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Critical Care Pharmacotherapy Issue

Critical Care Pharmacotherapy Issue

Management of Endocrine Emergencies in the ICU

Journal of Pharmacy Practice

1-13

ª The Author(s) 2019 Article reuse guidelines:

Judith Jacobi, PharmD, FCCP, MCCM, BCCCP 1

Judith Jacobi, PharmD, FCCP, MCCM, BCCCP 1 Abstract Endocrine emergencies are frequent in critically

Abstract Endocrine emergencies are frequent in critically ill patients and may be the cause of admission or can be secondary to other critical illness. The ability to anticipate endocrine abnormalities such as adrenal excess or , hypothyroidism, can mitigate their duration and severity. Hyperglycemic crisis may trigger hospital and intensive care unit (ICU) admission and may be life threatening. Recognition and safe treatment of severe conditions such as acute adrenal insufficiency, thyroid crisis, and hypoglycemia and hyperglycemic crisis may be lifesaving. Electrolyte abnormalities such as hypercalcemia and hypocalcemia may have underlying endocrine causes, and may be treated differently with recognition of those disorders- electrolyte replacement alone may not be adequate for efficient reso- lution. Sodium disorders are common in the ICU and are generally related to altered water balance however may be related to pituitary abnormalities in selected patients, and recognition may improve treatment effectiveness and safety.

Keywords diabetic ketoacidosis, adrenal insufficiency, calcium, thyroid, Cushing’s syndrome

Introduction

Critically ill patients present with a variety of symptoms such as somnolence, abdominal pain, hypotension, and tachycar- dia—many of which overlap with endocrine emergencies. Additionally, endocrine emergencies can be elicited by critical illness and are often secondary to another insult. While a few are quite distinct, others may be subtle, with overlapping or nonspecific symptoms. This review illustrates those challenges in a critically ill patient.

Adrenal Insufficiency (Addison’s Disease)

Patients with adrenal insufficiency (AI) present with nonspe- cific findings, including malaise, fatigue, anorexia, abdominal tenderness (may mimic acute abdomen), nausea, vomiting, and diarrhea, leading to hypotension, tachycardia, and weight loss, but also constipation, arthralgia/myalgia, and back pain are reported. In the most severe form or adrenal crisis, patients may experience severe weakness, depression, psychosis, or altered consciousness and confusion mimicking sepsis. Symp- toms are related to deficiency of both glucocorticoid and mineralocorticoid. Hyperpigmentation of the skin or gingiva may be observed in chronic primary AI. Hypoglycemia, hypo- natremia, hyperkalemia, metabolic acidosis, and eosinophilia may be evident, especially during an adrenal crisis. Seizures have occurred due to severe hypoglycemia. Production of cortisol from the adrenal gland is controlled by the hypothalamic–pituitary–adrenal (HPA) axis. Hypotha- lamic release of corticotropin-releasing hormone (CRH)

stimulates the release of pituita ry adrenocorticoid hormone (ACTH) that subsequently stimulates adrenal secretion of cor- tisol. Hormone release is regulated by feedback, and an abnormality leads to downstream effects. Inadequate pituitary ACTH production leads to low cortisol but an increase in CRH. In primary AI, a high level of ACTH may be evident. Primary AI is the result of a defect in the zona fasciculata of the adrenal cortex due to autoimmune adrenalitis, hemorrhage, or infection (eg, meningococcus, tuberculosis, syphilis, disse- minated fungal infection, human immunodeficiency virus, cytomegalovirus); however, the loss of glucocorticoid or mineralocorticoid production is more often secondary to corti- costeroid withdrawal. Secondary AI is the result of hypothala- mic or pituitary failure from causes such as traumatic brain injury, or other syndromes such as hemochromatosis, histiocy- tosis, or withdrawal of megestrol acetate. If secondary AI is suspected, testing of other hormones under hypothalamic/pitui- tary influence is needed, such as insulin-like growth factor 1, growth hormone, prolactin, t hyroid-stimulating hormone (TSH), thyroxine, luteinizing hormone, follicular-stimulating hormone, cortisol, testosterone, or estradiol. 1 Patients with chronic AI may function without significant problem until

1 Pharmacy Department, Indiana University Health Methodist Hospital, Indianapolis, IN, USA

Corresponding Author:

Judith Jacobi, Pharmacy Department, Indiana University Health Methodist Hospital, 1701 N Senate Blvd, AG 401, Indianapolis, IN 46201, USA. Email: jjacobi@iuhealth.org

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stress such as surgery or an acute infection, which then triggers an adrenal crisis. Diagnostic testing is important but should not delay treat- ment when clinical suspicion suggests AI. A stimulation test using cosyntropin 250 mg intravenously is diagnostic if the cortisol increases by less than * 7 mg/dL from baseline and the value remains less than 18 mg/dL when checked 30 and 60 min- utes after administration. The Endocrine Society Guideline for primary AI provides additional guidance for the diagnosis of PAI. 2 The guidelines suggest the use of a low-dose cosyntropin test using 1 mg only when the substance is in short supply, although others have suggested that either test is adequate to rule-in primary and secondary AI, especially for mild disease. 3 If unable to do the cosyntropin test, a cortisol level less than 5 m g/dL and ACTH level greater than 2 times the upper limit of normal are diagnostic of primary AI. Elevated plasma renin and reduced aldosterone levels confirm the presence of mineralo- corticoid deficiency. Further assessment of 21-hydroxylase antibodies can identify an autoimmune etiology and computed tomography scanning can identify infiltrating disease or tumors and adrenal hemorrhage. Medications may cause AI, including adrenal enzyme inhi- bitors such as mitotane, ketoconazole, metyrapone, etomidate, and aminoglutethimide. Accelerated cortisol metabolism may induce AI with acute thyroxine-4 (T4) therapy; thus, hydrocor- tisone is used when first treating severe hypothyroidism. The checkpoint modulators (eg, abatacept, ipilimumab, nivolumab) may enhance autoimmunity and cause AI, among their other autoimmune effects. Critically ill patients may develop a critical illness–related corticosteroid insufficiency syndrome (CIRCI). 4 Although the use of a random cortisol level <10 mg/dL has been suggested to be diagnostic, the CIRCI guideline group does not recommend cortisol or ACTH stimulation testing in patients suspected of this syndrome. 4 Due to concurrent disruption of protein pro- duction in critical illness, a free cortisol levels may be more diagnostic of CIRCI, but it is not readily available. Treatment of acute AI includes glucocorticoid and miner- alocorticoid replacement usi ng intravenous hydrocortisone 50 mg every 6 hours or 100 mg every 8 hours. If planning a cosyntropin stimulation test, dexamethasone 3 to 4 mg every 6 to 8 hours is used to avoid interference with the cortisol assay. When the patient is stable, the hydrocortisone dose may be tapered to a physiologic range (10-20 mg in the morning and 5-10 mg in the early afternoon), although 3-dose regimens have also been used, with the highest dose in the morning and lower doses with lunch and in the afternoon. If compliance is an issue, prednisone, 3 to 5 mg/d, may be used. Titration is based on clinical response. Fludrocortisone supplementation of the mineralocorticoid component is typically not needed, unless patients have symptoms of aldosterone deficiency, such as hyperkalemia or non–anion gap metabolic acidosis. For CIRCI in patients with persistent shock who are unre- sponsive to fluids and vasopressors, hydrocortisone therapy should be initiated without testing. Intravenous hydrocortisone dose in septic shock is suggested to be 50 mg every 6 hours

