Literature data about the therapeutic management of children with CIRCI are lacking, and the question about what type of intervention should be appropriated is still debated.

Current guidelines [1] recommend the use of hydrocortisone in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (> 0.1 μg/kg/min of norepinephrine or equivalent) and/or in those with early severe acute respiratory distress syndrome (PaO2/FiO2 of < 200 and within 14 days of onset).

The beneficial effect of hydrocortisone in these patients has not been well ascertained, so the risks and benefits of this approach continue to be explored, especially in the paediatric field.

Glucocorticoids are effective in restoring cardiovascular homeostasis in sepsis through genomic and nongenomic effects [36], so they appear to be very useful in the management of adrenal insufficiency.

Several factors could influence the response to glucocorticoid administration in CIRCI patients: the type of underlying disease and the complex pathogenesis of this condition, involving different mechanisms, such as reduced steroid clearance and corticosteroid resistance.

Among adult patients, the treatment protocol involved the administration of 50 mg intravenous hydrocortisone every 6 h or a bolus of 100 mg followed by continuous infusion at 10 mg/h [26]. No indications are provided about hydrocortisone dosage in paediatric patients with CIRCI.

Treatment with a stress dose of hydrocortisone may be started early and without the need for dynamic testing if the random cortisol level is < 276 nmol/L (10 μg/dL). If random cortisol levels are between 276 and 938 nmol/L (10–34 μg/dL) and the 250 μg ACTH test reveals a delta cortisol < 248 nmol/L (9 μg/dL), the diagnosis of CIRCI is made, and glucocorticoid treatment is indicated.

Additionally, the question about the duration of steroid supplementation is still debated. A recent work, by Arcellana et al. [37] indicated that 200 mg/day hydrocortisone should be given for at least 72 h and up to 7 days, to have a significant benefit [1, 38], but no univocal indication is provided about this topic.

Hydrocortisone supplementation in septic patients has been extensively studied in the last 20 years.

Several studies have shown that sepsis induces changes in HPA axis activity, cortisol metabolism and peripheral tissue resistance to glucocorticoids, so the risk of developing CIRCI is very high in this population.

It has been observed that the presence of adrenal failure in patients with a septic state (including both sepsis and septic shock) is associated with increased mortality and a long duration of intensive care unit stay. It also seems that the need for inotropic support and high doses of inotropic drugs might be considered as an indicator of adrenal insufficiency in ICU patients [8].

The 2019 Cochrane review about the use of corticosteroids for treating sepsis in children and adults confirms that patients with septic shock may obtain a survival benefit from corticosteroid treatment, but it could not be the same for those with CIRCI [7].

Moreover, the analysis of trials including patients with CIRCI does not show a significant reduction in the risk of death at 28 days [1].

The inconsistency of data derived from the few clinical studies on this topic has probably affected the results shown by the Cochrane review, so the examination of the effects of glucocorticoid supplementation in critically ill children is becoming increasingly necessary.

Hebbar et al. examined corticosteroid supplementation for patients with SIRS with or without sepsis.

Children with hypotension, unresponsive to fluid resuscitation, and on IV vasopressor infusions have been treated with a loading dose of IV hydrocortisone (100 mg/m2) followed by 25 mg/m2 per dose given every 6 h for 7 days without any taper [39] (Table 2).

Early initiation of steroid therapy is particularly useful in some patients, even in the presence of sepsis without shock [40, 41].

They are represented by children with purpura fulminans and Waterhouse-Friedrichsen syndrome, children who previously received steroid therapies for chronic illness, and those with pituitary or adrenal abnormalities. The risk of adrenal failure is very high in these patients, and prompt initiation of hydrocortisone treatment could prevent acute adrenal crisis.

Several conditions are associated with neonatal adrenal insufficiency, but no clear definition of CIRCI in neonatal age has already been provided.

Early diagnosis of adrenal insufficiency seems to be important, especially in asphyxiated neonates with hemodynamic instability because of the well-known positive effect of hydrocortisone on systemic blood pressure.

Adrenal insufficiency in hypoxic ischemic injury could be due both to reduced perfusion of the adrenal gland and to a transient refractory state of the HPA axis. Hypoxic insult may affect the adrenal gland, leading to adrenal haemorrhage, impaired adrenal performance, low serum cortisol concentrations and an increased risk of heart dysfunction [42].

Hydrocortisone treatment is used frequently as a rescue therapy in asphyxiated newborns with vasopressor-resistant hypotension, and it appears to be a treatment option in several clinical review articles [43].

Steroid supplementation with hydrocortisone causes an increase in blood pressure soon after the start of treatment [44], but its administration should be considered carefully because of the risk of adverse neurodevelopmental effects (e.g., abnormal brain development) [45, 46].

Moreover, adrenal insufficiency is observed in critically ill neonates who are born at term, especially during the first week after delivery [47]. In this population, a strong improvement in hemodynamic parameters after hydrocortisone therapy was observed, unlike in neonates without evidence of adrenal failure.

The beneficial effect of hydrocortisone therapy has also been observed in premature newborns, with a reduction in the duration and/or amount of catecholamine administration [48,49,50].

We are not able to confirm whether the definition of CIRCI could be extended to neonatal age. Additionally, the use of glucocorticoids in critically ill neonates is controversial, so a specific characterization of this condition and of the most appropriate therapeutic approach should be provided by further studies.

CIRCI may be common in patients with major trauma, and it is associated with uncontrolled inflammation, vasopressor dependency and poor clinical outcomes.

Paediatric reports about this specific condition are not available, and we should refer only to adult protocols. Current guidelines suggest against steroid supplementation in this group of patients because of the absence of improvement in short-term mortality (Table 2).

Despite extensive research into CIRCI, there is little information about CIRCI in burn patients. It is well known that patients with major burn injury experience a severe systemic inflammatory response that puts them at risk for CIRCI [11].

This risk is particularly increased in patients with advanced age and a greater total body surface area (TBSA) burn, both of which are also independent risk factors for mortality after burn injury. It has been demonstrated that the early identification of the highest risk patients results in earlier initiation of physiologic steroid replacement and leads to a significant reduction in morbidity and mortality [51].

Paediatric acute respiratory distress syndrome (PARDS) is another condition associated with CIRCI. The link between these conditions could be found in the setting of systemic dysregulated inflammation that characterizes acute respiratory distress syndrome pathophysiology [52].

Steroids are potentially useful in PARDS, but the last Paediatric Acute Lung Injury Consensus Conference guidelines (PALICC- 2) do not recommend corticosteroids as routine therapy [53]. There are several conditions for which steroid effects may be beneficial in patients with PARDS: treatment of a coexistent steroid-responsive disease; treatment of inflammation early to minimise lung damage and management of critical illness-related corticosteroid insufficiency [54].

The 2017 recommendations for the management of critical illness-related corticosteroid insufficiency do not analyse CIRCI in PARDS, but recommend methylprednisolone at a dose of 1 mg/kg/day in adults with ARDS and a PaO2/FiO2 < 200 within the first 6 days of illness. After day 6 of illness, they recommend increasing the dose to 2 mg/kg/day and a slow taper over at least 13 days (Table 2).

Although the use of corticosteroids in PARDS is not routinely recommended, the need for further study to identify the correct patient population, timing of administration and dosing regimen could also be useful for the management of the associated CIRCI condition.