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Diagnostic approach and steroid treatment for suspected adrenal crisis, refractory septic shock and critical illness-related corticosteroid insufficiency.
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Critical illnesses are hallmarked by increased systemic cortisol availability, a vital part of the stress response. Acute stress may trigger a life-threatening adrenal crisis when a disease of the hypothalamic-pituitary-adrenal (HPA)-axis is present and not adequately treated with stress doses of hydrocortisone. Stress doses of hydrocortisone are a...
Contexts in source publication
Context 1
... always be monitored carefully in the peri-operative phase after elective surgery but also when admitted in an urgent setting (eg, trauma or burn victims). Appropriate treatment should be given promptly when an adrenal crisis is suspected (clinical practice guidelines (50); primary, secondary, and tertiary adrenal insufficiency is reviewed in (9); Fig. ...
Context 2
... to the in 2017 established guidelines for the diagnosis and management of CIRCI (48), despite lack of consensus on a single test to reliably diagnose CIRCI, the patient's increment in plasma total cortisol of ≤9 µg/dL after ACTH stimulation could be interpreted as relative adrenal insufficiency or CIRCI, as it was rebranded back then (14,48) (Fig. 1). However, as explained in the introduction and reviewed in (5, 6), the low increment in plasma total cortisol is likely the result of a substantial increase in cortisol distribution volume, rather than of an already maximally stimulated adrenal cortex that is unable to produce more glucocorticoids. Hence, a low increment in total ...
Context 3
... The 250 µg of ACTH stimulation test with assessment of the incremental total cortisol response is not appropriate to diagnose CIRCI as the result is confounded by the increased cortisol distribution volume. Potentially, repeated ACTH stimulation tests with assessment of the increment in plasma free cortisol over time in ICU could be informative (Fig. 1). However, a specific threshold for an adequate increment in plasma free cortisol has not been established. In addition, a 100 µg of CRH stimulation test and assessment of the incremental response in plasma ACTH can indicate whether central HPA axis suppression is present or not (Fig. 1). However, as is the case for the ACTH stimulation ...
Context 4
... plasma free cortisol over time in ICU could be informative (Fig. 1). However, a specific threshold for an adequate increment in plasma free cortisol has not been established. In addition, a 100 µg of CRH stimulation test and assessment of the incremental response in plasma ACTH can indicate whether central HPA axis suppression is present or not (Fig. 1). However, as is the case for the ACTH stimulation test, a single threshold level for the ACTH response to CRH to allow or refute CIRCI diagnosis remains unknown. Imaging techniques, such as bedside ultrasound, computed tomography, or magnetic resonance imaging, may help differentiating with rare complications of critical illnesses such ...
Context 5
... treatment can be recommended. For reasons described above (19), we recommend treatment with hydrocortisone using a daily dose of 60 mg and dividing it in 2 bolus injections, 40 mg IV in the early morning and 20 mg IV in the evening, to mimic at least to some extent the normal diurnal variation which is disrupted in critically ill patients (52) (Fig. 1). Some diagnostic tests as proposed above may be informative (Fig. 1), but initiating hydrocortisone treatment without further laboratory investigations may also be reasonable provided clinical responses are defined a priori and are carefully documented in the hours and days following treatment initiation (Fig. 2). In case such clear ...
Context 6
... recommend treatment with hydrocortisone using a daily dose of 60 mg and dividing it in 2 bolus injections, 40 mg IV in the early morning and 20 mg IV in the evening, to mimic at least to some extent the normal diurnal variation which is disrupted in critically ill patients (52) (Fig. 1). Some diagnostic tests as proposed above may be informative (Fig. 1), but initiating hydrocortisone treatment without further laboratory investigations may also be reasonable provided clinical responses are defined a priori and are carefully documented in the hours and days following treatment initiation (Fig. 2). In case such clear clinical response is absent, it is advisable to stop the treatment. In ...
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The hypothalamic-pituitary-adrenal (HPA) axis is a key adaptive neuroendocrine system, dysfunction of which plays an important role in the increasing incidence of stress-dependent age-related pathology. Among the environmental factors effecting increase age-related diseases, great importance is given to disturbances of the light-dark schedule, part...
