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Cited by 123Adrenal Hormones and DisordersStress Responses and CortisolElectrolyte and hormonal disorders

Adrenal crisis: prevention and management in adult patients

Open access
Dineen, Rosemary, Thompson, Christopher J, Sherlock, Mark·2019·Therapeutic Advances in Endocrinology and Metabolism
DOI 10.1177/2042018819848218PMC PMC6566489
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Abstract

Adrenal crisis is an acute life-threatening emergency contributing to the excess mortality that is reported in patients with adrenal insufficiency. The incidence of adrenal crisis is estimated to be 8 per 100 patient years in patients with adrenal insufficiency. Patients with adrenal crisis present systemically unwell with nonspecific signs and symptoms often leading to misdiagnosis and delayed treatment. An adrenal crisis may be the first presentation of adrenal insufficiency or can occur in patients who have been established on glucocorticoid replacement therapy. Infections are the major precipitating factor, but other causes include physical stress such as a surgical procedure or trauma, forgetting or discontinuing glucocorticoid therapy, pronounced physical activity, and psychological stress. The emergency treatment involves prompt recognition and administration of parenteral hydrocortisone, rehydration and management of electrolyte abnormalities. Prevention is centred around patient education. All patients should be educated on stress dosing and parenteral glucocorticoid administration. They should carry a steroid dependency alert card and wear a medical alert bracelet or similar identification. Despite many improvements in the management of patients with adrenal insufficiency, adrenal crisis continues to occur and represents a major source of morbidity, mortality and distress for patients. Improved patient and clinician education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are central to the management of this life-threatening event.

AI snapshot

Written from the paper’s full text.

TL;DR

Adrenal crisis is a life-threatening emergency in adults with adrenal insufficiency, with incidence around 8 per 100 patient years and substantial morbidity and mortality despite glucocorticoid replacement. This narrative review summarizes emergency treatment—prompt parenteral hydrocortisone and rehydration—and prevention through patient/clinician education, stress dosing, steroid alerts, and emergency hydrocortisone kits.

Key findings

  • Adrenal crisis incidence is estimated at 8 per 100 patient years; reported prevalence ranges from 5.2 to 8.3 per 100 patient years. In a prospective study of more than 400 patients with adrenal insufficiency, Hahner and colleagues reported 8.3 adrenal crises per 100 patient-years and a mortality rate from adrenal crisis of 0.5/100 patient years.
  • In the European Adrenal Insufficiency Registry, major causes of death were cardiovascular disease (35%) and infection (15%). The EU-AIRE study reported 1.5% mortality in patients with secondary adrenal insufficiency; those who died had 11.1 adrenal crisis per 100 patient years and higher mean daily hydrocortisone doses (24.0 ± 7.6 versus 19.3 ± 5.7 mg, p = 0.002).
  • Common precipitants include gastroenteritis (35–45%) and fever (17–24%). In Hahner et al., emotional stress triggered 30% of adrenal crises, gastrointestinal symptoms 35%, and infections 32%; a previous adrenal crisis confers approximately threefold higher risk of further crises.
  • Emergency treatment is IV hydrocortisone 100 mg bolus followed by 200 mg/24 h or 50 mg IV/IM every 6 h, plus rapid isotonic saline (1 L in the first hour, usually 4–6 L in 24 hours). In one prospective study, 62% of patients who self-injected glucocorticoid were treated as outpatients versus 27% who received parenteral glucocorticoid from a medical professional (p = 0.008); only 20 physicians (9.6%) correctly identified all situations requiring hydrocortisone adjustment.

Methods

  • Narrative review focused on prevention and management of adrenal crisis in adult patients; no primary data collection is described.
  • Synthesizes cited literature including registry data (European Adrenal Insufficiency Registry, EU-AIRE), prospective and retrospective studies, guidelines, and consensus statements.
  • Main analysis is narrative synthesis; no systematic search strategy or meta-analysis is described in the paper.

Limitations

  • The paper does not include a formal limitations section (not stated in the paper).
  • Stated: there is no universally accepted definition of adrenal crisis, and differing definitions among expert clinicians and research studies complicate reported prevalence estimates.
  • Stated: no randomized controlled studies have evaluated the hydrocortisone dose for increased requirements, no education program has yet demonstrated a consequent decrease in incidence or severity of adrenal crises, and the pathophysiology of adrenal crisis is not fully understood. Evident from the text: as a narrative review, it does not provide a systematic search or quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1177/2042018819848218

Cites

71 of 71 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 84 cited sources checked · 20 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    A continuous infusion of hydrocortisone produces a steady-state insert of cortisol concentration.

