s, the use of “early” (within 24 h of diagnosis), “short” (< 24 h), "high" dose (methylprednisone) and "high" dose glucocorticosteroids was introduced. "(methylprednisolone 30 mg/kg every 4 to 6 h) for the treatment of infectious shock. However, no improvement in the prognosis of patients with severe infections and infectious shock was seen with this treatment principle in subsequent multicenter, prospective, randomized, controlled clinical trials. In 1998 and 1999, Bollaert and Briegel et al. demonstrated in their respective clinical trials that the application of physiologic doses of glucocorticoids improved the hemodynamic status of patients with vasoactive drug-dependent infectious shock. In 2000, Annane et al. applied the traditional ACTH stimulation test to evaluate the adrenocortical function in patients with infectious shock and proposed the concept of RA I and its diagnostic criteria, which provided another theoretical basis for the correction of RA I with exogenous glucocorticoids and thus improved the prognosis of patients with infectious shock. In 2002, a large multicenter clinical trial enrolling 299 patients showed that low-dose (hydrocortisone 50 mg every 6 h + fludrocortisone 50 ug once daily) and long-course (7 d) glucocorticoid supplementation reduced 28-d mortality and vasoactive drug dependence in RA I patients with severe infections and infectious shock, confirming the validity of this idea. The evidence-based guidelines for the treatment of severe infections and infectious shock were revised in 2003 and include the following recommendations regarding the use of glucocorticoids: for patients with confirmed infectious shock who are still dependent on vasoactive drugs to maintain circulation after adequate fluid volume expansion, dexamethasone may be used prior to ACTH stimulation testing, and hormone replacement therapy (hydrocortisone 200-300 mg/day) may be continued depending on the results of the test. Depending on the results of the test, hormone replacement therapy (hydrocortisone 200-300 mg/d plus (or fludrocortisone 50ug/d alone) may be continued for 7 days or the hormone may be discontinued. If an ACTH stimulation test cannot be performed, it is recommended that the above hormone replacement therapy be given according to the patient's clinical condition and reduced as appropriate when the condition improves. It is not recommended for use in patients other than those with infectious shock, but for patients with A I or those on previous long-term hormone therapy, treatment may be based on medication history. Although there is a good theoretical basis and good therapeutic effect for RA I supplementation with physiologic doses of glucocorticoids in critically ill patients with severe infections and infectious shock, there are still some problems to be solved in clinical application: ①Beneficiary population: The attempt to define the diagnostic criteria of RA I by traditional ACTH stimulation test is an important guideline in hormone research. However, due to the specificity of the subject population, the problems that may exist in the simple application of the test need to be improved by further clinical trials to find "patches", and the identification of the beneficiary subgroup is the fundamental prerequisite for glucocorticoid replacement therapy. ②Treatment regimen: "small dose" and "long course" are the qualitative descriptions of the principles of glucocorticoid replacement therapy, and large-scale clinical trials should be conducted to determine the "optimal type" and "optimal dose" of hormone therapy. The quantification and concretization of treatment regimens is an important basis for glucocorticoid replacement therapy, as well as the determination of the "optimal type", "optimal dose" and "optimal duration" of hormone therapy in large-scale clinical trials. ③Evaluation index: So far, clinical trials have only been able to evaluate the effect of hormone replacement therapy from a retrospective perspective. Patients with severe infections and infectious shock are in critical condition and need well correlated and clinically accessible parameters to provide titration guidance during treatment. The best way to find evaluation indicators is to combine theories from hemodynamics, oxygen metabolism and other research fields. The importance of normal HPA axis function and glucocorticoid metabolism as one of the basic elements of the body's stress response and resistance to external stimuli should not be overlooked. A deeper understanding of the mechanisms and compensatory strategies of the neuroendocrine