Citations
... Increased systemic cortisol availability is a vital component of the stress response during critical illnesses, severe stress, trauma, extensive surgery, or sepsis [27]. CIRCI is defined as a condition in which patients with prolonged critical illness require mechanical and/or pharmacological vital organ support for several days, with symptoms and signs compatible with adrenal insufficiency. ...
... CIRCI is thus an acquired adrenal insufficiency among the latter patients. Currently, there is no validated diagnostic test or imaging technique for the diagnosis [27]. In the case of suspicion of CIRCI and GC treatment, mainly with hydrocortisone, endocrinological follow-up is suggested for the patient. ...
Glucocorticoids (GCs) have been widely used in symptomatic patients for the treatment of COVID-19. The risk for adrenal insufficiency must be considered after GC withdrawal given that it is a life-threatening condition if left unrecognized and untreated. Our study aimed to diagnose adrenal insufficiency early on through a GC reduction schedule in patients with COVID-19 infection.
From November 2021 to May 2022, 233 patients were admitted to the Geriatric Division of the University Hospital of Padova with COVID-19 infection. A total of 122 patients were treated with dexamethasone, after which the GC tapering was performed according to a structured schedule. It consists of step-by-step GC tapering with prednisone, from 25 mg to 2.5 mg over 2 weeks. Morning serum sodium, potassium, and cortisol levels were assessed 3 days after the last dose of prednisone.
At the end of GC withdrawal, no adrenal crisis or signs/symptoms of acute adrenal insufficiency were reported. Median serum cortisol, sodium, and potassium levels after GC discontinuation were, respectively, 427 nmol/L, 140 nmol/L, and 4 nmol/L (interquartile range 395–479, 138–142, and 3.7–4.3). A morning serum cortisol level below the selected threshold of 270 nmol/L was observed in two asymptomatic cases (respectively, 173 and 239 nmol/L, reference range 138–690 nmol/L). Mild hyponatremia (serum sodium 132 to 134 nmol/L, reference range 135–145 nmol/L) was detected in five patients, without being related to cortisol levels.
A structured schedule for the tapering of GC treatment used in patients with severe COVID-19 can reduce the risk of adrenal crisis and acute adrenal insufficiency.
... Furthermore, the administration of the sedative drug Etomidate, a known inhibitor of cortisol synthesis, was found to be associated with increased morbidity and mortality in critically ill patients, including trauma and surgical patients (13)(14)(15)(16)(17)(18). Of note, the clinical impact of CIRCI and the recommendation to supplement steroids in cases of inadequate cortisol levels have been repeatedly challenged in the literature and inconsistency in practice remains among intensivists (19)(20)(21)(22). In this retrospective study, we analyzed results of cortisol levels in the first morning following admission of critically ill patients to the surgical ICU (SICU) in a tertiary medical center and compared it with 90-day mortality and with ICU length of stay (LOS). ...
IMPORTANCE
To explore the correlation between cortisol levels during first admission day and clinical outcomes.
OBJECTIVES
Although most patients exhibit a surge in cortisol levels in response to stress, some suffer from critical illness-related corticosteroid insufficiency (CIRCI). Literature remains inconclusive as to which of these patients are at greater risk of poor outcomes.
DESIGN
A retrospective study.
SETTING
A surgical ICU (SICU) in a tertiary medical center.
PARTICIPANTS
Critically ill patients admitted to the SICU who were not treated with steroids.
MAIN OUTCOMES AND MEASURES
Levels of cortisol taken within 24 hours of admission (day 1 [D1] cortisol) in 1412 eligible patients were collected and analyzed. Results were categorized into four groups: low (0–10 µg/dL), normal (10–25 µg/dL), high (25–50 µg/dL), and very high (above 50 µg/dL) cortisol levels. Primary endpoint was 90-day mortality. Secondary endpoints were the need for organ support (use of vasopressors and mechanical ventilation [MV]), ICU length of stay (LOS), and duration of MV.