    “A continuous infusion of hydrocortisone, produces a steady-state insert of cortisol concentration.53”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Gagliardi L Nenke MA Thynne TR et al Continuous subcutaneous hydrocortisone infusion therapy in Addison’s disease: a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab 2014; 99: 4149– 4157. 25127090 source

      The Interventions section describes changing basal infusion rates and additional hydrocortisone boluses, rather than a regimen intended to maintain a steady cortisol concentration. The Pilot study reports cortisol peaks about 40 minutes after boluses, contrary to the claimed steady state. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    An adrenal crisis may occur in the setting of an acute insult to the adrenal or pituitary gland such as an infarction or haemorrhage.

    “An adrenal crisis may occur in the setting of an acute insult to the adrenal or pituitary gland such as an infarction or haemorrhage.33–35”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [33] McGowan-Smyth S. Bilateral adrenal haemorrhage leading to adrenal crisis. BMJ Case Rep 2014; 2014 DOI: 10.1136/bcr-2014-204225. PMC4078423 24969071 source

      The Summary reports adrenal crisis following bilateral adrenal haemorrhage, and the Discussion states that patients with adrenal insufficiency after adrenal haemorrhage are at risk of crisis. The paper does not address pituitary insults or infarction, so it supports only the adrenal-haemorrhage example. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [34] Sahin M Oguz A Tuzun D et al Primary adrenal failure due to antiphospholipid syndrome. Case Rep Endocrinol 2015; 2015: 161497. PMC4637077 26583075 source

      The Case section reports an acute adrenal crisis, and the Discussion says adrenal failure in antiphospholipid syndrome is probably related to hemorrhagic infarction or necrosis. The paper does not address pituitary infarction or hemorrhage as a cause of adrenal crisis, and it presents the adrenal mechanism as probable rather than demonstrated in this patient. Page numbers are not supplied in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [35] Ham PB Cunningham AJ Mentzer CJ et al Traumatic panhypopituitarism resulting in acute adrenal crisis. J Trauma Acute Care Surg 2015; 79: 484– 489. 26307884 source
  • Premisecitation

    In patients with hypopituitarism, growth hormone replacement therapy can also unmask adrenal insufficiency.

    “In patients with hypopituitarism, growth hormone replacement therapy can also unmask AI.42”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] Agha A Monson JP. Modulation of glucocorticoid metabolism by the growth hormone - IGF-1 axis. Clin Endocrinol (Oxf) 2007; 66: 459– 465. 17371460 source
  • Premisecitation

    A recent systematic review of more than 2900 patients undergoing surgery revealed that the perioperative cortisol response is influenced by patient-specific factors in addition to the type of surgery performed.

    “A recent systematic review of more than 2900 patients undergoing surgery revealed that the perioperative cortisol response is influenced by patient specific factors in addition to the type of surgery performed.31”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Prete A Yan Q Al-Tarrah K et al The cortisol stress response induced by surgery: a systematic review and meta-analysis. Clin Endocrinol (Oxf) 2018; 89: 554– 567. 30047158 source
  • Premisecitation

    Unmasking of secondary adrenal insufficiency may occur in patients who are abruptly withdrawn from supraphysiologic doses of glucocorticoid, including oral and inhaled steroids.

    “Unmasking of SAI may occur in patients who are abruptly withdrawn from supraphysiologic doses of glucocorticoid, which includes not only oral but also inhaled steroids.36”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Todd GR Acerini CL Ross-Russell R et al Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002; 87: 457– 461. 12456538 PMC1755820 source
  • Classified as probably not a substantial claim. 29
  • May combine two claims. 32

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Primary adrenal insufficiency is caused by impairment of function of the adrenal gland itself, most commonly caused by autoimmune-mediated adrenalitis, infection or inborn disruption of adrenal cortisol production in congenital adrenal hyperplasia.

    “Primary adrenal insufficiency (PAI) is caused by impairment of function of the adrenal gland itself, most commonly caused by autoimmune-mediated adrenalitis, infection or due to inborn disruption of adrenal cortisol production in congenital adrenal hyperplasia.3”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] Bancos I Hahner S Tomlinson J et al Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015; 3: 216– 226. 25098712 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent data from the European Adrenal Insufficiency Registry found the major causes of death in patients with adrenal insufficiency were cardiovascular disease (35%) and infection (15%).

