Recent Advancement on Current Trend in The Management of Endocrine Emergency in Critically Ill Patient

Endocrine emergencies represent a group of potentially life-threatening conditions that are frequently overlooked, resulting in delays in both diagnosis and treatment, factors that further contribute to their already high associated mortality rates. Although endocrine emergencies are often encountered in patients with a known endocrinopathy, the emergency may be the initial presentation in previously undiagnosed individuals. If these endocrine disorders are not rapidly identified or if specific treatment is delayed, significant complications or even death may occur. Careful evaluation of clinical history and a high degree of suspicion are the corner stone to diagnose such problems. Aggressive management of the patient is equally important as the complications are devastating and can prove highly fatal. The present article is an attempt to review some of the common endocrine emergencies in intensive care unit and the challenges associated with their diagnosis and management.


Therapeutic management
In case of severe hypoglycemia or patients on long acting OAD or insulin even with less severe hypoglycemia require hospitalization.Treatment with I/V glucose and patient education regarding prevention of further hypoglycemia is the cornerstone of management. 2 Initial treatment consists of IV injection of concentrated dextrose (usually 50 mL of 50% dextrose solution).Whatever caused the hypoglycemia is likely to still be present and the hypoglycemia is expected to recur once the dextrose administered has been metabolized.Therefore, a continuous IV infusion of dextrose should be started.The final aspect of acute management is to provide for serial blood or serum glucose testing to detect possible recurrences and tailor the rate of ongoing dextrose administration.

Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS):
Diabetic ketoacidosis (DKA) and the hyperglycemichyperosmolar state (HHS) appear as 2 extremes in the spectrum of diabetic decompensation. 4They remain the most serious acute metabolic complications of diabetes mellitus and are still associated with excess mortality.Because the approach to the diagnosis and treatment of these hyperglycemic crises are similar, we have opted to address them together.

Pathophysiology: Precipitating factors
Infection remains the most important precipitating factor in the development of DKA and HHS.In 20%-25% of cases, infections are the first manifestations of previously undiagnosed diabetes mellitus. 5Omissions or inadequate insulin doses are frequent precipitating factors, particularly for DKA. 6Other precipitating factors, especially for HHS, aresilent myocardial infarction, cerebrovascular accident, mesenteric ischemia, acute pancreatitis and use of medications such as steroids, thiazide diuretics, calciumchannel blockers, propranolol and phenytoin. 7In 2%-10% of cases of DKA, no obvious precipitating factor can be identified. 5

Diagnosis and Clinical presentation
A definitive diagnosis of DKA or HHS must be confirmed through laboratory investigation.The clinical presentation can provide helpful information for the preliminary bedside diagnosis. 8DKA usually occurs in younger, lean patients with type 1 diabetes and develops within a day or so, whereas HHS is more likely to occur inolder, obese patients with type 2 diabetes and can take days or weeks to fully develop.In addition, HHS usually occurs in elderly diabetic patients, often those with decreased renal function who do not have access to water. 9In both conditions, abdominal pain with nausea and vomiting can develop owing to acidosis per se or to decreased mesenteric perfusion and can be mistaken for an acute surgical abdomen.Kussmaul-Kien respiration (rapid and deep respiration) with breath acetone is typical of DKA but is absent in HHS.DKA and HHS are usually accompanied by hypothermia, a normal or elevated temperature may indicate underlying infection.

Management
The success of treatment of DKA and HHS depends on adequate correction of dehydration, hyperglycemia, ketoacidosis and electrolyte deficits (Fig. 2).Any comorbid precipitating event should be identified and treated appropriately.

