The survival of patients with acute adrenal insufficiency, also called Addisonian crisis , was prolonged after 1950 by glucocorticoid replacement therapy. However, many patients still suffer from episodes of acute adrenal insufficiency, which are life-threatening emergencies. These episodes appear to be increasing despite preventive strategies.
| Definitions of acute adrenal insufficiency |
There is no universally accepted definition of acute adrenal insufficiency. In general, acute physiological disturbances in patients known to suffer from adrenal insufficiency are called adrenal crises on the basis of clinical evaluation.
Adults Acute adrenal insufficiency in an adult is defined as an acute deterioration in health status associated with absolute hypotension (systolic pressure <100 mm Hg) or relative hypotension (systolic pressure ≥20 mm Hg lower than usual, with resolving features). within 1 to 2 hours after parenteral administration of a glucocorticoid (i.e., marked resolution of hypotension within 1 hour and improvement of symptoms within 2 hours). Children Because identifying hypotension in infants and young children during an emergency can be difficult, acute adrenal insufficiency in this age group is defined as acute deterioration in health associated with an acute hemodynamic disturbance (hypotension or sinus tachycardia in relation to clinical data). normal for age) or a significant electrolyte alteration (hyponatremia, hyperkalemia or hypoglycemia not attributable to another disease). After parenteral administration of glucocorticoids, symptoms resolve considerably. |
| Clinic |
Simultaneous signs and symptoms in patients of any age are:
- acute abdominal symptoms
- confusion, daze, or both
- hyponatremia
- hyperkalemia
- hypoglycemia
- fever
When hypotension attributed to acute adrenal insufficiency is unresponsive or poorly responsive to glucocorticoid administration, the coexistence of other diseases associated with hypotension, such as sepsis, should be considered.
Addisonian crises are the most serious manifestation of adrenal insufficiency, but share symptoms with milder states of adrenal insufficiency, such as anorexia, nausea, vomiting, fatigue, postural dizziness, abdominal pain, pain in the limbs, back pain and alteration of consciousness.
The biochemical alterations in both are hyponatremia, hyperkalemia (in primary adrenal insufficiency [Addison’s disease and congenital adrenal hyperplasia]) and hypoglycemia (more common in children than in adults).
However, acute illness in a patient previously diagnosed with primary adrenal insufficiency without evidence of hemodynamic compromise or hypotension (or in young children, delayed capillary refill or tachycardia as other physical manifestations) should be considered physiologically distinct from adrenal crisis and classify it as symptomatic adrenal insufficiency , precursor to adrenal crisis or impending adrenal crisis.
Significant symptoms in the absence of hypotension probably indicate incipient acute adrenal insufficiency. Treatment with hydrocortisone and intravenous (IV) fluids can prevent the development of a true adrenal crisis.
| Pathophysiological characteristics |
| Adrenal crises are caused by absolute or relative deficiency of cortisol , an endogenous glucocorticoid, and therefore there is insufficient tissue glucocorticoid activity to maintain homeostasis. |
Cortisol has a half-life in the circulation of 90 minutes; consequently the tissues become deficient several hours after deprivation. Cortisol has highly pleiotropic effects.
The physiological consequences of cortisol deficiency are broad and begin with the loss of the suppressive action of endogenous glucocorticoids on inflammatory cytokines , which rapidly increases cytokine concentrations. This in turn causes fever, malaise, anorexia and body pain.
Consequently, cortisol deficiency generates altered immune cell populations (neutropenia, eosinophilia, lymphocytosis); loss of the synergistic action of cortisol with catecholamines on vascular reactivity, leading to vasodilation and hypotension; hepatic effects on intermediate metabolism, with reduction of gluconeogenesis, hypoglycemia or both and reduction of free fatty acids and amino acids in the circulation.
At the cellular level, cortisol loss depresses the action of activator protein 1 (AP-1) and nuclear factor κB (NF-κB), generating free activation of genes that produce inflammatory proteins, since the normal inhibition of cortisol is lost. cortisol from NF-κB binding to the glucocorticoid receptor.