(<400 mg/d) for at least 3 and up to 7 days until hemodynamic stability/vasopressor discontinuation weaning. 4 Use of hydro- cortisone 200 mg/d is not consistently associated with reduced mortality versus placebo but contributes to faster shock reso- lution and ventilator weaning. 5,6 Prevention of adrenal crisis for patients at risk due to chronic steroid use is important. Stress-dose steroids may be dosed to match the intensity of the medical illness or planned procedure—from 25 mg hydrocortisone (or equivalent) on day of procedure for minor stress (colonoscopy, gastroenteritis, and laparoscopic procedure) to 50 to 75 mg hydrocortisone on day of procedure, tapering to usual dose over 1 to 2 days for mod- erate stress (severe gastroenteritis, pneumonia, febrile illness, and open abdominal surgeries). 7 Higher doses of 100 to 150 mg on the day of procedure are suggested for severe stress (cardi- ovascular surgery, Whipple procedure, pancreatitis, active labor), tapering to usual dose over 1 to 2 days when clinically stable. 7 Patients should be educated to self-adjust dosing during intercurrent illness and to carry some type of alert mechanism (wallet card, emergency information on phone, bracelet) that they have AI.

Adrenal Excess (Cushing Syndrome)

Although an excessive production of cortisol is not often an emergency, it may contribute to the development of other crit- ical illnesses such as bacterial, viral and opportunistic infec- tion, gastrointestinal bleedi ng, hyperglycemic crisis, hypertensive crisis, or hip fracture. Primary Cushing syndrome is the result of tumors, most commonly pituitary adenomas secreting ACTH or rarely cortisol-secreting adrenal tumors. Most Cushing syndrome cases are secondary to chronic corti- costeroid use in therapeutic do ses. Corticoste roids from all routes of administration can contribute, including systemic, inhaled (nasal and respiratory), local injection, and topical, especially with inhibition of cytochrome P450 metabolism with agents such as itraconazole, ritonavir, and antidepressants, and steroid-like agents such as megestrol may contribute. Cri- tically ill patients will have hyperglycemia, are at risk for gas- tric ulcers, exhibit neutrophilia that makes infection diagnosis more difficult, and have increased risk of infection due to sup- pression of innate immunity and T-cell responses, myopathy that may increase the risk of respiratory depression, or hyper- tension. A review of diagnostic testing and treatment of Cush- ing syndrome is available for more information on use of potential tests such as late-night serum and salivary cortisol level, urine-free cortisol level, low-dose dexamethasone sup- pression, and the dexamethasone-CRH test. 8

Thyroid Insufficiency

Patients with hypothyroidism exhibit a decrease in metabolic rate, causing low temperature, low glucose, low potassium and sodium, and somnolence; however, it is only the most severe presentation that would constitute a medical emergency. Myx- edema coma usually develops in a patient with chronic

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hypothyroidism plus a precipitating factor such as severe infec- tion, cardiovascular event, trauma, burn, or major surgery, and the risk may be increased by nonadherence to thyroid replace- ment therapy. Patients with myxedema coma exhibit exagger- ated symptoms of hypothyroidism with core temperature as low as 21 C, bradycardia, prolonged QT interval, reduced car- diac output, and pericardial effusion and are at risk of cardio- vascular collapse. Central nervous symptoms of stupor, obtundation, and frank coma may occur. Muscle weakness and altered response to hypoxia and hypercarbia may lead to respiratory failure. Generalized skin and soft-tissue swelling, periorbital edema, ptosis, and cool dry skin may be observed. Diagnosis of severe hypothyroidism requires clinical suspi- cion and can be confirmed with demonstration of elevated TSH and low thyroxine (T4) and triiodothyronine (T3) levels on admission. Unfortunately, diagnosis of thyroid dysfunction becomes more difficult in patients with ongoing critical illness. Levels of T3 may decline within hours after admission or sur- gery and the magnitude of further decline is correlated with the severity of illness. 9 The combination of low T3 and potentially inappropriately low thyroid hormone levels was historically called sick euthyroid syndrome but is now called nonthyroidal illness syndrome (NTIS). Low circulating T3, increased rever- seT3 (rT3), low TSH, and low T4 are observed. Multiple mechanisms contribute to low thyroxine levels as a protective mechanism in illness and malnutrition to reduce energy requirements. Reduced protein production and binding may accelerate clearance of free hormone, and intracellular altera- tion of the deiodinase enzymes leads to increased metabolism

to the inactive form of thyroxine, rT3. Changes in tissue levels

of thyroxine also occur but are not consistent across tissues. Whether this is truly protective or maladaptive in chronic crit-

ical illness is not clear. Persistent symptoms of hypothyroidism such as impairment in consciousness, reduced myocardial function, hypothermia, and muscle weakness may impair recovery. A high index of suspicion for the negative effects of NTIS is needed to identify this syndrome in patients with chronic critical illness. Failure to provide an adequate dose of thyroxine may create

a thyroid hormone deficiency. Concurrent drug therapy may

impact levothyroxine absorption or metabolism and should be evaluated when patients have an acute change in thyroid hor- mone levels (Table 1). 9 Like the HPA axis, thyroid hormone production is also on a feedback loop. Hypothalamic dysfunction lowers thyrotropin- releasing hormone levels, pituitary dysfunction lowers TSH levels, and primary thyroid dysfunction lowers thyroxine levels (but increases TSH). Thyroxine is highly protein bound, so measurement of unbound (free) T4 may be more accurate for diagnosis of hypothyroidism with reduced protein production (critical illness, pregnancy, estrogen/progestin therapy). The free to total T4 fraction is the most important test to determine how the thyroid is functioning, in conjunction with TSH. The complex pattern of thyroid hormone changes in critically ill patients requires a systematic approach to diagnosis as illu- strated in Figure 1. 10

Table 1. Drug Interactions Impacting Thyroid Replacement. 11

Affects Thyroid

Reduces Thyroid

Absorption or Effect Action (Inactivation

 

Measured With

or Increased

Medication

TSH Elevation)

Protein Binding)

Calcium carbonate Proton pump inhibitors

þ No effect (although gastric acidity is important for absorption) þ þ þ þ þ þ þ

 

Cholestyramine Colesevelam Sevelamer Polystyrene sulfonate Sucralfate Aluminum antacids Raloxifene Tyrosine kinase inhibitors Phenobarbital Phenytoin Carbamazepine Rifampin Sertraline Amiodarone Estrogen Tamoxifen Opioids Mitotane Fluorouracil Capecitabine Androgens

þ þ þ þ þ þ þ þ þ þ þ þ þ þ (Reduce thyroid requirements)

Abbreviation: TSH, thyroid-stimulating hormone.