    “Recent data from the European Adrenal Insufficiency Registry8 (including both PAI and SAI patients) found the major causes of death in patients with AI were cardiovascular disease (35%) and infection (15%), supporting previous registry data for patients with PAI.9,10”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [8] Quinkler M Ekman B Zhang P et al Mortality data from the European Adrenal Insufficiency Registry-Patient characterization and associations. Clin Endocrinol (Oxf) 2018; 89: 30– 35. 29682773 source
    • cites [9] Bergthorsdottir R Leonsson-Zachrisson M Oden A et al Premature mortality in patients with Addison’s disease: a population-based study. J Clin Endocrinol Metab 2006; 91: 4849– 4853. 16968806 source
    • cites [10] Erichsen MM Lovas K Fougner KJ et al Normal overall mortality rate in Addison’s disease, but young patients are at risk of premature death. Eur J Endocrinol 2009; 160: 233– 237. 19011006 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The incidence of adrenal crisis appears to increase with age, with one study reporting a rate of 24.3 admissions per million per year in patients aged 60-69 years.

    “The incidence of adrenal crisis appears to increase with age with one study reporting a rate of 24.3 admissions per million per year in patients aged 60–69 years.16”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Rushworth RL Torpy DJ. A descriptive study of adrenal crises in adults with adrenal insufficiency: increased risk with age and in those with bacterial infections. BMC Endocr Disord 2014; 14: 79. 25273066 PMC4200115 source

  • May combine two claims.

    Premisecitation

    An adrenal crisis can occur in the setting of bilateral adrenal metastasis and secondary to immunomodulator anticancer agents.

    “An adrenal crisis can occur in the setting of bilateral adrenal metastasis37,38 and secondary to immunomodulator anticancer agents.39”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [37] Iqbal MS Hardman J. Addisonian crisis secondary to bilateral adrenal metastases in rectal carcinoma: report of a rare case and literature review. J Gastrointest Cancer 2013; 44: 225– 227. 22890387 source
    • cites [38] Akcay MN Tekin SB Akcay G. Addisonian crisis due to adrenal gland metastasis in Hodgkin’s disease. Int J Clin Pract 2003; 57: 840– 841. 14686577 source
    • cites [39] Trainer H Hulse P Higham CE et al Hyponatraemia secondary to nivolumab-induced primary adrenal failure. Endocrinol Diabetes Metab Case Rep 2016; 2016: 16- 0108. PMC5097140 27857838 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Expert consensus statements and guidelines exist on the management of adrenal insufficiency and emphasis is placed on the importance of prompt initiation of treatment in patients with suspected adrenal crisis.

    “Expert consensus statements and guidelines exist on the management of AI and above all, emphasis is placed on the importance of prompt initiation of treatment in patients with suspected adrenal crisis.18,51,52”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [18] Bornstein SR Allolio B Arlt W et al Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101: 364– 389. 26760044 PMC4880116 source
    • cites [51] Arlt W and Society for Endocrinology Clinical Committee. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocr Connect 2016; 5: G1– G3. 27935813 PMC5314805 source
    • cites [52] Higham CE Olsson-Brown A Carroll P et al SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: acute management of the endocrine complications of checkpoint inhibitor therapy. Endocr Connect 2018; 7: G1– G7. 29930025 PMC6013692 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Addison's disease-specific quality of life questionnaire (AddiQoL) was established by the European consortium EURADRENAL to assess health-related QoL in patients with PAI.

    “The Addison’s disease-specific quality of life questionnaire (AddiQoL) was established by the European consortium EURADRENAL to assess health-related QoL in patients with PAI.70”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [70] Oksnes M Bensing S Hulting AL et al Quality of life in European patients with Addison’s disease: validity of the disease-specific questionnaire AddiQoL. J Clin Endocrinol Metab 2012; 97: 568– 576. 22090270 source

      The Questionnaires section describes AddiQoL as a disease-specific measure of health-related quality of life in Addison’s disease, and the Discussion reports that this study validated a revised 30-item version. The Funding section identifies Euradrenal as a supporter of this work, but the paper says the original questionnaire had already been developed; it does not establish that EURADRENAL created it. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Therapeutic patient education is recommended by two international consensus statements on the management of PAI.

    “Therapeutic patient education is recommended by two international consensus statements on the management of PAI.18,64”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [18] Bornstein SR Allolio B Arlt W et al Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101: 364– 389. 26760044 PMC4880116 source
    • cites [64] Husebye ES Allolio B Arlt W et al Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med 2014; 275: 104– 115. 24330030 source

  • May combine two claims.

    Premisecitation

    Patients with adrenal crisis respond well to the recommended therapy, with low mortality rates in hospitalized patients.

    “patients respond well to the recommended therapy, with low mortality rates in hospitalized patients.16”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Rushworth RL Torpy DJ. A descriptive study of adrenal crises in adults with adrenal insufficiency: increased risk with age and in those with bacterial infections. BMC Endocr Disord 2014; 14: 79. 25273066 PMC4200115 source

      The Results report 4 deaths among 467 hospitalized patients whose principal diagnosis was adrenal crisis (0.9%), supporting the low-mortality claim for that group. The Discussion describes recommended hydrocortisone treatment, but the study does not report patients’ responses to that treatment or establish that it caused the low mortality. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Guidelines recommend that all patients should carry steroid emergency cards.