Thyrotoxic crisis:
The thyrotoxic crisis, or thyroid storm, is a life threatening exacerbation of the hyperthyroid state characterized by decompensationof one or more organ systems. 12Usually it complicates Graves disease, but sometimes it occurs in association with toxic nodular goiter.There is no clear cut off value of circulating thyroid hormones (TH) defining the thyroid storm, since the results of laboratory tests show, in most cases, similar serum levels of TH to those observed in uncomplicated thyrotoxicosis. 13Nevertheless, the rapid recognition of the thyrotoxic crisis and the institution of immediate drug therapy is important in limiting the morbidity and mortality associated with this condition. 14,15

Pathogenesis:
The thyrotoxic crisis typically occurs in patients in whom preexisting hyperthyroidism has not been diagnosed or has been treated insufficiently.The crisis has an abrupt onset, and is almost always evoked by a precipitating factor.How such precipitating events result in an accentuation of thyrotoxicosis is unclear.The magnitude and the steepness of the hormone increase may be more important than the absolute values of circulating TH's levels. 12,16Other possible mechanisms explaining the progression from uncomplicated thyrotoxicosis to thyroid storm include an increase of tissue iodothyronine levels or an enhancement of the cellular response to TH.
It is known that TH increase cellular adrenoceptor expression or modify postreceptor pathways leading to a tissue hypersensitivity to catecholamines. 18,19

Clinical presentation:
The clinical picture of the thyroid storm is characterized by four main features: (1) Fever 20,21 (2) sinus tachycardia or a variety of supraventricular arrhythmias (paroxysmalatrial tachycardia, atrial flutter and atrial fibrillation), often accompanied by various degrees of congestive heart failure, 17,22 (3) central nervous system symptoms (agitation, restlessness, confusion, delirium and coma) [13][14][15][16][17][18][19][20][21][22][23][24][25] and finally (4) gastrointestinal symptoms, in particular vomiting, diarrhea, intestinal obstruction. 26,27Unexplained jaundice is suggestive for thyroid storm, but is a poor prognostic sign. 13,28Dehydration with electrolytes imbalance is another frequent feature.Other typical symptoms and signs of thyrotoxicosis may complete the clinical presentation (goiter, ophtalmopathy, tremor, hyperreflexia, Plummer's nail, systolic hypertension).Younger patients often present sympathetic related symptoms, while older one frequently show cardiovascular dysfunctions. 29Atypical presentations, such as normothermic crisis, hepatic failure or apathetic storm (extreme weakness) have been reported. 30agnosis: Thyroid storm is not an entity distinct from thyrotoxicosis, but rather one end of a spectrumof severity of hyperthyoridism. 31Since it is difficult in most emergency departments to obtain rapid confirmatory laboratory or nuclear medicine tests, the diagnosis of thyrotoxic crises is often made on the basis of clinical findings alone, even if the symptoms and signs may not be specific.Furthermore, low levels of thyroid stimulating hormone (TSH) and high levels of free triiodothyronine (T3) and free L-thyroxine (T4) are characteristic, but as yet stated, not helpful in distinguishing uncomplicated thyrotoxicosis from thyroid storm. 13,32nagement: Patients with thyroid storm should be treated in the ICU.This allows close cardiac and neurologic monitoring and early recognition of dehydration, cardiac dysrhythmias, heart failure, and respiratory failure.The use of pharmacologic agents to inhibit thyroid hormone synthesis is the primary specific treatment of thyroid storm.Lugol's iodine solution is admin-istered as adjunctive therapy to block release of this stored hormone.Other iodinecontaining agents, such as the oral radiocontrast agent sodium ipodate, oral potassium iodide solution, or IV sodium iodide, can also be used for this purpose.It is important not to administer any of these iodinecontaining preparations until at least 1 h after propylthiouracil has been started.If iodine is given first, it will augment thyroid hormone synthesis.β-Adrenergic blocking drug (propranolol) is routinely administered to patients with thyroid storm.It blunts the cardiovascular effects of thyrotoxicosis, including tachycardia and hypertension.If there are relative contraindications to propranolol, a cardioselective β-blocker (eg, metoprolol) may be employed.Propranolol, sodium ipodate, and corticosteroids are known to inhibit conversion of T4 to T3 in peripheral tissues.Routine hydrocortisone administration has been recommended in thyroid storm because of the possibility of coexisting adrenal insufficiency. 1,33