RESULTS
The majority of patients (63%) had high or very high D1 cortisol levels, whereas 7.6% had low levels and thus could be diagnosed with CIRCI. There were statistically significant differences in 90-day mortality between the four groups and very high levels were found to be an independent risk factor for mortality, primarily in patients with Sequential Organ Failure Assessment (SOFA) less than or equal to 3 or SOFA greater than or equal to 7. Higher cortisol levels were associated with all secondary endpoints. CIRCI was associated with favorable outcomes.
CONCLUSIONS AND RELEVANCE
In critically ill surgical patients D1 cortisol levels above 50 mcg/dL were associated with mortality, need for organ support, longer ICU LOS, and duration of MV, whereas low levels correlated with good clinical outcomes even though untreated. D1 cortisol level greater than 50 mcg/dL can help discriminate nonsurvivors from survivors when SOFA less than or equal to 3 or SOFA greater than or equal to 7.
... The term CIRCI should not be used to describe impaired function of the HPA axis already present prior to the onset of a critical illness, such as preexisting (undiagnosed/untreated/latent) intrinsic disease affecting the HPA axis (e.g., Addison's disease), which led to a full-blown adrenal crisis triggered by stress conditions (Fig. 2) [24]. ...
Critical illness-related corticosteroid insufficiency or CIRCI is characterized by acute and life-threatening disfunction of hypothalamic–pituitary–adrenal (HPA) axis observed among intensive care unit- staying patients.
It is associated with increased circulating levels of biological markers of inflammation and coagulation, morbidity, length of ICU stay, and mortality.
Several mechanisms are involved in CIRCI pathogenesis: reduced CRH-stimulated ACTH release, peripheral resistance to glucocorticoids, altered cortisol synthesis, impaired cortisol-free fraction and bioavailability.
Diagnostic and therapeutic management of this condition in children is still debated, probably because of the lack of agreement among intensive care specialists and endocrinologists regarding diagnostic criteria and prevalence of CIRCI in paediatric age.
In the present narrative review, we focused on definition of CIRCI in paediatric age and we advise on how to diagnose and treat this poorly understood condition, based on current literature data.
... Furthermore, plasma concentrations and binding-affinity of cortisol carrier proteins are reduced, resulting in higher free cortisol concentrations [16,17]. In prolonged critical illness a decrease of plasma total and free cortisol concentrations and delayed suppressed ACTH response to CRH test are indicative of central adrenal insufficiency that may develop over weeks [18]. Therefore, cortisol inactivation and the time course of illness should be considered when analyzing the steroid metabolome in preterm infants. ...
Adrenal function is essential for survival and well-being of preterm babies. In addition to glucocorticoids, it has been hypothesized that C19-steroids (DHEA-metabolites) from the fetal zone of the adrenal gland may play a role as endogenous neuroprotective steroids. In 39 term-born (≥37 weeks gestational age), 42 preterm (30–36 weeks) and 51 early preterm (<30 weeks) infants 38 steroid metabolites were quantified by GC-MS in 24-h urinary samples. In each gestational age group, three distinctive cluster were identified by pattern analysis (k-means clustering). Individual steroidal fingerprints and clinical phenotype were analyzed at the 3rd day of life. Overall, the excretion rates of C21-steroids (glucocorticoid precursors, cortisol, and cortisone metabolites) were low (<99 μg/kg body weight/d) whereas the excretion rates of C19-steroids were up to 10 times higher. There was a shift to higher excretion rates of C19-steroids in both preterm groups compared to term infants but only minor differences in the distribution of C21-steroids. Comparable metabolic patterns were found between gestational age groups: Cluster 1 showed mild elevation of C21- and C19-steroids with the highest incidence of neonatal morbidities in term and severe intraventricular hemorrhage in early preterm infants. In cluster 2 lowest excretion in general was noted but no clinically unique phenotype. Cluster 3 showed highest elevation of C21-steroids and C19-steroids but no clinically unique phenotype. Significant differences in steroid metabolism between clusters are only partly reflected by gestational age and disease severity. In early preterm infants, higher excretion rates of glucocorticoids and their precursors were associated with severe cerebral hemorrhage. High excretion rates of C19-steroids in preterm infants may indicate a biological significance.