    “Guidelines recommend that all patients should carry steroid emergency cards.18,51”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [18] Bornstein SR Allolio B Arlt W et al Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101: 364– 389. 26760044 PMC4880116 source
    • cites [51] Arlt W and Society for Endocrinology Clinical Committee. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocr Connect 2016; 5: G1– G3. 27935813 PMC5314805 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One study of adrenal crisis admissions reported that 66.9% of adrenal crisis patients (n = 337) had visited the hospital within 90 days before the onset of the crisis.

    “One study of adrenal crisis admissions reported that 66.9% of adrenal crisis patients (n = 337) had visited the hospital within 90 days before the onset of the crisis.48”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Iwasaku M Shinzawa M Tanaka S et al Clinical characteristics of adrenal crisis in adult population with and without predisposing chronic adrenal insufficiency: a retrospective cohort study. BMC Endocr Disord 2017; 17: 58. 28893233 PMC5594557 source

  • May combine two claims.

    Premisenone given

    Adrenal crisis is an acute life-threatening emergency that contributes to excess mortality in patients with adrenal insufficiency.

    “Adrenal crisis is an acute life-threatening emergency contributing to the excess mortality that is reported in patients with adrenal insufficiency.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Chronic exogenous glucocorticoid treatment can impair pituitary regulation of cortisol production, often termed tertiary adrenal insufficiency.

    “However, chronic exogenous glucocorticoid treatment can also impair pituitary regulation of cortisol production, often termed tertiary adrenal insufficiency (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a cross-sectional study of both primary and secondary adrenal insufficiency patients, only 50% of patients were diagnosed within the first 6 months after the onset of symptoms, with 20% of patients reporting symptoms for greater than 5 years before diagnosis.

    “In a cross-sectional study of both PAI and SAI patients, only 50% of patients were diagnosed within the first 6 months after the onset of symptoms, with 20% of patients reporting symptoms for greater than 5 years before diagnosis.13”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Bleicken B Hahner S Ventz M et al Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci 2010; 339: 525– 531. 20400889 source

  • May combine two claims.

    Premisenone given

    Many patients with primary adrenal insufficiency have negligible cortisol synthesis whereas some patients with secondary adrenal insufficiency still have some cortisol synthesis but insufficient amounts to maintain health and therefore require replacement therapy.

    “Many patients with PAI have negligible cortisol synthesis whereas some patients with SAI still have some cortisol synthesis (but insufficient amounts to maintain health and therefore require replacement therapy).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Treatment of primary adrenal insufficiency with dexamethasone alone, without concurrent fludrocortisone, can trigger an adrenal crisis as dexamethasone has no mineralocorticoid activity.

    “Treatment of PAI with dexamethasone alone, without concurrent fludrocortisone, can also trigger an adrenal crisis as dexamethasone has no mineralocorti-coid activity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    An adrenal crisis may be the first presentation of adrenal insufficiency or can occur in patients who have been established on glucocorticoid replacement therapy.

    “An adrenal crisis may be the first presentation of adrenal insufficiency or can occur in patients who have been established on glucocorticoid replacement therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Critically ill patients have paradoxically low ACTH levels and exhibit impaired cortisol clearance, which contributes to the observed hypercortisolism.

    “Elevated cortisol concentrations in acute stress have traditionally been attributed to stress-induced activation of the HPA axis with ACTH-driven cortisol secretion, however studies have shown that critically ill patients have paradoxically low ACTH levels and exhibit impaired cortisol clearance which contributes to the observed hypercortisolism.24”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Van den Berghe G Boonen E Walker BR Reduced cortisol metabolism during critical illness. N Engl J Med 2013; 369: 481. 23902491 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The incidence of adrenal crisis is estimated to be 8 per 100 patient years in patients with adrenal insufficiency.

    “The incidence of adrenal crisis is estimated to be 8 per 100 patient years in patients with adrenal insufficiency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The higher hydrocortisone doses in patients with secondary adrenal insufficiency who died may reflect physicians' response to repeated adrenal crises, with increased doses of glucocorticoid therapy in an attempt to prevent recurrence of adrenal crisis.

    “In addition, patients with SAI who died were on higher mean daily doses of hydrocortisone (24.0 ± 7.6 versus 19.3 ± 5.7 mg, p = 0.002), which may reflect the physicians response to repeated adrenal crises, with increased doses of glucocorticoid therapy in an attempt to prevent recurrence of adrenal crisis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a prospective study of more than 400 patients with adrenal insufficiency, Hahner and colleagues reported 8.3 adrenal crises per 100 patient-years, with a mortality rate from adrenal crisis of 0.5/100 patient years.

