Critical Care Pharmacotherapy Issue

Journal of Pharmacy Practice

1-13
Management of Endocrine Emergencies ª The Author(s) 2019
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in the ICU DOI: 10.1177/0897190019834771
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Judith Jacobi, PharmD, FCCP, MCCM, BCCCP1

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 stimulates the release of pituitary adrenocorticoid hormone

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)
(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, thyroid-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
2 Journal of Pharmacy Practice XX(X)
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
mg/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 using 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 bleeding, 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 doses. Corticosteroids 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
Jacobi 3

hypothyroidism plus a precipitating factor such as severe infec- Table 1. Drug Interactions Impacting Thyroid Replacement.11
tion, cardiovascular event, trauma, burn, or major surgery, and
Affects Thyroid Reduces Thyroid
the risk may be increased by nonadherence to thyroid replace- Absorption or Effect Action (Inactivation
ment therapy. Patients with myxedema coma exhibit exagger- Measured With or Increased
ated symptoms of hypothyroidism with core temperature as Medication TSH Elevation) Protein Binding)
low as 21 C, bradycardia, prolonged QT interval, reduced car-
diac output, and pericardial effusion and are at risk of cardio- Calcium carbonate þ
Proton pump inhibitors No effect (although
vascular collapse. Central nervous symptoms of stupor,
gastric acidity is
obtundation, and frank coma may occur. Muscle weakness and important for
altered response to hypoxia and hypercarbia may lead to absorption)
respiratory failure. Generalized skin and soft-tissue swelling, Cholestyramine þ
periorbital edema, ptosis, and cool dry skin may be observed. Colesevelam þ
Diagnosis of severe hypothyroidism requires clinical suspi- Sevelamer þ
cion and can be confirmed with demonstration of elevated TSH Polystyrene sulfonate þ
Sucralfate þ
and low thyroxine (T4) and triiodothyronine (T3) levels on
Aluminum antacids þ
admission. Unfortunately, diagnosis of thyroid dysfunction Raloxifene þ þ
becomes more difficult in patients with ongoing critical illness. Tyrosine kinase inhibitors þ
Levels of T3 may decline within hours after admission or sur- Phenobarbital þ
gery and the magnitude of further decline is correlated with the Phenytoin þ
severity of illness.9 The combination of low T3 and potentially Carbamazepine þ
inappropriately low thyroid hormone levels was historically Rifampin þ
Sertraline þ
called sick euthyroid syndrome but is now called nonthyroidal
Amiodarone þ
illness syndrome (NTIS). Low circulating T3, increased rever- Estrogen þ
seT3 (rT3), low TSH, and low T4 are observed. Multiple Tamoxifen þ
mechanisms contribute to low thyroxine levels as a protective Opioids þ
mechanism in illness and malnutrition to reduce energy Mitotane þ
requirements. Reduced protein production and binding may Fluorouracil þ
accelerate clearance of free hormone, and intracellular altera- Capecitabine þ
Androgens  (Reduce thyroid
tion of the deiodinase enzymes leads to increased metabolism
requirements)
to the inactive form of thyroxine, rT3. Changes in tissue levels
of thyroxine also occur but are not consistent across tissues. Abbreviation: TSH, thyroid-stimulating hormone.
Whether this is truly protective or maladaptive in chronic crit-
ical illness is not clear. Persistent symptoms of hypothyroidism
Common critical care drug therapies may alter thyroid hor-
such as impairment in consciousness, reduced myocardial
mones, including amiodarone, furosemide >80 mg/d, dopa-
function, hypothermia, and muscle weakness may impair
mine, glucocorticoids, and somatostatin analogs.10,11 Chronic
recovery. A high index of suspicion for the negative effects
of NTIS is needed to identify this syndrome in patients with medications such as lithium and metformin may also impact
chronic critical illness. TSH and thyroxine levels. Table 1 summarizes some key drug
Failure to provide an adequate dose of thyroxine may create effects. Severe hypothyroidism could reduce the metabolism of
a thyroid hormone deficiency. Concurrent drug therapy may other drugs, such as sedatives, although these medications are
impact levothyroxine absorption or metabolism and should be titrated to effect, so the clinical impact may be minimal.
evaluated when patients have an acute change in thyroid hor- Levothyroxine (T4) is the most common replacement therapy
mone levels (Table 1).9 and relies on conversion to the active metabolite, T3 with deio-
Like the HPA axis, thyroid hormone production is also on a dinase (D) enzymes. The D2 enzyme is primarily responsible for
feedback loop. Hypothalamic dysfunction lowers thyrotropin- T4 to T3 conversion, although the D1 enzyme also contributes
releasing hormone levels, pituitary dysfunction lowers TSH and captures iodine from inactivated thyroid hormones. The D1
levels, and primary thyroid dysfunction lowers thyroxine levels enzyme is inhibited by propylthiouracil and will be discussed in
(but increases TSH). Thyroxine is highly protein bound, so “Hyperthyroid” section. The D3 enzyme is responsible for inac-
measurement of unbound (free) T4 may be more accurate for tivation of T3 by conversion to rT3. Mutations of the deiodinase
diagnosis of hypothyroidism with reduced protein production enzymes and thyroid transporters have been described without a
(critical illness, pregnancy, estrogen/progestin therapy). The clear connection to clinical effects.12
free to total T4 fraction is the most important test to determine Treatment of acute thyroid insufficiency will depend on the
how the thyroid is functioning, in conjunction with TSH. The age, weight, and risk of complications. For myxedema coma, an
complex pattern of thyroid hormone changes in critically ill intravenous loading dose of levothyroxine of 200 to 400 mg is
patients requires a systematic approach to diagnosis as illu- recommended, although a lower dose may be safer for small or
strated in Figure 1.10 older patients, or those with cardiovascular disease or
4 Journal of Pharmacy Practice XX(X)