... Due to disease severity, affected patients are frequently prone to prolonged critical illness, which subsequently leads to dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis (2). As concomitant failure of maintaining an autonomous stress response, criticalillness-related corticosteroid insufficiency (CIRCI) is often associated with the continued requirement of vasopressor support, electrolyte disturbances, and poor neurological recovery post sedation (3). In case of primary adrenal insufficiency, coevaluation of the renin-angiotensin-aldosterone system (RAAS) activity in these patients was previously proposed to improve reliable interpretation (4). ...
Background
Prolonged critical illness is often accompanied by an impairment of adrenal function, which has been frequently related to conditions complicating patient management. The presumed connection between hypoxia and the pathogenesis of this critical- illness- related corticosteroid insufficiency (CIRCI) might play an important role in patients with severe acute respiratory distress syndrome (ARDS). Since extracorporeal membrane oxygenation (ECMO) is frequently used in ARDS, but data on CIRCI during this condition are scarce, this study reports the behaviour of adrenal function parameters during oxygenation support with veno-venous (vv)ECMO in coronavirus disease 2019 (COVID-19) ARDS.
Methods
A total of 11 patients undergoing vvECMO due to COVID-19 ARDS at the Medical University of Vienna, who received no concurrent corticosteroid therapy, were retrospectively included in this study. We analysed the concentrations of cortisol, aldosterone, and angiotensin (Ang) metabolites (Ang I–IV, Ang 1–7, and Ang 1–5) in serum via liquid chromatography/tandem mass spectrometry before, after 1 day, 1 week, and 2 weeks during vvECMO support and conducted correlation analyses between cortisol and parameters of disease severity.
Results
Cortisol concentrations appeared to be lowest after initiation of ECMO and progressively increased throughout the study period. Higher concentrations were related to disease severity and correlated markedly with interleukin-6, procalcitonin, pH, base excess, and albumin during the first day of ECMO. Fair correlations during the first day could be observed with calcium, duration of critical illness, and ECMO gas flow. Angiotensin metabolite concentrations were available in a subset of patients and indicated a more homogenous aldosterone response to plasma renin activity after 1 week of ECMO support.
Conclusion
Oxygenation support through vvECMO may lead to a partial recovery of adrenal function over time. In homogenous patient collectives, this novel approach might help to further determine the importance of adrenal stress response in ECMO and the influence of oxygenation support on CIRCI.
... Critical illness-related corticosteroid insufficiency (CIRCI) refers to the development of central adrenal insufficiency in long-term critically ill patients [1]. The prevalence of this condition exhibits variation based on the extent and length of its manifestation. ...
... The incidence of adrenal insufficiency in critically ill patients is anticipated to range from 0% to 30%, while in patients with septic shock, it may vary from 25% to 40% [2]. CIRCI is associated with increased levels of circulating biomarkers related to inflammation and coagulation 1 1 1 1 1 across various aspects, including disease severity, morbidity, length of stay in the intensive care unit, and mortality [3]. The condition known as CIRCI is a complex and commonly observed phenomenon, and our comprehension of it continues to evolve [4]. ...
... The questionnaire tool for this study was constructed based on a previous literature review [1,3]. The questionnaire tool collected data on participants' demographic and practice characteristics such as age, gender, nationality, specialty, level of experience, years of experience, region of practice, and place of practice (see Appendices). ...
Background
The presence of critical illness-induced corticosteroid insufficiency (CIRCI) is correlated with elevated concentrations of circulating biomarkers associated with inflammation and coagulation in multiple domains. The management of adrenal insufficiency remains a topic of ongoing debate and disagreement among endocrinologists and intensivists. This study aimed to assess the extent of understanding regarding CIRCI among endocrinologists and intensivists who are actively practicing in Saudi Arabia.
Methods
This is an online cross-sectional survey study that was conducted between June and August 2023 to assess knowledge of CIRCI among endocrinologists and intensivists working in Saudi Arabia. The questionnaire tool for this study was constructed based on a previous literature review. Binary logistic regression analysis was used to define factors that affect participants’ knowledge of CIRCI.