Common critical care drug therapies may alter thyroid hor- mones, including amiodarone, furosemide >80 mg/d, dopa- mine, glucocorticoids, and somatostatin analogs. 10,11 Chronic medications such as lithium and metformin may also impact TSH and thyroxine levels. Table 1 summarizes some key drug effects. Severe hypothyroidism could reduce the metabolism of other drugs, such as sedatives, although these medications are titrated to effect, so the clinical impact may be minimal. Levothyroxine (T4) is the most common replacement therapy and relies on conversion to the active metabolite, T3 with deio- dinase (D) enzymes. The D2 enzyme is primarily responsible for T4 to T3 conversion, although the D1 enzyme also contributes and captures iodine from inactivated thyroid hormones. The D1 enzyme is inhibited by propylthiouracil and will be discussed in “Hyperthyroid” section. The D3 enzyme is responsible for inac- tivation of T3 by conversion to rT3. Mutations of the deiodinase enzymes and thyroid transporters have been described without a clear connection to clinical effects. 12 Treatment of acute thyroid insufficiency will depend on the age, weight, and risk of complications. For myxedema coma, an intravenous loading dose of levothyroxine of 200 to 400 m g is recommended, although a lower dose may be safer for small or older patients, or those wit h cardiovascular disease or

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4 Journal of Pharmacy Practice XX(X) Figure 1. Patterns of thyroid function tests and etiology. *

Figure 1. Patterns of thyroid function tests and etiology. * signifies that TSH may be either fully suppressed (as in primary hyperthyroidism) or partially suppressed (measurable but below the lower limit of normal). ATD indicates antithyroid drugs; FDH, familial dysalbuminemic hyperthroxinemia; FT3, free triiodothyronine; FT4, free thyroxine; NTI, nonthyroidal illness; TKIs, tyrosine kinase inhibitors; TSH, thyroid- stimulating hormone. Reprinted with permission. 10

arrhythmias. 12 Hydrocortisone should also be given if concur- rent AI is suspected, to avoid acute AI. A maintenance dose of levothyroxine, 1.6 m g/kg, or the prior home regimen can be initiated. Alternatively, a lower intravenous dose of levothyrox- ine 100 mg/d has been studied for myxedema coma and may reduce the risk of atrial arrhythmias. 13 The primary goal in acute therapy is normalization of clinical signs and symptoms as hor- monal levels will not reach steady state for weeks. Serial mea- surement of TSH, T4, or free T4 and T3 every week would provide evidence that the levels are normalizing and warn of high levels of T3. While replacement of liothyronine (T3) is not typically needed, it may be given for patients persistent symp- toms despite adequate T4 or with increased T3 metabolism caused by tyrosine kinase inhibitors (eg, dasatinib, fostamatinib, imatinib, nilotinib). The high cost of intravenous liothyronine is a frequent barrier to availability and use. When used, an intra- venous liothyronine loading dose of 5 to 20 mg may be given and followed by 2.5 to 10 m g every 8 hours, with concurrent levothyroxine. A reduced dose of T3 should be used for patients with older age, cardiovascular disease, or arrhythmias. 12

For patients on chronic replacement, thyroid therapy should be continued during hosp italization, although concur- rent enteral feeding, especia lly through a jejunal tube, may alter bioavailability and prol onged use (weeks) of this com- bination has resulted in hypothyroidism. 14 The authors sug- gest 25 mg incremental dose increases and weekly monitoring of thyroid function with prolonged concurrent therapy. Hold- ing tube feeds for 1 hour pre- and post-thyroxine therapy was not adequate to optimize absorption. For patients who eat meals, levothyroxine should be given 1 hour prior to a meal, and concurrent calcium, aluminum, sucralfate, sevelamer, or iron therapy should be delayed. 12 If converting from oral to intravenous therapy, a 25 % dose reduction is suggested. 12 The long elimination half-life of l evothyroxine (5-7 days) has led to short-term avoidance of intravenous levothyroxine as a cost-saving strategy, but the impact on patient outcome is not known, and prolonged interruption of thyroid therapy may produce thyroid insufficienc y symptoms. Patients with NTIS are suggested to have the potential for a poor outcome. 15 The role of replacement of thyroid in NTIS is not well defined. It

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appears to improve surrogate end points such as thyroxine levels, hemodynamics, or cardiac performance, but studies are not large enough to show improved patient outcome. 9 Short-term thyroid r eplacement in NTIS does not appear to cause harm, although excessive dosing could increase the risk of atrial fibrillation and may l ead to inappropriate long-term therapy.

Thyroid Excess

Patients with excess thyroid hormone production (thyrotoxico- sis) present with signs and symptoms of overstimulation. Com- plaints of disturbed sleep, palpitations, fatigue, anxiety, tremor, heat intolerance, sweating and polydipsia, and ophthalmopathy (ptosis, periorbital edema, and diplopia) are typical. Thyrotox- icosis can be precipitated by infection, surgery/trauma, iodine administration, antithyroid medication nonadherence, thyroid adenoma, or concurrent medical problems. Primary thyroid excess is most commonly caused by Graves’ disease—an auto- immune syndrome that may have genetic predisposition or be triggered by environmental factors, stress, or infection with Yersinia enterocolitica . The most severe manifestation, thyro- toxic storm may lead to intensive care unit (ICU) admission for symptoms such as fever, altered mental status (ranging from agitation/psychosis/neuropsychiatric symptoms to confusion and coma), diffuse muscle weakness, tremor or fasciculations, and cardiovascular problems (tachycardia out of proportion to fever, arrhythmias, and heart failure). 16 Pheochromocytoma, neuroleptic malignant syndrome, or malignant hyperthermia should be considered in the differential diagnosis. Diagnosis of thyroid excess is confirmed with elevated total and free T4, T3 along with low TSH, but hormone levels will not differentiate thyrotoxicosis from thyroid storm. 17 Initial care is supportive, and the underlying trigger should be identi- fied and managed while control of hyperthermia and arrhyth- mias is initiated. The exact etiology is determined with radioactive iodine uptake testing that may demonstrate diffuse uptake in Graves’ dis ease, irregular uptake in multinodular goiter, or focal accumulation with adenoma. Alternatively, thyroid ultrasound and measurement of TSH receptor antibo- dies may be used to avoid exposure to radioactive iodine. Diag- nostic criteria and a scoring system for thyroid storm have been proposed, and the components illustrate the potential scope of potential symptoms 18 (Table 2). Treatment is multifaceted with a focus on symptom relief and reduction of thyroid hormone levels. Patients with preex- isting liver disease, pregnancy, or heart failure warrant special consideration. 17 Beta-blockers are used to control the cardio- vascular effects of thyroid hormone excess. Intravenous pro- pranolol 1 mg every 10 to 15 minutes until the patient is stabilized is common, followed by 10 to 40 mg by mouth every 4 to 6 hours. However, any other beta-blocker or calcium chan- nel blockers may be used. Cholestyramine is an adjunct to sequester thyroid hormone in the intestinal tract, trapping it during enterohepatic recircul ation. Hydrocortisone 100 mg intravenous every 8 hours reduces conversion of T4 to T3 and