immune system in these processes and their application in clinical practice will certainly promote further rapid development in various research fields of critical care medicine. The content of the above article {Na Cui (review), Dawei Liu (reviewer)}★ Although initial studies and related meta-analyses confirmed the efficacy of low-dose glucocorticoids in infectious shock, the subsequent highly anticipated [6] CORTICUS study did not achieve the expected results. The CORTICUS study, conducted in 52 medical centers in 9 European countries, was originally designed to enroll only 499 patients with infectious shock. The results showed that after 11 d of treatment with hydrocortisone (50 mg every 6 h for 5 d, followed by tapering to discontinuation over the next 6 d), the time to shock reversal was significantly reduced in the glucocorticoid group, but hydrocortisone did not reduce the rate of death from infectious shock, regardless of the response to ACTH stimulation (no response to ACTH stimulation: 39.2% in the hydrocortisone group and 39.2% in the placebo control group). % in the hydrocortisone group vs. 36.1% in the placebo control group; in patients with infectious shock who responded to ACTH stimulation: 28.8% in the hydrocortisone group vs. 28.7% in the control group, P = 0.51) and the rate of recovery from shock (80.5% in the hydrocortisone group vs. 74.6% in the control group, P = 0.14); and glucocorticoid treatment increased the incidence of secondary [6] infections, new systemic infections, and infectious shock. incidence . The failure of this study was a major blow to contemporary glucocorticoid therapy. After the publication of the CORTICUS study, the 2008 guidelines for the management of severe sepsis and infectious shock were significantly revised to recommend that low-dose glucocorticoid therapy (2C) be given intravenously only to patients with infectious shock who remain hypotensive despite adequate fluid resuscitation and vasopressors, and that glucocorticoids not be recommended as [... 7] general adjuvant therapy for patients with infectious shock . (Ji Xianfei, Li Chunsheng) ★ The mechanism of glucocorticoids against infectious shock Glucocorticoids can promote the biosynthesis of catecholamines, improve vascular permeability, increase the effect of vasoconstriction of vasopressin, angiotensin II and endothelin, and increase the sensitivity of the circulatory system to catecholamines during infectious shock [18] . In addition, cortisol has a clear inhibitory effect on pro-inflammatory mediators (e.g., TNF, IL?1, IL?6, IL?8, IL?12, γ?interferon, etc.) [19] [20] with . de Kruif et al. found that prednisolone dose-dependently inhibited the release of pro-inflammatory mediators such as TNF?α, IL?6, and IL?8 in healthy volunteers injected with endotoxin, as well as inhibited endothelial cells, neutrophil activation, and blocked the acute [21] phase response without altering the coagulation and fibrinolytic systems. buchele et al. found that small doses of hydrocortisone improved the microcirculation in patients with infectious shock. [22] Johannes et al. reported that low-dose dexamethasone (0.1 mg/kg) increased oxygen delivery, improved oxygenation, and significantly reduced oxygen consumption in the kidney of rats with infectious shock, while increasing mean arterial pressure and renal blood flow, inhibiting nitric oxide synthase synthesis, and reversing endotoxin-induced renal failure, and they suggested that low-dose dexamethasone could potentially be used to prevent acute renal failure due to infectious shock. renal failure due to infectious shock. Moreover, small doses of glucocorticoids were found to increase rather than suppress innate immunity in people with infectious shock [23] . There is controversy regarding the beneficial use of low-dose glucocorticoids in infectious shock. We believe that the broad anti-inflammatory, immunomodulatory, and vascular sensitization to catecholamines properties of low-dose glucocorticoids should give them a place in the adjuvant treatment of infectious shock. In view of this, there is a need for more in-depth basic and clinical research on the prognostic impact of hormone replacement therapy. Larger clinical trials are needed to determine whether small doses of glucocorticosteroids improve survival in patients with infectious shock (or severe infectious shock), the optimal timing of glucocorticosteroid initiation, the optimal dose, the duration, and whether to stop or taper the dose suddenly. These are all topics that need to be explored in the future. (Xianfei Ji, Chunsheng Li)