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 mg/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 mg 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 hospitalization, although concur-
rent enteral feeding, especially through a jejunal tube, may
alter bioavailability and prolonged 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 levothyroxine (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 insufficiency 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
Jacobi 5

appears to improve surrogate end points such as thyroxine Table 2. Diagnostic Criteria for Thyroid Storm.18
levels, hemodynamics, or cardiac performance, but studies
Measure Points
are not large enough to show improved patient outcome.9
Short-term thyroid replacement in NTIS does not appear to Temperature ( C)
cause harm, although excessive dosing could increase the risk 37.2-37.7 5
of atrial fibrillation and may lead to inappropriate long-term 37.8-38.2 10
therapy. 38.3-38.8 15
38.9-39.4 20
39.5-3.9 25
Thyroid Excess >40 30
Central nervous system symptoms
Patients with excess thyroid hormone production (thyrotoxico- Absent 0
sis) present with signs and symptoms of overstimulation. Com- Mild (agitation) 10
plaints of disturbed sleep, palpitations, fatigue, anxiety, tremor, Moderate (delirium, psychosis, extreme lethargy) 20
heat intolerance, sweating and polydipsia, and ophthalmopathy Severe (seizure, coma) 30
Gastrointestinal-hepatic dysfunction
(ptosis, periorbital edema, and diplopia) are typical. Thyrotox-
Absent 0
icosis can be precipitated by infection, surgery/trauma, iodine Moderate (diarrhea, nausea/vomiting, abdominal pain) 10
administration, antithyroid medication nonadherence, thyroid Severe (unexplained jaundice) 20
adenoma, or concurrent medical problems. Primary thyroid Cardiovascular dysfunction
excess is most commonly caused by Graves’ disease—an auto- Tachycardia (beats/min)
immune syndrome that may have genetic predisposition or be 90-109 5
triggered by environmental factors, stress, or infection with 110-119 10
120-129 15
Yersinia enterocolitica. The most severe manifestation, thyro-
130-139 20
toxic storm may lead to intensive care unit (ICU) admission for 140 25
symptoms such as fever, altered mental status (ranging from Congestive heart failure
agitation/psychosis/neuropsychiatric symptoms to confusion Absent 0
and coma), diffuse muscle weakness, tremor or fasciculations, Mild (lower extremity edema) 5
and cardiovascular problems (tachycardia out of proportion to Moderate (bilateral rales) 10
fever, arrhythmias, and heart failure).16 Pheochromocytoma, Severe (pulmonary edema) 15
Atrial fibrillation
neuroleptic malignant syndrome, or malignant hyperthermia
Absent 0
should be considered in the differential diagnosis. Present 10
Diagnosis of thyroid excess is confirmed with elevated total Precipitating history
and free T4, T3 along with low TSH, but hormone levels will Absent 0
not differentiate thyrotoxicosis from thyroid storm.17 Initial Present 10
care is supportive, and the underlying trigger should be identi-
A score 45 is highly suggestive of thyroid storm, 25 to 44 of impending
fied and managed while control of hyperthermia and arrhyth- thyroid storm, and <25 unlikely to be thyroid storm.
mias is initiated. The exact etiology is determined with
radioactive iodine uptake testing that may demonstrate diffuse
treats potential concomitant AI. Adjunctively, the level of cir-
uptake in Graves’ disease, irregular uptake in multinodular
goiter, or focal accumulation with adenoma. Alternatively, culating hormones can be reduced with plasmapheresis, plasma
thyroid ultrasound and measurement of TSH receptor antibo- exchange, or peritoneal dialysis, but these are not rapid
dies may be used to avoid exposure to radioactive iodine. Diag- interventions.
nostic criteria and a scoring system for thyroid storm have been Reduction of thyroid hormone production is primarily
proposed, and the components illustrate the potential scope of accomplished with antithyroid drugs. In thyroid storm (score
potential symptoms18 (Table 2). 45, Table 2), a high dose of propylthiouracil is suggested to