Table 2. Diagnostic Criteria for Thyroid Storm. 18

Measure

Points

Temperature ( C)

37.2-37.7

5

37.8-38.2

10

38.3-38.8

15

38.9-39.4

20

39.5-3.9

25

>40

30

Central nervous system symptoms Absent

0

Mild (agitation)

10

Moderate (delirium, psychosis, extreme lethargy)

20

Severe (seizure, coma)

30

Gastrointestinal-hepatic dysfunction Absent

0

Moderate (diarrhea, nausea/vomiting, abdominal pain)

10

Severe (unexplained jaundice) Cardiovascular dysfunction Tachycardia (beats/min)

20

90-109

5

110-119

10

120-129

15

130-139

20

140

25

Congestive heart failure Absent

0

Mild (lower extremity edema)

5

Moderate (bilateral rales)

10

Severe (pulmonary edema)

15

Atrial fibrillation Absent

0

Present

10

Precipitating history Absent

0

Present

10

A score 45 is highly suggestive of thyroid storm, 25 to 44 of impending thyroid storm, and <25 unlikely to be thyroid storm.

treats potential concomitant AI. Adjunctively, the level of cir- culating hormones can be reduced with plasmapheresis, plasma exchange, or peritoneal dialysis, but these are not rapid interventions. Reduction of thyroid horm one production is primarily accomplished with antithyroid drugs. In thyroid storm (score 45, Table 2), a high dose of propylthiouracil is suggested to reduce production of T4 and conversion to T3. Severe symp- toms are treated with a loading dose of 600 to 1000 mg, fol- lowed by 250 mg every 4 to 6 hours, with dose reduction as symptoms abate. Less severe initial symptoms of hyperthyroid- ism may be managed with 100 to 300 mg every 8 hours and tapered to 50 mg given 2 to 3 times daily. Propylthiouracil is preferred during the first trimester of pregnancy to minimize the impact of uncontrolled hyperthyroidism on the neonate, but it may cause maternal hepatic toxicity in the later stages of pregnancy when methimazole is preferred. Teratogenic effects have not been observed, but other adverse effects including fetal hypothyroidism have been reported.

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In Graves’ disease with less severe thyrotoxicosis, methi- mazole is preferred to propylthiouracil. 17 Doses similarly vary based on intensity of symptoms and T4 level. Methimazole is not used in the first trimester of pregnancy. Marrow injury, including agranulocytosis, aplastic anemia, granulocytopenia, and thrombocytopenia along with hepatotoxi- city, has been reported with both antithyroid drugs, usually in the first few months of therapy. Patients should be educated to iden- tify fever, sore throat, chills, myalgia, or diarrhea as potential agranulocytosis. When present, cross-reactivity between agents precludes switching from one agent to the other. Therapy with saturated solution of potassium iodide 250 mg by mouth every 6 hours is started 1 hour after the antithyroid drug therapy to reduce release of preformed T4 and T3 from the thyroid gland. Ablation of the thyroid tissue with surgery or radioactive iodine is used for a toxic adenoma or toxic multi- nodular goiter or as a drug therapy alternative for Graves’ disease, after thyroid hormone levels are normalized with antithyroid drugs. Acute thyroiditis has occurred after treat- ment. Radioactive iodine therapy is not used during or before pregnancy, breast-feeding, with thyroid cancer, or in the case of severe Graves’ orbitopathy.

Hyperglycemia

Hyperglycemia is a common fin ding in critically ill patients with and without diabetes. However, hyperglycemic crisis is a medical emergency that frequently leads to ICU admission. Two syndromes have been descri bed—diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS), although the treatment is similar. The most common cause

of DKA/HHS is nonadherence to ins ulin therapy, but an infec-

tion, cardiac ischemia, trauma, or other acute illness can also be a trigger. Diabetic ketoacidosis occurs in the face of insulin defi- ciency, usually in patients with type 1 diabetes, but has also been described in conjunction with use of sodium glucose cotransporter 2 (SGLT-2) inhibitors. 1 Diabetic ketoacidosis is

characterized by metabolic acidosis with an elevated anion gap due to excessive ketone (acetone, beta-hydroxybutyric acid, and acetoacetate) production from lipolysis with symptoms of hyperventilation, hyperglycemia (glucose 500-800 mg/dL) causing intravascular volume depletion from osmotic diuresis, tachycardia, hypotension, shock, and confusion/coma. Mea- surement of beta-hydroxybutyric acid has been suggested for

a specific diagnosis of ketoacidosis. 19 Hypokalemia may be

masked by acidosis and extracellular potassium shift. A pro- inflammatory state is manifest and may contribute to compli- cations such as venous thromboembolism or a sepsis-like picture. The degree of abnormality varies from mild acidosis (pH 7.25-7.3), to moderate (pH 7-7.24), to severe (pH < 7) with concurrent worsening of mental status. Patients with euglyce- mic DKA (glucose <300 mg/dL) do not have elevated glucose concentrations but elevated ketones from relative insulin defi- ciency brought on by SGLT-2 inhibitor-induced glucosuria and reduced carbohydrate intake (often with an acute illness or

surgery). 20 Clinicians should be suspicious of this syndrome with growing utilization of these drugs presenting with meta- bolic acidosis. It may be prudent to discontinue use of SGLT-2 inhibitors several days prior to a planned surgery. Patients with HHS usually have only a mild acidosis (lactic or mild starvation ketosis) but more significantly elevated glu- cose levels (>600 mg/dL), more significant dehydration and hyperosmolarity (>320 mOsm/kg), and significant stupor or coma compared with DKA. Treatment of both syndromes has been fairly standard, requiring restoration of intrav ascular volume, correction of electrolyte deficiency, and replacement of insulin as illustrated in Figure 2. 21,22 A systematic and protocolized approach to treatment has been associated with more efficient resolution of the syndrome. 23 Immediate resuscitation with crystalloid fluids (0.9% NaCl or Ringer’s lactate) is needed, based on the degree of hypotension, with ongoing fluid replacement to cor-

rect the 10 to 12 L potential deficit using hypotonic fluid unless

the corrected sodium deficit is severe 22 (Figure 2). Hydration

alone improves glycemic control and acid–base balance. A recent review concluded that data are insufficient to recom- mend one crystalloid over another, although balanced salt solu- tions are favored in most critical care patients. 24,25 While sodium chloride solutions may increase the risk of hyperchlor- emia and a lower urine output, addition of potassium and dex- trose can be done more readily. In one small study, use of Ringer’s lactate was associated with a longer time to achieve glucose control in DKA perhaps related to lactate serving as a substrate for gluconeogenesis, but there was no difference in time to closure of the anion gap. 26

