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REVIEW
83SPRING 2012 | INTERNATIONAL JOURNAL OF INTENSIVE CARE
➟
Electrolyte disturbances associated
with medications in the critically ill
EPIDEMIOLOGY
Electrolyte disturbances are common in the ICU.1
Hyponatraemia is the most frequent electrolyte disorder,
affecting about 30–40% of hospitalised patients, while
the estimated incidence in the critically ill patient popula-
tion has been estimated at 25%.7Other common electrolyte
abnormalities observed in the ICU setting include those
of potassium, calcium, phosphate and magnesium.6,8,9
Although the incidence of electrolyte disorders has
been approximately identified, that of medication-related
electrolyte disturbances in the ICU remains largely
unknown.3Most critically ill patients have several comor-
bid disease states, both acute and chronic disease, and are
prescribed numerous medications, all of which may con-
tribute to electrolyte disturbances.3Therefore, it is not
always possible to identify electrolyte disorders that are
directly associated with a specific medication in this patient
population.
PATHOPHYSIOLOGY AND MECHANISMS
The development of drug-induced electrolyte disturbances
in the ICU occurs through a wide array of complex path-
ways involving single or multiple mechanisms.3–5 The exact
manner in which medications can induce or contribute to
electrolyte abnormalities varies depending upon the agent’s
properties, and possibly related to its mechanism of
action.3–5 However, some proposed mechanisms of drug-
induced disorders are completely unrelated to the known
effects of the medication’s pharmacology.3–5 Mannitol, an
osmotic diuretic, has been shown to result in hyperna-
traemia due to volume depletion.10,11 Obviously, this effect
would be expected given its known mechanism of action,
but the impact of other medications on electrolyte serum
concentrations may not be as apparent. For example, both
heparin and low molecular-weight heparins have been asso-
ciated with hyperkalaemia.12 The proposed mechanism
involves a reduction in both the number and affinity of
angiotensin II receptors.12 Therefore, a decrease in aldos-
terone synthesis leads to a hyperkalaemic state. Aggressive
electrolyte replacement administered in ICU patients is the
most recognised explanation for elevated electrolyte serum
concentrations.3Tables 1–5 summarise the proposed
mechanisms for each medication-induced electrolyte dis-
order.
CLINICAL PRESENTATION
Overall, the clinical manifestations of electrolyte disorders
in ICU patients can be non-specific and potentially related
to multiple acute or chronic disease states.1The severity of
the clinical signs and symptoms of electrolyte imbalances
may be associated with the rate of fluctuation in the serum
concentration as well as the magnitude of change.1,3
Significant variability is seen in symptoms, which range
from asymptomatic to life-threatening complications for
any given electrolyte disorder.1,3 Unfortunately, the clinical
Electrolyte imbalances are common in critically ill patients.
Although many disease states typically encountered in the
intensive care unit may be responsible for the development of
electrolyte disorders, medications can also contribute to these
disturbances. Medications can interfere with the absorption of
electrolytes, alter hormonal responses affecting homeostasis
and directly impact organ function responsible for maintaining
electrolyte balance. The purpose of this review is to address
commonly prescribed medications in the intensive care unit
and potential electrolyte disturbances that may occur as a
result of their use. This review also discusses the postulated
mechanisms associated with these drug-induced disorders.
The specific drug-induced electrolyte disorders discussed
involve abnormalities in sodium, potassium, calcium,
phosphate and magnesium. Clinicians encountering electrolyte
disturbances should be vigilant in monitoring the patient’s
medications as a potential aetiology. Insight into these drug-
induced disorders should allow the clinician to provide optimal
medical management for the critically ill patient, thus
improving overall healthcare outcomes.
Electrolyte disturbances are common in the critically
ill.1Patients in the intensive care unit (ICU) may be
more susceptible to electrolyte abnormalities than the
non-critically ill population,1 and the incidence electrolyte
disorders in ICU patients has been estimated at 25%.2A
high proportion of critically ill patients may experience elec-
trolyte disturbances as a result of medication therapy.3–5
Unfortunately, an accurate incidence of drug-induced dis-
orders remains unknown since the vast majority of these
patients have several confounding factors as a potential
cause.3–5 In addition, the incidence varies depending upon
the specific electrolyte disorder.3–5
Electrolytes are vital to various important physiological
functions in the body.1Normal electrolyte homeostasis
encompass a complex system involving multiple organs,
neurohormonal pathways, fluid status and acid–base bal-
ance.1,6 The clinical manifestations can range from asymp-
tomatic to death, depending upon the specific electrolyte
disorder and the magnitude of the abnormality in the
patient’s serum concentration.1–3 However, common signs
and symptoms of most disorders include altered mental sta-
tus, muscular weakness, cardiac rhythm disturbances and
respiratory failure.1–3
Unfortunately, awareness of these medication-induced
disorders in ICU patients may be low.1Clinicians’ recogni-
tion of common ICU medications as potential contributors
to electrolyte abnormalities can be hindered by the com-
plexity of the patient. ICU patients often present with mul-
tiple disease states, both acute and chronic, which may be
considered the sole cause. In addition, knowledge of both
direct and indirect drug-induced abnormalities may not be
widely known.1–5 The purpose of this review is to increase
awareness of common medications as a potential source of
electrolyte disturbances in ICU patients.