Treatment is multifaceted with a focus on symptom relief reduce production of T4 and conversion to T3. Severe symp-
and reduction of thyroid hormone levels. Patients with preex- toms are treated with a loading dose of 600 to 1000 mg, fol-
isting liver disease, pregnancy, or heart failure warrant special lowed by 250 mg every 4 to 6 hours, with dose reduction as
consideration.17 Beta-blockers are used to control the cardio- symptoms abate. Less severe initial symptoms of hyperthyroid-
vascular effects of thyroid hormone excess. Intravenous pro- ism may be managed with 100 to 300 mg every 8 hours and
pranolol 1 mg every 10 to 15 minutes until the patient is tapered to 50 mg given 2 to 3 times daily. Propylthiouracil is
stabilized is common, followed by 10 to 40 mg by mouth every preferred during the first trimester of pregnancy to minimize
4 to 6 hours. However, any other beta-blocker or calcium chan- the impact of uncontrolled hyperthyroidism on the neonate, but
nel blockers may be used. Cholestyramine is an adjunct to it may cause maternal hepatic toxicity in the later stages of
sequester thyroid hormone in the intestinal tract, trapping it pregnancy when methimazole is preferred. Teratogenic effects
during enterohepatic recirculation. Hydrocortisone 100 mg have not been observed, but other adverse effects including
intravenous every 8 hours reduces conversion of T4 to T3 and fetal hypothyroidism have been reported.
6 Journal of Pharmacy Practice XX(X)
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 finding 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 described—diabetic ketoacidosis
(DKA) and hyperglycemic hyperosmolar syndrome (HHS),
although the treatment is similar. The most common cause
of DKA/HHS is nonadherence to insulin 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 intravascular 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 severe22 (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 typically 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.
Jacobi
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 patients 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 routes 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
7
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. Although 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
8 Journal of Pharmacy Practice XX(X)
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. Calcium 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
Jacobi
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).
9
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 calcium 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 thyroidectomy 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
10
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 patient 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
Journal of Pharmacy Practice XX(X)
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 identified 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 of 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
Jacobi
There is a situation where hypernatremia may become
severe and constitute an endocrine crisis and that is DI. In this
setting, patients excrete large amounts of dilute urine as a result
of acute dysfunction of the pituitary gland following trauma or
hemorrhage, leading to reduced ADH production. Gestational
DI may result from degradation of arginine vasopressin (AVP)
by an enzyme produced in the placenta or renal insensitivity to
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
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. Excessive 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
11
or a balanced fluid such as lactated Ringers. Water deficit is
traditionally calculated (based on sodium lowering and weight)
and replaced with fluids that are hypotonic relative to the
patient’s serum, but as mentioned, these formulas may be unre-
liable and frequent sodium monitoring is needed during
replacement.68
Patients with hypervolemic hypernatremia may be treated
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
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 https://orcid.org/
0000-0003-2421-0734
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