    “In a prospective study of more than 400 patients with AI, Hahner and colleagues reported 8.3 adrenal crises per 100 patient-years, with a mortality rate from adrenal crisis of 0.5/100 patient years.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Hahner S Spinnler C Fassnacht M et al High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab 2015; 100: 407– 416. 25419882 source

  • May combine two claims.

    Premisecitation

    In a large Norwegian study, approximately 40% of patients with Addison's disease had a delay in diagnosis of greater than 6 months from the onset of their symptoms, with 64% of the patients diagnosed only after an acute hospital admission.

    “Similarly, in a large Norwegian study, approximately 40% of patients with Addison’s disease had a delay in diagnosis of greater than 6 months from the onset of their symptoms, with 64% of the patients diagnosed only after an acute hospital admission.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Erichsen MM Lovas K Skinningsrud B et al Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab 2009; 94: 4882– 4890. 19858318 source

  • May combine two claims.

    Premisecitation

    In patients with secondary adrenal insufficiency who died, 11.1 adrenal crisis per 100 patient years were reported, significantly higher than has been reported in other cohorts of patients with secondary adrenal insufficiency.

    “In those patients with SAI who died, 11.1 adrenal crisis per 100 patient years were reported, significantly higher than that has been reported in other cohorts of patients with SAI.11,12”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Hahner S Loeffler M Bleicken B et al Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol 2010; 162: 597– 602. 19955259 source
    • cites [12] Smans LC Van der Valk ES Hermus AR et al Incidence of adrenal crisis in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2016; 84: 17– 22. 26208266 source

  • May combine two claims.

    Premisecitation

    In retrospective and prospective studies the most frequent precipitating causes of adrenal crisis are gastroenteritis (35-45%) and fever (17-24%), but other stressful events such as trauma, surgery, dental procedures and major psychological distress can cause adrenal crisis.

    “In retrospective and prospective studies the most frequent precipitating causes of adrenal crisis are gastroenteritis (35–45%) and fever (17–24%),15,17,43 but other stressful events such as trauma,35 surgery,44 dental procedures45 and major psychological distress46 can cause adrenal crisis.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [15] Hahner S Spinnler C Fassnacht M et al High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab 2015; 100: 407– 416. 25419882 source
    • cites [17] White K Arlt W. Adrenal crisis in treated Addison’s disease: a predictable but under-managed event. Eur J Endocrinol 2010; 162: 115– 120. 19776201 source
    • cites [43] Reisch N Willige M Kohn D et al Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency. Eur J Endocrinol 2012; 167: 35– 42. 22513882 source
    • cites [35] Ham PB Cunningham AJ Mentzer CJ et al Traumatic panhypopituitarism resulting in acute adrenal crisis. J Trauma Acute Care Surg 2015; 79: 484– 489. 26307884 source
    • cites [44] Hernandez Padilla P [Adrenal crisis in the surgical patient]. Cir Cir 1962; 30: 123– 141. 13906750
    • cites [45] Cawson RA James J. Adrenal crisis in a dental patient having systemic corticosteroids. Br J Oral Surg 1973; 10: 305– 309. 4516115 source
    • cites [46] Thomsen AF Kvist TK Andersen PK et al The risk of affective disorders in patients with adrenocortical insufficiency. Psychoneuroendocrinology 2006; 31: 614– 622. 16545526 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Secondary adrenal insufficiency is caused by disruption of the hypothalamic-pituitary-adrenal axis with insufficient stimulation of the adrenal gland due to inadequate secretion or synthesis of ACTH.

    “Secondary adrenal insufficiency (SAI) is caused by disruption of the hypothalamic-pituitary-adrenal axis with insufficient stimulation of the adrenal gland due to inadequate secretion or synthesis of ACTH.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Grossman AB. Clinical Review#: the diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab 2010; 95: 4855– 4863. 20719838 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Available literature reports a prevalence of adrenal crisis ranging from 5.2 to 8.3 per 100 patient years.

    “Available literature reports a prevalence of adrenal crisis ranging from 5.2 to 8.3 per 100 patient years.12,15”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Smans LC Van der Valk ES Hermus AR et al Incidence of adrenal crisis in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2016; 84: 17– 22. 26208266 source
    • cites [15] Hahner S Spinnler C Fassnacht M et al High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab 2015; 100: 407– 416. 25419882 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Conventional treatment of adrenal insufficiency involves lifelong glucocorticoid replacement therapy.