Insulin replacement is not geared toward normalization of glucose, rather to replace a basal insulin deficit. A fixed rate of infusion is preferred to titrated insulin using 0.1 U/kg/h with an optional intravenous bolus of 0.1 U/kg for obese or signifi- cantly insulin-resistant patients. 27 However, an infusion of 0.14 U/kg/h without a bolus dose has also been suggested. 28 Preparation of the intravenous tubing by flushing an extra 20

mL of the insulin infusion has been suggested to saturate

insulin-binding sites and maximize insulin delivery. 29 The

maintenance fluid should include dextrose once the glucose level has fallen to below 250 mg/dL in DKA and 300 mg/dL

in HHS to protect against hypoglycemia and osmotic shifts (Figure 2). Insulin resistance may be reduced with resuscitation

and falling glucose levels, necessitating a reduction in insulin

infusion rate to 0.05 U/kg/h or increase in glucose dose. Patients with hyperglycemia t ypically have low sodium levels reported due to a lab anomaly. The reported serum sodium should be increased by 2.4 mEq/L for each 100 mg/dL elevation in glucose above normal. 30 Sodium bicarbonate is only used for severe acidosis, as ketones will be metabolized to bicarbonate. Potassium is replaced acutely, prior to any insulin therapy, if the level is less than 3.3 mEq/L, and should

be added to maintenance fluids if the level is less than 5.3 mEq/L

and urine output is adequate (more than 0.5 mL/kg/h). 22

Additional electrolyte replacement is typically needed, so phosphorus and magnesium should be monitored routinely.

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Jacobi 7 Figure 2. Management of hyperglycemic crisis. BG indicates blood glucose; DKA, diabetic ketoacidosis; IV,

Figure 2. Management of hyperglycemic crisis. BG indicates blood glucose; DKA, diabetic ketoacidosis; IV, intravenous; SC, subcutaneous. Reprinted with permission. 22

Insulin and dextrose combine to shift phosphorus intracellularly, so levels less than 1.5 mg/dL warrant therapy to prevent severe hypophosphatemia and muscle weakness or injury. 31 Magne- sium therapy should be individualized based on concentrations and potential for arrhythmias. Subcutaneous insulin has been studied for the management of DKA in patients with uncomplicated cases using lispro insulin 0.3 U/kg followed by 0.1 U/kg administered hourly in non-ICU settings. 32 Subcutaneous insulin therapy in con- junction with a DKA protocol did not produce comparable patient outcomes compared with intravenous insulin but was significantly less costly for pat ients who were not persistently hypotensive, comatose, and did not have complications such as myocardial infarction, heart failure, end-stage renal dis- ease, or dementia. Workload considerations and intensity of monitoring are important when determining treatment loca- tion. A Cochrane review did not find any compelling outcome differences between the route s of therapy, suggesting more research is needed, including consideration of patient satisfaction. 33 Studies in children and adults have also examined the poten- tial utility of early treatment with glargine insulin, concurrently with insulin infusion. A pilot study using insulin glargine 0.3 U/kg subcutaneous within 2 hours of the initiation of insulin infusion demonstrated safety and similar outcomes. 34 A review of this practice suggested that further study is needed, although the Joint British Diabetes Societies guideline expert opinion suggests that home basal insulin be continued throughout

insulin infusion therapy in DKA to minimize rebound hyper- glycemia after the infusion. 35,36 Typically, in the United States, transition to a basal and bolus insulin regimen is done after the anion gap has closed in DKA or after rehydration, glycemic control, and osmotic stabilization in HHS. 21 The basal insulin is ideally given 2 hours prior to stopping the infusion to account for time to onset of action and avoid rebound hyperglycemia or recurring keto- sis. In HHS, mental status may take quite a bit longer to nor- malize. A patient who remains unstable may be transitioned to a titrated insulin infusion for ongoing management. Osmotic shifts are an important consideration in DKA or HHS and renal failure. Hemodialysis will lower both the glu- cose and blood urea nitrogen, potentially causing significant osmotic shifts and a more rapid decline in glucose concentra- tion than with insulin alone. Al though cerebral edema is reported in children more than adults, this catastrophic adverse effect is a potential with concurrent therapies. Further, dialysis patients will not need the same degree of fluid and potassium repletion, so treatment should be individualized. 37

Hypoglycemia

Acute hypoglycemia is a common consequence of insulin or oral hypoglycemic treatment with reduced glucose intake but may arise from insulin dosing errors, hepatic insufficiency (reduced gluconeogenesis), decreased insulin clearance (renal failure), or changes in corticosteroid therapy without changes

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in insulin regimen or intentional overdoses. Severe hypoglyce-

mia can lead to seizures, cerebral, or cardiac injury. Early recognition of the signs and symptoms (sympathetic stimula- tion, sweating, anxiety, visual changes confusion, aphasia, etc) leads to earlier therapy. However, recognition of hypoglycemia may be difficult in patients who are sedated or who have a

blunted hypoglycemic response with chronic diabetes and auto- nomic failure or with concurrent beta-blocker therapy. Hypo- glycemia may be classified as mild 55 to 69 mg/dL, moderate 50 to 54 mg/dL, or severe (less than 40 mg/dL), and all are associated with 2- to 3-fold higher ICU mortality than normo- glycemia, and any value less than 70 mg/dL should be an alert value for patient treatment and assessment of the insulin and

nutritional regimen. 38,39 Prevention through the use of appro- priate monitoring and a validated insulin protocol is essential. 40

A single dose of insulin to treat hyperkalemia creates a risk of

hypoglycemia, especially in patients with creatinine clearance <30 mL/min or dialysis patients, suggesting ongoing monitor- ing for 3 to 4 hours. The traditional combination of 10 units of insulin with 50 % dextrose caused a hypoglycemia rate approaching 30 % in renal failure without adequate monitor-

ing. 41 Use of lower insulin doses has been suggested in this population. Hypoglycemia can typically be managed with dextrose replacement via the intravenous or oral routes or glucagon. The optimal dextrose dose and route has not been established or addressed in any treatment guidelines. Concentrated dextrose, 25 % or 50 %, is typically used, but complications from extra- vasation of this hyperosmolar fluid and cardiac arrest with rapid administration have been reported. 42 Infusion of 10 % dextrose in 50-mL aliquots, titrated to relief of hypoglycemia, produced similar recovery from hypoglycemia with less inad- vertent hyperglycemia. 43