Results
A total of 76 physicians were involved in this study. Around 32.9% (n= 25) of the participants described CIRCI correctly as an impairment of the hypothalamic-pituitary axis during critical illness. Around 35.5% (n=27) of the participants identified that widespread use of corticosteroids in critically ill patients prompted the need to revisit the concept, diagnosis, and management of CIRCI, and a similar proportion of the participants (35.5%) (n=27) identified that the role of corticosteroids in the management of CIRCI in critically ill patients may be beneficial in selected cases. Around 42.1% (n=32) of the participants identified that CIRCI is specific to critically ill patients while AI can occur in any individual. Around 17.1% (n=13) of the participants confirmed that there is no task force agreement on whether corticosteroids should be used in adult patients with sepsis but without shock. The mean knowledge score of the study participants was 3.6 (sd: 2.2) out of 10, which demonstrates a weak level of knowledge of CIRCI (36.0%). Binary logistic regression analysis identified that physicians from the southern and western regions were less likely to be knowledgeable of CIRCI compared to physicians from the central region (p< 0.05).
Conclusion
The study revealed that the level of familiarity with CIRCI among endocrinologists and intensivists in Saudi Arabia fell short of the desired benchmark. Clinicians may opt to utilize delta cortisol levels following cosyntropin administration and random plasma cortisol levels as diagnostic measures for CIRCI, instead of relying on plasma-free cortisol or salivary cortisol levels in conjunction with plasma total cortisol. Adherence to customized treatment protocols is crucial to attain the most favorable results for patients.
... Of course, these alternative interventions may also have off-target effects; thus, RCTs would require appropriate efficacy as well as safety endpoints (21,83). While awaiting the evidence from future RCTs, caution must be taken not to neglect individual patient needs for treatment whenever central adrenal insufficiency is suspected (44,69). ...
... The proposed revised concept of the HPA axis response to critical illness is far from final or complete as many aspects regarding underlying mechanisms and clinical implications remain unknown. For example, the complex and time-variable alterations within the HPA axis add substantial difficulty to the diagnosis of both primary and central adrenal insufficiency in the ICU and tests used in the outpatient setting are not valid in this setting (44,59,69). It is clear that more in-depth basic research in clinically relevant models and more clinical trials are needed to provide the evidence that then can form the basis for updated clinical practice guidelines. ...
Based on insights obtained during the last decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical (HPA) axis in response to critical illness is in need of revision. After a brief central HPA axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally-activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11βHSD1, GRα and FKBP51 that appear to titrate increased GRα-action in vital organs and tissues while reducing GRα-action in neutrophils possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of POMC into ACTH, thereby reducing ACTH-driven cortisol secretion, while ongoing central activation results in increased circulating POMC. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative", as opposed to "absolute", adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. They also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.
... Surviving critical illness depends on maintaining adequate adrenocortical function, which is typically reflected in elevated plasma cortisol levels among most critically ill patients. However, the increased systemic cortisol availability observed in critical illness is not solely attributable to a centrally activated HPA axis but rather to peripheral adaptations [24]. These adaptations include the release of circulating cortisol from plasma binding proteins, such as transcortin (CBG) and albumin, resulting in an increase in the free and active form of cortisol. ...
Sepsis is associated with dysregulated cortisol secretion, leading to abnormal levels of cortisol in the blood. In the early stages of the condition, cortisol levels are typically elevated due to increased secretion from the adrenal glands. However, as the disease progresses, cortisol levels may decline due to impaired adrenal function, leading to relative adrenal insufficiency. The latter is thought to be caused by a combination of factors, including impaired adrenal function, decreased production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and pituitary gland, and increased breakdown of cortisol. The dysregulation of cortisol secretion in sepsis is thought to contribute to the pathophysiology of the disease by impairing the body’s ability to mount an appropriate inflammatory response. Given the dysregulation of cortisol secretion and corticosteroid receptors in sepsis, there has been considerable interest in the use of steroids as a treatment. However, clinical trials have yielded mixed results and corticosteroid use in sepsis remains controversial. In this review, we will discuss the changes in cortisol secretion and corticosteroid receptors in critically ill patients with sepsis/septic shock. We will also make special note of COVID-19 patients, who presented a recent challenge for ICU management, and explore the scope for corticosteroid administration in both COVID-19 and non-COVID-19 septic patients.