    “Conventional treatment of adrenal insufficiency (AI) involves lifelong glucocorticoid replacement therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Even in patients with treated adrenal insufficiency, there continues to be significant morbidity and reduced life expectancy.

    “It has become increasingly evident that, even in patients with treated AI, there continues to be significant morbidity and reduced life expectancy.5–7”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Sherlock M Ayuk J Tomlinson JW et al Mortality in patients with pituitary disease. Endocr Rev 2010; 31: 301– 342. 20086217 source
    • cites [6] Sherlock M Reulen RC Alonso AA et al ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly. J Clin Endocrinol Metab 2009; 94: 4216– 4223. 19808848 source
    • cites [7] Johannsson G Skrtic S Lennernas H et al Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments. Curr Med Res Opin 2014; 30: 1833– 1847. 24849526 source

  • May combine two claims.

    Premisenone given

    Increased cortisol secretion exercises an anti-inflammatory effect by reducing leukocytic responses and blocking cytokine production.

    “The increased cortisol secretion subsequently exercises an anti-inflammatory effect by reducing leukocytic responses, and blocking cytokine production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    In primary adrenal insufficiency, all steroid hormones synthesised by the adrenal gland are deficient (aldosterone, cortisol and sex steroids), whereas in secondary adrenal insufficiency only hormones predominantly controlled by ACTH (cortisol and sex steroids) are deficient, and aldosterone replacement is not required.

    “In PAI, all steroid hormones synthesised by the adrenal gland are deficient (aldosterone, cortisol and sex steroids) whereas in SAI only hormones that are predominantly controlled by ACTH (cortisol and sex steroids) are deficient, however, aldosterone replacement is not required as it is controlled by the renin–angiotensin–aldosterone system.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    An adrenal crisis may occur in patients with undiagnosed adrenal insufficiency or in patients with chronic adrenal insufficiency who are replaced with glucocorticoids but experience an intercurrent infection or an acute, major stress, with a discrepancy between their glucocorticoid dose and their increased glucocorticoid requirements.

    “It may be the primary presentation in patients with undiagnosed AI or in patients with chronic AI, who are replaced with glucocorticoids, but experience an intercurrent infection or an acute, major stress, and there is a discrepancy in their glucocorticoid dose and their increased glucocorticoid requirements during these events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Primary adrenal insufficiency patients are often at a higher risk of adrenal crisis compared with patients with secondary adrenal insufficiency and may develop more severe adrenal crisis.

    “As PAI patients are also deficient in mineralocorticoids, which are key regulators of blood pressure and electrolyte balance, PAI patients are often at a higher risk of adrenal crisis compared with patients with SAI and may develop more severe adrenal crisis.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Burger-Stritt S Kardonski P Pulzer A et al Management of adrenal emergencies in educated patients with adrenal insufficiency-A prospective study. Clin Endocrinol (Oxf) 2018; 89: 22– 29. 29617051 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A postal survey of over 1000 patients with primary adrenal insufficiency from four countries reported an 8% annual frequency of adrenal crisis.

    “A postal survey of over 1000 patients with PAI from four countries reported an 8% annual frequency of adrenal crisis.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] White K Arlt W. Adrenal crisis in treated Addison’s disease: a predictable but under-managed event. Eur J Endocrinol 2010; 162: 115– 120. 19776201 source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Patients with adrenal crisis present systemically unwell with nonspecific signs and symptoms, often leading to misdiagnosis and delayed treatment.

    “Patients with adrenal crisis present systemically unwell with nonspecific signs and symptoms often leading to misdiagnosis and delayed treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Infections are the major precipitating factor for adrenal crisis, but other causes include physical stress such as a surgical procedure or trauma, forgetting or discontinuing glucocorticoid therapy, pronounced physical activity, and psychological stress.

    “Infections are the major precipitating factor, but other causes include physical stress such as a surgical procedure or trauma, forgetting or discontinuing glucocorticoid therapy, pronounced physical activity, and psychological stress.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The range in prevalence of adrenal crisis reported in the literature is attributed not only to the heterogeneous nature of the populations studied, but also complicated by the lack of a universally accepted definition of an adrenal crisis.

    “The range in prevalence of adrenal crisis reported in the literature is attributed not only to the heterogenous nature of the populations studied, but also complicated by the lack of a universally accepted definition of an adrenal crisis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Adrenal crisis can be reliably identified in clinical practice and research despite the lack of a universally accepted definition.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The pathophysiology of adrenal crisis formation is not fully understood.

    “The pathophysiology of adrenal crisis formation is not fully understood.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Despite improvements in the management of patients with adrenal insufficiency, adrenal crisis continues to occur and represents a major source of morbidity, mortality and distress for patients.