Acute adrenal insufficiency:
Cortisol is the predominant corticosteroid secreted from the adrenal cortex in humans.
5][36][37] Stimulation of the hypothalamic-pituitaryadrenal axis in this context is caused by elevated levels of circulating cytokines, among other factors. 380] In addition, during critical illness, levels of corticosteroid-binding globulin decrease rapidly, 41 leading to increased levels of circulating free corticosteroids.Levels of free cortisol may also increase at sites of inflammation owing to the cleavage of corticosteroid-binding globulin by neutrophil elastase, an effect that liberates cortisol. 42In addition to having systemic actions, inflammatory cytokines can increase tissue cortisol levels through changes in peripheral cortisol metabolism 43 and can increase the affinity of glucocorticoid receptors for cortisol. 44These changes in cortisol action appear to be important adaptive mechanisms regulating the inflammatory response. 45During severe illness, many factors can impair the normal corticosteroid response (Fig. 1C).These factors include preexisting conditions affecting the hypothalamicpituitary-adrenal axis, 45 but corticosteroid insufficiency can also occur during the course of acute illness.Responses

Management:
Since adrenal insufficiency appears to be common in patients with septic shock, treatment should be initiated at the time of diagnostic testing and can be stopped if results do not indicate the presence of adrenal insufficiency.
In patients in whom improved outcomes are seen, high doses of corticosteroids may be required to overcome tissue-specific resistance to corticosteroids. 55Supraphysiologic doses of glucocorticoids in patients with critical illness outside the situations in which benefit has been proved are not indicated.

Etilogy:
Myxedema most commonly develops in patients with neglected, inadequately treated, or undiagnosed hypothyroidism.Multiple factors appear to precipitate myxedema coma, including gastrointestinal bleeding; infection; metabolic disturbances such as acidosis, hypoxemia, and hypercapnia; stroke; and cardiovascular compromise (Table V)

Pituitary apoplexy:
Pituitary apoplexy is an uncommon event heralded by abrupt onset of severe headache, restriction of visual fields, deterioration of visual acuity, and weakness of ocular motility frequently coupled with clinical indications of decreased endocrine function.Hemorrhage into or necrosis of a preexisting sellar mass, usually a pituitary macroadenoma, produces an expansion of sellar contents.Compression of adjacent structures elicits the variable expression of symptoms referable to displacement of the optic nerves and chiasm and impingement of the third, fourth, and sixth cranialnerves.Damage to or destruction of the anterior pituitary leads to multiple acute and/or chronic hormone deficiencies in many patients. 63

Treatment
The pituitary gland remains capable of secreting adequate amounts of hormones when as little as 10% of residual tissue remains; however, a dearth or absence of sufficient hormone can lead to adrenal crisis.The definitive treatment for pituitary apoplexy is surgery for decompression of constricted cavernous and/or suprasellar structures, especially in cases in which visual acuity or field defects, decreased level of consciousness, or progressive deterioration of visual or oculomotor abilities are present.A significant visual compromise, diminished level of consciousness, and declining visual status are clear indicationsfor operative intervention. 64Extensive intracavernous extensionor invasion limit the opportunity for complete tumorremoval.Medical management includes close monitoring of endocrine,neurological, and ophthalmological function, hormone administration, and support with intravenous fluids and electrolytes.

Conclusion
Endocrinal emergencies are life threatening as well as uncommon.Timely diagnosis is the greatest Challenge for the physician and intensivist.Prompt recognition and management is mandatory to avoid their dreadful consequences.A brief clinical history suspicion through experienced clinical eye can be helpful to manage the patient before it brings fatal complications.Laboratory investigation helps the confirmation of the clinical suspicion to become a diagnosis but that is also time consuming and very difficult for health facilities in a country like Bangladesh.

Fig.- 2 :
Fig.-2: Investigation of Adrenal Corticosteroid Function in Critically Ill Patientson the Basis of Cortisol Levels and Response to the Corticotropin Stimulation.Test.REF:Cooper et al46

Fig.- 3 :
Fig.-3: Suggested Corticosteroid-Replacement Doses during Intercurrent and Acute Illness in Patients with Proven or Suspected Adrenal Insufficiency, Including Those Receiving Corticosteroid Therapy.One milligram of prednisolone has corticosteroid potency equivalent to that of 4 mg of hydrocortisone.Ref:Cooperet al46

Table - I
Typical

Table - III
Features Suggesting Corticosteroid Insufficiency

Table - V
Clinical and laboratory features of myxedema crisis.