... The body's functioning in constant readiness to defend itself against stress leads to depletion of its resources. This condition weakens the immune system and contributes 80-90% to the development of disease [1][2][3][4][5][6][7]. ...
Coping with a chronic disease such as rheumatoid arthritis (RA) involves significant changes in life and promotes stressful situations. The inability to cope with stress can contribute to the lack of effectiveness of therapy. The aim of this study was to evaluate the relationship between perceived stress, coping strategies, and the clinical status of RA patients determined by C-reactive protein (CRP) and Disease Activity Score (DAS28). 165 subjects were studied, 84 of them had RA and the rest were controls. Standardised questionnaires were used: the Inventory for the Measurement of Coping Strategies (Mini-COPE) and the Perceived Stress Scale (PSS-10). A self-administered questionnaire was used to collect sociodemographic data. The blood levels of protein CRP and cortisol were determined. DAS28 was obtained from medical records. The study was cross-sectional. The mean severity of perceived stress PSS-10 was not significantly different between the control and study groups. RA patients most often used coping strategies such as active coping, planning, and acceptance. Compared to the control group, they used the strategy of turning to religion significantly more often (1.8 vs 1.4; p = 0.012). Women with RA who had higher cortisol levels were more likely to use positive reevaluation, seeking emotional support and instrumental support, as well as the denial strategy. In men with RA, high stress was associated with twice as high CRP levels compared to patients with low stress ( p = 0.038). As the levels of CRP protein levels ( p = 0.009) and the DAS28 index ( p = 0.005) increased, patients were more likely to use a denial strategy.
... Regardless of the cause of AI, a prompt and timely clinical diagnosis is crucial for the optimal management of patients as the delay can lead to adrenal crisis during periods of stress, a condition associated with high morbidity and mortality [3][4][5][6]. Moreover, though classical cases of primary AI may not pose much diagnostic challenges to physicians and laboratory scientists, some patients with AI can present with atypical symptoms and signs and cause a dilemma in clinical and laboratory evaluation. ...
The diagnosis of adrenal insufficiency (AI) requires a high index of suspicion, detailed clinical assessment including detailed drug history, and appropriate laboratory evaluation. The clinical characteristics of adrenal insufficiency vary according to the cause, and the presentation may be myriad, e.g. insidious onset to a catastrophic adrenal crisis presenting with circulatory shock and coma. Secondary adrenal insufficiency (SAI) often presents with only glucocorticoid deficiency because aldosterone production, which is controlled by the renin angiotensin system, is usually intact, and rarely presents with an adrenal crisis. Measurements of the basal serum cortisol at 8 am (<140 nmol/L or 5 mcg/dL) coupled with adrenocorticotrophin (ACTH) remain the initial tests of choice. The cosyntropin stimulation (short synacthen) test is used for the confirmation of the diagnosis. Newer highly specific cortisol assays have reduced the cut-off points for cortisol in the diagnosis of AI. The salivary cortisol test is increasingly being used in conditions associated with abnormal cortisol binding globulin (CBG) levels such as pregnancy. Children and infants require lower doses of cosyntropin for testing. 21-hydoxylase antibodies are routinely evaluated to rule out autoimmunity, the absence of which would require secondary causes of adrenal insufficiency to be ruled out. Testing the hypothalamic–pituitary–adrenal (HPA) axis, imaging, and ruling out systemic causes are necessary for the diagnosis of AI. Cancer treatment with immune checkpoint inhibitors (ICI) is an emerging cause of both primary AI and SAI and requires close follow up. Several antibodies are being implicated, but more clarity is required. We update the diagnostic evaluation of AI in this evidence-based review.