Additionally, mineralocorticoid deficiency , which is prominent in primary but not secondary adrenal insufficiency, may worsen adrenal crises through sodium and water loss and potassium retention.
| Epidemiological characteristics |
Every year 6 - 8% of patients with adrenal insufficiency suffer an adrenal crisis. These crises are uncommon in patients with adrenal insufficiency due to prolonged glucocorticoid therapy, despite a variable degree of adrenal suppression.
Susceptibility to Addisonian crises varies among patients with adrenal insufficiency. Risk factors are old age, a history of previous crises, the presence of autoimmune polyglandular syndromes, type 1 diabetes mellitus, and coexisting non-endocrine disorders, such as asthma and heart disease.
Additionally, unknown factors may increase the risk of adrenal crisis, as some patients have numerous episodes, while others have few or no episodes. The association between Addisonian crisis and the chronic asthenia characteristic of adrenal insufficiency is acceptable, but not proven. However, a recent multicenter prospective study with data from 110 patients with primary adrenal insufficiency showed a positive association between episodes of incipient adrenal crisis and poor quality of life.
It has been suggested, on the basis of epidemiological data, that increasing rates of acute adrenal insufficiency may be due to treatments with low doses of short-acting glucocorticoids (hydrocortisone or cortisone acetate) in patients with adrenal insufficiency.
| Mortality |
Addisonian crisis contributes to mortality among patients with adrenal insufficiency; the death rate can reach 6% of crisis episodes. These may contribute to increased mortality attributed to infectious diseases among patients with adrenal insufficiency.
Fatal adrenal crises have occurred in patients without a previous diagnosis of adrenal insufficiency, although symptoms may have been missed before the fatal episode.
| Events that precipitate acute adrenal crisis |
Infections frequently precipitate Addisonian crises . Gastroenteritis is also a precipitating factor and can be dangerous, as vomiting and diarrhea impair medication absorption and can also worsen dehydration . But the abdominal symptoms of adrenal crisis can lead to the misdiagnosis of gastroenteritis.
Other pathophysiological states can precipitate acute adrenal insufficiency if the body cannot increase endogenous cortisol and if the amount of replacement treatment is not increased. These disorders include serious injuries and major surgery , but also situations that are generally associated with the need for mild increases in cortisol (exercise and emotional distress) have precipitated seizures in up to 10% of episodes.
Episodes of acute adrenal insufficiency associated with the release of acute-phase cytokines and other substances have been reported following relatively minor medical procedures, such as vaccinations and zoledronic acid infusion.
Some types of immunotherapy or chemotherapy can precipitate adrenal crises. For example, immune checkpoint inhibition therapy, which is used to treat melanoma and some other malignancies, can cause adrenal insufficiency (risk <1%). If this happens, rapid replacement with glucocorticoids is necessary.
Noncompliance with glucocorticoid replacement may also precipitate acute adrenal insufficiency. Patients should be educated about the dangers of skipping or stopping doses, especially perioperatively or during long-term glucocorticoid therapy for other conditions in which the daily dose is greater than the replacement dose (3 to 5 mg prednisone). or its equivalent per day), since sudden discontinuation of glucocorticoid treatment may act as a precipitant. Likewise, abrupt cessation of treatment due to medical indication can cause acute adrenal insufficiency.
Undiagnosed coexisting thyrotoxicosis or initiation of thyroxine therapy in a patient with undiagnosed adrenal insufficiency may precipitate acute adrenal insufficiency.
Furthermore, cytochrome P-450 3A4 (CYP3A4) inducers, such as avasimibe, carbamazepine, rifampicin, diphenylhydantoin and St. John’s wort, can increase the metabolism of hydrocortisone, making it necessary to increase the dose of glucocorticoids in patients receiving treatment due to adrenal insufficiency. It can also induce an addisonian crisis in patients with undiagnosed adrenal insufficiency.