    “Despite many improvements in the management of patients with adrenal insufficiency, adrenal crisis continues to occur and represents a major source of morbidity, mortality and distress for patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Deficiency of the steroid hormones synthesized and secreted by the adrenal gland is associated with significant morbidity and mortality.

    “Deficiency of the steroid hormones synthesized and secreted by the adrenal gland is associated with significant morbidity and mortality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A history of a previous adrenal crisis is the most important risk factor for further crises, with approximately threefold higher risk observed in the prospective study by Hahner et al.

    “A history of a previous adrenal crisis is the most important risk factor for further crises, with approximately threefold higher risk observed in the prospective study by Hahner et al.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Hahner S Spinnler C Fassnacht M et al High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab 2015; 100: 407– 416. 25419882 source

  • May combine two claims.

    Interpretationcitation

    The ability for psychological stress to trigger an adrenal crisis is under-recognized and patients are often advised that this does not lead to adrenal crisis, which based on the above data is incorrect.

    “The ability for psychological stress to trigger an adrenal crisis is under recognized and patients are often advised that this does not lead to adrenal crisis, which based on the above data is incorrect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Addison's Clinical Advisory Panel (ACAP) gives specific guidance to the ADSHG and physicians on glucocorticoid requirements and recommendations for adjustment for surgical procedures.

    “The Addison’s Clinical Advisory Panel (ACAP), a group of UK Endocrinologists who specialise in adrenal disease, give specific guidance to the ADSHG and physicians on glucocorticoid requirements and recommendations for adjustment for surgical procedures.57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Addison’s Disease Self Help Group. ADSHG surgical guidelines, https://www.addisons.org.uk/files/file/4-adshg-surgical-guidelines/ (2015, accessed 14 September 2017).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Improved education of physicians is a key target to reduce death from adrenal crisis in patients with known or suspected AI.

    “It is clear that improved education of physicians is a key target to reduce death from adrenal crisis in patients with known or suspected AI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In their prospective study of primary adrenal insufficiency patients, Hahner et al. found that emotional stress was identified as a triggering factor in 30% of adrenal crisis, as frequently as gastrointestinal symptoms or infections (35% and 32%, respectively).

    “In their prospective study of PAI patients, Hahner et al. found that emotional stress was identified as a triggering factor in 30% of adrenal crisis, as frequently as gastrointestinal symptoms or infections (35% and 32%, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The cortisol level achieved by 50 mg IV hydrocortisone is greater than that reported in septic shock (mean, 880 nmol/l) or following major surgery such as coronary artery bypass surgery (median, 744 nmol/l).

    “This level is greater than that reported in septic shock (mean, 880 nmol/l)55 or following major surgery such as coronary artery bypass surgery (median, 744 nmol/l).56”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Ho JT Al-Musalhi H Chapman MJ et al Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab 2006; 91: 105– 114. 16263835 source
    • cites [56] Widmer IE Puder JJ Konig C et al Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metab 2005; 90: 4579– 4586. 15886236 source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Self-evaluation by regular identification of health-related QoL via patient diaries or mobile applications may provide a tool to help guide patients to assess their risk of adrenal crisis and prompt physicians to alert patients who report fatigue with their replacement to the warning signs of impending crisis.

    “Self-evaluation by regular identification of health-related QoL via patient diaries or mobile applications may provide a tool to help guide patients to assess their risk of adrenal crisis and indeed prompt physicians to alert patients who report fatigue with their replacement, to the warning signs of impending crisis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    In a patient with primary adrenal insufficiency, hydrocortisone doses of >50 mg/day have sufficient action at the mineralocorticoid receptor, therefore additional mineralocorticoid therapy is not required at this point.

    “In a patient with PAI, hydrocortisone doses of >50 mg/day have sufficient action at the mineralocorticoid receptor, therefore additional mineralocorticoid therapy is not required at this point.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The predominant clinical features of adrenal crisis include hypotension and hypovolaemia (in patients with primary adrenal insufficiency due to concomitant mineralocorticoid deficiency), but patients often have nonspecific symptoms such as anorexia, nausea, vomiting, abdominal pain, fatigue, lethargy, fever or altered consciousness.

    “The predominant clinical features of adrenal crisis include hypotension and hypovolaemia (in patients with PAI due to concomitant mineralocorticoid deficiency), but patients often have nonspecific symptoms, such as anorexia, nausea, vomiting, abdominal pain, fatigue, lethargy, fever or altered consciousness (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Hypotension occurs secondary to hypovolemia, but also due to hypocortisolism; if adrenal insufficiency is not suspected, it may be refractory to parenteral fluids and inotropes.