Parathyroid Emergencies Hypercalcemia

A crisis with hyperparathyroidism is related to very high cal-

cium concentrations in the plasma. Calcium levels >12 mg/dL can contribute to a variety of adverse effects, but total levels >14 mg/dL (ionized calcium >1.4 mmol/L) lead to profound volume depletion, altered sensorium, cardiac decompensation, and abdominal pain that mimics an acute abdomen. Additional symptoms include polyuria, thirst, mood disturbances, cogni- tive dysfunction, shortened QT interval, pancreatitis, hyperten- sion, and muscle weakness. High levels of calcium in the nephron cause a nephrogenic diabetes insipidus (DI) with impaired ability to concentrate the urine, and vasopressin bind- ing or aquaporin downregulation contribute to water loss. Malignancy with accelerated bone resorption or a primary hyperparathyroid state is present in 90% of patients with hyper- calcemia. Metastatic breast cancer, squamous cell head/neck cancer, renal cell carcinoma, and multiple myeloma are asso- ciated with hypercalcemia through humoral bone resorption or bone destruction. Autonomous parathyroid hormone (PTH)

secretion by adenomas as the cause of primary hyperparathyr- oidism is the most common cause of hypercalcemia in an ambulatory population. 44 Prolonged immobilization is another cause of bone resorption and hypercalcemia. Other causes of hypercalcemia include other hormonal abnormalities such as thyrotoxicosis, pheochromocytoma, and AI. Drug-induced hypercalcemia may occur with thiazide diuretics, hypervitami- nosis D or A, theophylline toxicity, lithium, and oral calcium administration (especially the carbonate salt) with significant milk ingestion can lead to the milk-alkali syndrome with ele- vated calcium. Clinicians should recognize that a “normal” total calcium in a critically ill patient may represent hypercalcemia, based on alterations in protein binding and pH, as discussed in “Hypocalcemia” section. Calciu m level is normally closely regulated by PTH and levels of PTH respond quickly to changes in calcium. An adjustment in the reported total cal- cium level is available in the setting of low albumin, although this is an unreliable method in critically ill patients, where ionized calcium should be measured directly. 45,46 In conditions such as sepsis, with fluctuating albumin, an ionized calcium level >1.4 mmol/L is more reliable for hypercalcemia diagnosis. The diagnostic workup of hypercalcemia includes assess- ment of concentrations of total and ionized calcium, PTH, 25-hydroxyvitamin D, thyroid hormones, and workup for malignancies. High calcium and high PTH suggest primary or tertiary hyperparathyroidism. High calcium and low PTH are secondary to malignancy or other causes. Treatment of hypercalcemia, regardless of etiology, is with hydration—0.9% NaCl infusion—1 L in the first hour and 3 to 5 L in the next 24 hours, with ongoing efforts to maintain hydration. Furosemide may be added to manage volume over- load but is not used to impact calcium levels and is not recom- mended for routine use. 47 Calcitonin 100 units subcutaneous injection every 6 hours or as an infusion of 10 U/kg over 6 hours may be used as a rapid-acting therapy in severe hypercalcemia to inhibit osteoclast activity and bone resorption. Anaphylaxis, flushing, and nausea may occur. Glucocorticoid therapy may reduce the expected tachyphylaxis. Ambulation of the patient is also helpful to minimize bone resorption from immobility but may not be feasible in a critically ill patient. Addition of a bisphosphonate such as zoledronic acid or pamidronate is used for ongoing management of hypercalce- mia (if creatinine clearance >30 mL/min). 48 The intensity of pamidronate dosing can vary with calcium concentration—30 mg over 2 hours if level <12 mg/dL, 60 mg over 4 hours for 12 to 14 mg/dL, and 90 mg over 6 hours for calcium level >14 mg/ dL. 46 The onset of effect is delayed for 2 to 5 days, so doses should not be repeated for at least 7 days. Osteonecrosis of the jaw is a unique adverse effect of bisphosphonates, so patients should be advised to discuss this therapy prior to dental proce- dures in the future. The bisphosphonate should not be used before parathyroidectomy due to the risk of hypocalcemia. Hemodialysis against a low calcium bath is an option in patients who already require that therapy. While phosphate

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therapy will immediately lower the calcium concentration in an emergency, it may cause undesirable tissue deposition of precipitates. In primary hyperparathyroidism, a calcimimetic such as cinacalcet, etelcalcetide, or denosumab, may be considered for chronic suppression of PTH, especially leading up to parathyr- oidectomy, a definitive treatment option for primary hyperparathyroidism.

Hypocalcemia

Hospitalized patients commonly have low total calcium con- centrations, but episodes of significant hypocalcemia that can be considered an endocrine emergency are rare. Calcium plays an essential role in nerve conduction, muscle contraction, and relaxation, including the myocardium and vasculature. Intra- cellular calcium regulates cyclic adenosine monophosphate– mediated pathways. The parathyroid gland regulates calcium concentrations rigidly. Severe hypocalcemia (ionized calcium <1 mmol/L) may result in neuromuscular manifestations of perioral paresthesias, neuromuscular weakness, muscle irritability, seizures, hyper- active tendon reflexes, or tetany (carpopedal—strong contrac- tions of the hands or feet—elicited by inflating the blood pressure cuff above systolic pressure or facial, which is elicited by tapping the inferior cheekbone). Laryngospasm may also occur. Cardiac effects are nonspecific and include refractory hypotension, reduced cardiac contractility, and cardiac conduc- tion disturbances such as prolonged QT interval, bradycardia, heart block, and heart failure. Coagulation may be impaired and petechiae/purpura may be visible. Carpopedal and general- ized tetany (unrelieved and strong contractions of the hands and in the large muscles of the rest of the body) may be seen. Calcium is bound to albumin, and a low total often reflects the low protein. Only 50% of plasma calcium is ionized, 40% is protein bound (90% to albumin), and 10% circulates bound to anions such as phosphate, carbonate, citrate, lactate, or sulfate. The free-fraction of calcium is measured as ionized calcium, the active moiety. It should be measured directly to assess hypocal- cemia, especially in critically ill patients, where the formula to adjust for albumin concentration is unreliable (add 0.8 mg/dL for each g/dL albumin below 4 g/dL, at pH 7.4). 45,46 Acidosis decreases calcium binding to albumin and alkalemia the con- verse, so laboratory analysis of ionized Ca may report a pH correction to 7.4—primarily to account for analytic error (speci- men acidosis resulting from delayed assay). The accuracy of this step is unknown when the patient has a preexisting pH abnorm- ality. Unfortunately, abnormal ionized calcium levels may be just a marker for disease severity in critical illness and the role of therapy remains controversial. 49,50 It has been suggested that a decrease in ionized calcium is an adaptive response in critical illness and that replacement is not associated with improved outcome. There have been calls to eliminate routine testing of ionized calcium. 49,51 Hospitals should consider a threshold for treating ionized calcium levels based on the presence of symp- toms or severe reductions (eg, <0.9 or 1 mmol/L).