In contrast, CYP3A4 inhibitors such as voriconazole, grapefruit juice, itraconazole, ketoconazole, clarithromycin, lopinavir, nefazodone, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin and conivaptan can inhibit the metabolism of hydrocortisone, increasing cortisol values and increasing thus the adrenal suppressive effect of ongoing treatment with glucocorticoids, but the risk of acute adrenal insufficiency may increase once the drug is stopped.
| Treatment |
Treatment of acute adrenal insufficiency is effective if administered quickly, before prolonged hypotension generates irremediable effects.
It consists of the prompt administration of IV hydrocortisone , in a bolus of 100 mg, followed by 200 mg every 24 hours, administered as a continuous infusion or as IV or intramuscular boluses (50 mg every 6 hours, with subsequent doses adapted to the clinical response of the patient). patient).
If hydrocortisone is not available, another parenteral glucocorticoid can be used, such as dexamethasone (4 mg every 24 hours), methylprednisolone (40 mg every 24 hours), prednisolone (25 mg as a bolus, followed by two doses of 25 mg, for a total of 75 mg in the first 24 hours; thereafter, 50 mg every 24 hours).
In children , hydrocortisone should be administered as a parenteral bolus of 50 mg per m2 of body surface area, followed by 50 to 100 mg per m2 every 24 hours (as a continuous IV infusion or as IV or intramuscular boluses every 6 hours). Hydrocortisone (cortisol) is the drug of choice for the treatment of acute adrenal insufficiency.
Suggested doses for prednisolone and dexamethasone are based on their glucocorticoid potency relative to hydrocortisone, according to current guidelines for primary adrenal insufficiency.
Fludrocortisone is not necessary if hydrocortisone doses are greater than 50 mg administered every 24 hours. In patients with primary adrenal insufficiency, treatment with fludrocortisone is usually resumed once the addisonian crisis has resolved and given the possibility of replacement with oral hydrocortisone.
During an attack in adults, saline solution (1000 ml in the first hour) should be administered , with crystalloids (e.g. 0.9% isotonic sodium chloride) given according to standard guidelines and adjusted according to the patient’s circulatory status. their weight and coexisting disorders.
5% glucose in saline solution is administered for hypoglycemia (when blood glucose is less than 3.9 mmol per liter (70 mg per deciliter).
In children, a bolus of physiological solution is administered at a rate of 20 ml per kilo of weight, with repeated doses up to 60 ml per kilo during the first hour. If hypoglycemia is present, glucose is administered at 0.5 - 1 g per kilo.
Rarely, patients have adrenal insufficiency and diabetes insipidus . Fluids should be administered with caution to patients with diabetes insipidus, whether or not they are receiving treatment, as too much free water can cause hyponatremia and too little can cause hypernatremia. Careful matching of diuresis and saline infusion maintains isonatremia.
Investigation and treatment of precipitating disease is necessary in all patients with acute adrenal insufficiency. The persistence of shock despite seizure treatment suggests another cause of hypotension.
After treatment of acute adrenal insufficiency, the dose of hydrocortisone should be progressively decreased, generally over 3 days, until reaching the patient’s usual maintenance dose. Preventable precipitating causes will be evaluated and preventive strategies will be explained to the patient, including self-administration of parenteral hydrocortisone.
| Scope of attention |
Prevention of acute adrenal insufficiency depends on attentive and informed health professionals (ambulance, nursing, doctors) and the effectiveness of patient education so that, if necessary, the patient can initiate gradual increases in the glucocorticoid dose.
Clinical cases and systematic studies of the speed of medical care showed a range of possible delays and difficulties that may affect the incidence and outcome of acute adrenal insufficiency. Some factors, such as a delay in the arrival of the ambulance, may be unavoidable but it is important to take care of them.
Ensuring that ambulances have injectable hydrocortisone can be very helpful for treatment.
Recent evidence of poor knowledge about adrenal insufficiency and Addisonian crisis among some physicians underscores the importance of continuing education.