    “Hypotension (particularly postural hypotension) occurs secondary to hypovolemia, but also due to hypocortisolism hence, if AI is not suspected, it may be refractory to parenteral fluids and inotropes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Therapeutic patient education has been shown to be effective in chronic diseases.

    “Therapeutic patient education is an element of nonpharmacological patient management and has been shown to be effective in chronic diseases.65”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Lagger G Pataky Z Golay A. Efficacy of therapeutic patient education in chronic diseases and obesity. Patient Educ Couns 2010; 79: 283– 286. 20413242 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In primary adrenal insufficiency, hyponatraemia and hyperkalaemia can occur as a consequence of mineralocorticoid deficiency.

    “In PAI, hyponatraemia and hyperkalaemia can occur as a consequence of mineralocorticoid deficiency.”
    Quote in the paperNot a substantial claim
50 of 50

  • The paper relies on this without support.

    Patient education on stress dosing and parenteral glucocorticoid administration reduces the risk of adrenal crisis or improves outcomes.

    “Prevention is centred around patient education. All patients should be educated on stress dosing and parenteral glucocorticoid administration.”

  • The paper relies on this without support.

    Adrenal crisis can be reliably identified in clinical practice and research despite the lack of a universally accepted definition.

    “The range in prevalence of adrenal crisis reported in the literature is attributed not only to the heterogenous nature of the populations studied, but also complicated by the lack of a universally accepted definition of an adrenal crisis.”

  • The paper relies on this without support.

    Patient education is the most important component in the prevention of adrenal crisis.

    “Patient education is the most important component in the prevention of adrenal crisis.”

  • The paper relies on this without support.

    There are no randomized controlled studies that have evaluated the dose to be given in cases where the requirement for hydrocortisone is increased.

    “There are no randomized controlled studies that have evaluated the dose to be given in cases where the requirement for hydrocortisone is increased.”

  • The paper relies on this without support.

    Some patients are fearful of IM injections.

    “Some patients are fearful of IM injections”

  • The paper relies on this without support.

    No program has yet been able to demonstrate whether there is a consequent decrease in the incidence or severity of adrenal crises.

    “However, no program has yet been able to demonstrate whether there is a consequent decrease in the incidence or severity of adrenal crises.”

  • The paper relies on this without support.

    Adrenal crisis remains a significant cause of death in patients with AI.

    “adrenal crisis remains a significant cause of death in patients with AI.”
7 of 7

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reference 31 is attributed to the wrong authors

    Minor

    The treatment section attributes the cited data to Bancos et al., but reference 31 lists Prete et al. as its authors.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 8

  1. Kerrigan JR, 1993, J Clin Endocrinol Metab, 76, 1505
  2. Mohler JL, 1985, Surg Gynecol Obstet, 161, 445
  3. Van den Berghe G, 2013, N Engl J Med, 369, 481
  4. Sahin M, 2015, Case Rep Endocrinol, 2015
  5. Trainer H, 2016, Endocrinol Diabetes Metab Case Rep, 2016, 16
  6. Hernandez Padilla P, 1962, Cir Cir, 30, 123
  7. Addison’s Disease Self Help Group. ADSHG surgical guidelines, https://www.addisons.org.uk/files/file/4-adshg-surgical-guidelines/ (2015, accessed 14 September 2017).
  8. Schad R, 1979, Am J Hosp Pharm, 36, 1212

Cited by

Sorted by citations

Related

Authors
Dineen, R., Thompson, C. J., & Sherlock, M.
Affiliations
Royal College of Surgeons in Ireland (IE)
Corresponding author
Sherlock, Mark
ORCID
Venue
Therapeutic Advances in Endocrinology and Metabolism
Publisher
SAGE Publications
Published
2019-01
Volume
10
Pages
2042018819848218-2042018819848218
ISSN
  • 2042-0188 (ISSN-L)
  • 2042-0196
DOI
10.1177/2042018819848218
PMC
PMC6566489
OpenAlex
W2952629000
Semantic Scholar
2158507860516f04f9e5fe3ac92562c7f51570c5
Cited by
123
References
71
Citations by year
2026: 17 · 2025: 16 · 2024: 21 · 2023: 20 · 2022: 17 · 2021: 18 · 2020: 9 · 2019: 4 · 2018: 1
FWCI
8.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Therapeutic Advances in Endocrinology and Metabolism (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Irish Research Council
  • Meath Foundation
  • Shire Ltd.
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Electrolyte and hormonal disorders
Keywords
adrenal crisis, adrenal insufficiency, cortisol, glucocorticoid replacement therapy, stress dosing, patient education, prevention, emergency management, electrolyte imbalance, misdiagnosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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