The most common cause of hypocalcemia in critical care patients is rapid administration of a large amount of citrated blood or plasma. Acute pancreatitis causes hypocalcemia by precipitation of calcium soaps (free fatty acids that chelate calcium) in the abdominal cavity, along with glucagon- stimulated calcitonin release and reduced PTH secretion. Rhab- domyolysis with hyperphosphatemia or excessive phosphate administration may lead to cal cium phosphate precipitates. Less commonly, calcium deficiency also occurs with chronic untreated hyperphosphatemia, PTH deficiency, and vitamin D deficiency. Acute interruption of PTH therapy in patients with primary hypoparathyroidism may produce hypocalcemia. 52 Patients receiving calcimimetics who become calcium defi- cient may develop tetany with an acute elevation in PTH. Acute hypocalcemia may occur after thyroidectomy or thyr- oid injury (irradiation, radioiodine), parathyroidectomy, or from infiltrative disease of the parathyroid (hemochromatosis, sarcoidosis, amyloidosis, or metastatic disease). 53 Predictors of hypocalcemia after thyroidectom y include Graves’ disease, need for parathyroid autotransplantation, or inadvertent exci- sion of the parathyroid tissue, along with perioperative change in calcium and pre-op vitamin D status. 54 Hereditary or familial hypoparathyroidism syndromes may occur rarely. Drug-induced hypocalcemia may occur with calcimimetic agents (cinacalcet, etelcalcetide), cisplatin (due to hypomagne- semia), combination 5-fluorouracil and leucovorin, bispho- sphonate therapy, prolonged therapy with phenytoin or phenobarbital, foscarnet, denosumab, chronic therapy with agents that suppress gastric acid (prothrombin pump inhibitors and histamine-2 antagonists), and aluminum-containing prod- ucts. 55 Sepsis and other acute inflammatory illnesses cause hypocalcemia. Mortality rates are higher in patients with sepsis with hypocalcemia. 56 Magnesium and calcium maintain a synergistic relationship. Hypomagnesemia can lead to hypocalcemia that is resistant to calcium and vitamin D therapy. Acute magnesium therapy leads to rapid correction of the PTH level. Vitamin D is a necessary cofactor for the normal response to PTH, and defi- ciency causes PTH resistance and hypocalcemia. Treatment of symptomatic hypocalcemia depends on the cause, severity, symptoms, and rapidity of onset. 54 Patients with serum calcium less than 7.6 mg/dL or ionized calcium less than 1 mmol/L or those symptomatic at any calcium level should receive 100 to 300 mg of elemental calcium (1-3 g calcium gluconate or 0.5-1 g calcium chloride) in 100 mL dextrose over 10 minutes. The electrocardiogram and infusion site should be monitored. This dose should raise the calcium level by 0.5 to 1.5 mmol/L for 1 to 2 hours. Additional calcium infusion using 10 g calcium gluconate in 1 L of fluid can be given at a rate of 0.5 to 1 g/h and may be needed for continued replacement following parathyroidectomy. 57 An equivalent dose of calcium chloride may be used and infused through a central line. Hazards of calcium administration include phlebi- tis, cardiotoxicity, hypotension, bradycardia with rapid admin- istration, flushing, vomiting, and local tissue injury with or without extravasation. Patients on digoxin should be observed

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Journal of Pharmacy Practice XX(X)

for exacerbation of toxicity. The cause of hypocalcemia should be investigated and corrected. Routine administration of calcium to asymptomatic criti- cally ill patients follows a desire to correct an abnormal lab value; however, studies evaluating the impact of calcium ther- apy have shown minimal impact on outcome. 58 Only one retro- spective study has shown an association between calcium supplementation and reduced 28-day mortality using the Multi- parameter Intelligent Monitoring in Intensive Care II database (version 2.6). 59 The reliability of their finding is less reliable as these authors also presented contradictory data, showing that higher doses of calcium were associated with a greater risk of 90-day mortality. 60 Administration of calcium to asymptomatic ICU patients receiving parenteral nutrition was also associated with higher odds of mortality (odds ratio: 2.48, 95 % confidence interval: 1.08-5.69), and new-onset respiratory failure or shock as the calcium dose increased above 5 g total. 60 An earlier Cochrane summary was unable to find any trial that measured a positive outcome from calcium therapy. 61 A large rando- mized trial will be needed to identify if calcium supplementa- tion is beneficial to asymptomatic, critically ill patients.

Hyponatremia

Sodium disorders are common in critically ill patients and while many are due to patient care practices (fluid therapy, diuresis), gastrointestinal disturbances (diarrhea, fistula out- put), and renal issues (water and electrolyte elimination) such as heart failure or hepatic failure, endocrine problems may also occur, related to the pituitary gland. Hyponatremia may occur with syndromes of excess antidiuretic hormone (SIADH). Clin- icians should be aware of the potential for pseudohyponatre- mia, when exogenous substances such as elevated dextrose, mannitol therapy, triglycerides, or serum proteins alter the measured sodium concentration as discussed in “Hyperglycemia” section. Mild hyponatremia with sodium 130 to 135 mmol/L is often related to an excess of free water and is rarely symptomatic. Moderate (125-129 mmol/L) and profound (<125 mmol/L) sodium reduction may be symptomatic and constitutes an endo- crine crisis. The etiology should be investigated after an imme- diate response to the patien t symptoms. The degree of hyponatremia may not always correlate with symptoms, depending on the rate of development and ability of the brain to adapt to osmolar changes. Severe symptoms include muscle rigidity; cardiorespiratory arrest; altered level of conscious- ness, seizures, and confusion; and potential cerebral herniation. Less severe symptoms include muscle weakness, cramps or spasm, nausea/vomiting, or headache. Treatment of severe hyponatremia symptoms should be sys- tematic and controlled. Hypertonic sodium chloride 3% should be infused as 100 to 150 mL ( *2 mL/kg) over 20 minutes followed by a sodium concentration check, with additional 150 mL over 20 minutes while the lab is pending and if symp- toms are not relieved. 62 This regimen may be repeated until a 5-mEq/L increase in serum sodium is measured and the