Hospital analysis of episodes in which response time is critical in the treatment of patients with adrenal insufficiency, especially the time taken to administer IV hydrocortisone, can be used as a starting point and quality assurance. Audits of hospital treatment (intensive care unit admission, use of respiratory support, adverse sequelae, and mortality) can help ensure appropriate outcomes.
In the hospital, the use of an alarm system to indicate adrenal insufficiency could encourage the administration of glucocorticoid replacement therapy and appropriate doses of glucocorticoids for surgical procedures.
| Patient factors |
Patients with adrenal insufficiency are frequently dissatisfied with medical care, due to demanding schedules for glucocorticoid replacement, delay in initial diagnosis, decreased post-treatment well-being (in up to 40% of patients), and crisis-related anxiety. Addisonian.
Functional impairment in patients with adrenal insufficiency, manifested by fatigue, decreased work participation due to sickness and disability, may be related to non-circadian or personalized corticosteroid replacement treatment.
In addition, there is large interindividual variation in the pharmacokinetics of hydrocortisone, and hydrocortisone treatment affects mental and physical health through alteration of tryptophan metabolism.
| Prevention |
The main preventive strategies for acute adrenal insufficiency are:
-personalized indications for the complementary administration of glucocorticoids for physiological stress,
- use of parenteral hydrocortisone, preferably at home, when it is not possible to take glucocorticoids orally and
-provision of devices, such as a bracelet or necklace, that warn those caring for the patient about the risk of acute adrenal insufficiency when patients cannot communicate verbally.
The dose of oral glucocorticoids for stress , which aims to replicate the cortisol response to stress, is double or triple the replacement dose, depending on the intensity of the stress (e.g., double dose for fever <38.5 °C and triple dose for fever ≥38.5°C), until the disease improves).
Doses are based on mimicking the physiological response to the disease, but the pharmacokinetics of oral hydrocortisone are highly variable and patients with rapid metabolism may have a lower response to modest doses than those with slower metabolism.
Larger parenteral doses may be necessary in cases of severe stress such as major surgery and may achieve maximal adrenal secretion (approximately 200 mg of hydrocortisone every 24 hours [8.5 times normal production]).
Parenteral hydrocortisone (100 mg in adults) is recommended in patients with vomiting or diarrhea. Patients and their families should be taught how to give an intramuscular injection of hydrocortisone and provided with ampoules, needles, and syringes. When stress treatment is not used, the patient may progress to Addisonian crisis. Parenteral administration of home hydrocortisone can prevent it.
Subcutaneous administration of hydrocortisone in nonobese patients is an alternative to the intramuscular route that may be more acceptable to patients and has similar effects.
The article mentions some measures that increase communication, such as a “corticosteroid card” or its equivalent. Your employment can grow through patient education.
Despite efforts to encourage patients to manage their glucocorticoid therapy to prevent acute adrenal insufficiency, only some patients do so effectively. Intensive patient education programs are not successful.
| Reduced incidence of acute adrenal insufficiency |
The greater application of preventive strategies could reduce the incidence of acute adrenal insufficiency, rapid treatment at home and in health services could reduce its severity and sequelae.
Pre-emergency injection of intramuscular or subcutaneous hydrocortisone can prevent many episodes of acute adrenal insufficiency.
| Future approaches |
A prefilled syringe with hydrocortisone , similar to the epinephrine autoinjector, has been recommended but is not yet available. Other products or other routes for the administration of hydrocortisone could be devised that are easier for patients to use in emergencies, such as an intranasal or inhalable spray or powder.
Finally, other systems for adrenal hormone replacement, such as a “bioartificial adrenal cortex,” are attractive. For these purposes, allogeneic or xenogeneic adrenal cells could be used in an implanted container such as an alginate capsule.
Another method, in which the cells could avoid the patient’s immune system, could be feasible. If successful, these proposals will improve the quality of life of patients with adrenal insufficiency and eliminate crises.