hypertonic saline is then stopped. A sodium change of 4 to 6 mEq/L is adequate to avoid acute herniation from cerebral edema. 63 For ongoing treatment or for moderate hyponatremia, 0.9% sodium chloride is infused at 10 to 40 mL/h while the cause of hyponatremia is ident ified and specific treatment started. Sodium should be monitored every 4 to 6 hours. A proposed rule for urgent sodium replacement is a rule of 6s (acute change of 6 mmol/L in 6 hours, then 4-6 mmol/L/d for subsequent days). 64 This is more cautious than the traditional rule to change by no more than 8 to 10 mmol/L in 24 hours. It is imperative to avoid a rapid correction of sodium to minimize the risk of osmotic demyelination (formerly called central pon- tine myelinolysis). If the sodium changes rapidly by 10 mEq/L or more at any point, sodium infusion should be stopped. Cau- tious initiation of hypotonic fluid may be initiated, or therapy with desmopressin 2 to 4 mg every 8 hours to reduce water excretion. 64 Osmotic demyelination is a delayed finding, char- acterized by coma and progressive quadriplegia, dysarthria, and dysphagia. Alcoholism, malnutrition, hypokalemia, hepa- tic failure, and malignant disease increase the risk of these severe effects. While a sodium change of more than 12 mmol/L/d is a consistent cofactor, cases of osmotic demye- lination syndrome have reported characteristic lesions with smaller elevations. 65 Brisk diuresis is a common cause of over- correction, as is aggressive renal replacement therapy. Use of a lower replacement/dialysate sodium concentration or lower blood flow rates may be needed in the setting of hyponatremia. Diagnosis of the etiology o f hyponatremia is based on assessment of volume status, serum, and urine sodium, along with the determination of volume status. Other causes of hypo- natremia, other than SIADH, should be considered and therapy tailored accordingly. 66 Sodium concentrations are usually regulated by renal water excretion and thirst. Critically ill patients are unable to act upon thirst. The renin–angiotensin–aldosterone system also regu- lates sodium concentrations to a lesser degree but is often dis- rupted in critically ill patients through changes in perfusion, circulating volume, stress, pain, nausea, vomiting, and drugs like vasopressin. These factors contribute to SIADH. A full review of the mechanisms regulating sodium and water is available, especially for causes and treatment of hyponatremia without severe symptoms. 65

Hypernatremia

Mild hypernatremia is common in critically ill patients who are receiving diuretics and volume restriction, especially after prior use of 0.9% sodium chloride. The emphasis on active deresus- citation/diuresis of critically ill patients has increased the like- lihood of hypernatremia. However, there is an inadequate literature to guide an approach to water replacement in this setting. 67 The effectiveness of free water-deficit formulas has been challenged. 68 The development of ICU-acquired hyperna- tremia has been proposed to be a marker of severity of illness and not related to sodium-containing fluid resuscitation and water balance. 69

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There is a situation where hypernatremia may become

or a balanced fluid such as lactated Ringers. Water deficit is

severe and constitute an endocrine crisis and that is DI. In this setting, patients excrete large amounts of dilute urine as a result

traditionally calculated (based on sodium lowering and weight) and replaced with fluids that are hypotonic relative to the

of

acute dysfunction of the pituitary gland following trauma or

patient’s serum, but as mentioned, these formulas may be unre-

hemorrhage, leading to reduced ADH production. Gestational

liable and frequent sodium monitoring is needed during

DI

may result from degradation of arginine vasopressin (AVP)

replacement. 68

by

an enzyme produced in the placenta or renal insensitivity to

Patients with hypervolemic hypernatremia may be treated

the antidiuretic effect of AVP. Primary polydipsia can lead to suppressed secretion of AVP. Chronic forms of this condition may be compensated by consumption of adequate amounts of water, but any loss in this ability can lead to hypernatremia. A

with water via the enteral route or infusion of 5% dextrose with loop diuretic therapy. 74 Renal replacement therapy is another method to remove volume while normalizing electrolyte con- centrations, but overcorrection is a risk. 75,76

more detailed review of all aspects of DI is beyond the scope of this article. 70

Vasopressin is an endogenous peptide that serves multiple regulatory functions related to regulation of blood pressure, water balance, platelet function, and thermoregulation. It is synthesized in magnocellular neurons within the hypothala- mus; the distal axons of these neurons project to the posterior pituitary or neurohypophysis, from which AVP is released into the circulation. It has a short half-life necessitating administra- tion via continuous infusion but is recommended for acute use in DI when the need for ADH may be variable. 71 Patients with traumatic brain injury have a complex inter- play between pituitary hormones and releasing factors that is beyond the scope of this article. 72 Recognition of an acute change in sodium is essential to the management of hyperna- tremia in the setting of DI. Measurement of urine and plasma osmolarity could be done using a fluid deprivation test, but this may not be appropriate for a critically ill patient. If the diag- nosis is in question, the basal plasma AVP level should be measured, if >2 pg/mL, nephrogenic DI is the cause. Levels

<1 pg/mL indicate the need for brain magnetic resonance ima-

ging for diagnosis of pituitary DI versus polydipsia. A more rapid assessment of DI cause is through a therapeutic trial of AVP or desmopressin. In pituitary DI, the urine osmolarity and volume will normalize in 8 hours. Serum sodium should be monitored every 4 to 6 hours. Treatment of pituitary or gestational DI includes controlled water replacement and AVP or desmopressin therapy. Desmo- pressin is a synthetic analog of AVP with a longer duration of effect. It has more antidiuretic than vasopressor effect com- pared with AVP and can be given via intravenous, subcuta- neous, oral, and intranasal routes, although potency differs between forms. Desmopressin is more resistant to degradation

by vasopressinase than AVP in gestational DI. 73 In acute DI,

desmopressin is given as 1 mg subcutaneous every 12 hours or 2 mg intravenous every 12-hours and doses are adjusted based

on clinical response with close monitoring of urine output since response can be inconsistent. E xcessive dosing can lead to volume overload and hyponatremia. Water and volume replacement are important components

of therapy to replace a deficit and manage ongoing losses.

Acute hypernatremia may be corrected more rapidly, but con-

trolled reduction in sodium by no more than 10 mmol/L/d is suggested to avoid cerebral edema. Resuscitation to achieve hemodynamic goals can be done with 0.9% sodium chloride

Summary

Many endocrine emergencies present with nonspecific symp- toms and may be triggered by other illnesses and conditions. Clinical suspicion based on concurrent diseases, medications, and ongoing laboratory testing can identify these syndromes. A systematic approach to treatment and diagnosis is needed. Hor- mone replacement may be needed before diagnosis is com- plete. Electrolyte correction should be done at a controlled rate with close monitoring.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author- ship, and/or publication of this article.

ORCID iD

Judith Jacobi, PharmD, FCCP, MCCM, BCCCP

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