MS Buckley PharmD
FCCM BCPS,
Department of Pharmacy,
Banner Good Samaritan
Medical Center,
Phoenix, Arizona, USA
ELECTROLYTE DISTURBANCES IN THE ICU
84 INTERNATIONAL JOURNAL OF INTENSIVE CARE | SPRING 2012
➟
signs and symptoms of electrolyte abnormalities in an ICU
patient may be non-specific (e.g., nausea, vomiting, mus-
cle weakness).1,3 Nonetheless, medications can often be
readily identified as a potential cause of electrolyte disor-
ders, and of the patient’s symptoms.
Sodium
Sodium represents the most abundant extracellular cation
in the body.13 Water and sodium homeostasis are highly
integrated and regulated through various mechanisms to
maintain extracellular fluid volume as well as tonicity.13,14
Aldosterone and atrial natriuretic factor primarily effect
sodium serum concentrations.13,15 Although hypona-
traemia is defined as a serum sodium concentration of less
than 135 mmol/L, this value may not reflect total body sodi-
um as excess water intake can result in a dilutional effect.1,16
Conversely, hypernatraemia (serum sodium >145
mmol/L) can develop from pure water loss, although
patients might not present with clinical signs and symptoms
until serum sodium exceeds 158 mmol/L.1,14
Symptoms are usually progressive as the sodium concen-
tration declines, ranging from nausea and malaise in slight-
ly hyponatraemic patients to more severe symptoms,
including seizures or coma, if concentrations decline to less
than 115 mmol/L.16 Central nervous system clinical mani-
festations are the result of osmolarity and significant fluid
shifts.1Symptom severity is closely related to the magnitude
and rate of serum sodium concentration changes. Slower
rates provide brain cells with sufficient time to self-regulate,
thus resulting in less severe clinical manifestations.16 Both
hyper- and hyponatraemia are further classified as hyper-
volaemic, euvolaemic, and hypovolaemic, based upon vol-
ume status.1
Potassium
Potassium is the second most common cation following
sodium and is primarily found in the intracellular space.1
Insulin, ␣-adrenergic catecholamines and aldosterone pri-
marily control the transcellular shift of potassium and renal
elimination to maintain a narrow physiologic serum con-
centration.17 These neurohormones stimulate the Na+/K+
ATPase pump to result in intracellular potassium uptake,
although aldosterone is responsible for causing renal excre-
tion.18–21 Insulin and aldosterone are released to promote
potassium excretion or transcellular shifting through a
complex feedback system in response to states of hypo- and
hyperkalaemia.22
Electrolyte disorders involving potassium are common
in the ICU and may have fatal consequences.1Abnormal
neuromuscular and cardiac function can occur in either
hypo- or hyperkalaemia.1Although most patients are
asymptomatic, clinical manifestations of hypo- and hyper-
kalaemia may become apparent with serum potassium con-
centrations below 2.5 or above 5.5 mEq/L, respectively.1
Signs and symptoms of hypokalaemia include nausea, vom-
iting, muscle weakness, cramping and rhabdomyolysis,
while hyperkalaemic patients may present with weakness,
paralysis or respiratory failure.23,24 Both hypo- and hyper-
kalaemia can result in cardiac arrhythmias, including ven-
tricular tachycardia and ventricular fibrillation.25
Drug-induced potassium imbalances primarily involve
medications either directly or indirectly affecting renal
Table 1. Medication-induced causes of sodium disturbances
Mechanism Medication
Hyponatraemia
Impaired urinary diluting capacity Thiazide diuretics, loop diuretics
Volume expansion secondary to increased
osmolality Mannitol
Stimulation of thirst via conversion of angiotensin
1 to 2 ACE inhibitors
Renal salt wasting Trimethoprim sulfamethoxazole
Syndrome of inappropriate antidiuretic hormone
secretion Proton-pump inhibitors (specifically omeprazole and esomeprazole), nicotine,
chlorpropamide, tolbutamide, clofibrate, cyclophosphamide, morphine,
barbiturates, vincristine, acetaminophen, carbamazepine, ACE inhibitors, NSAIDs,
antipsychotics, desmopressin, oxytocin, and antidepressants (SSRIs, TCAs)
Secondary to inhibition of prostaglandins and
potentiation of vasopressin’s effect on the tubule NSAIDs
Hypernatraemia
Hypotonic fluid caused renally Loop diuretics
Volume depletion Mannitol
Nephrogenic diabetes insipidus Amphotericin B, demeclocycline, dexamethasone, dopamine, ifosfamide,
lithium, ofloxacin, orlistat, foscarnet
Exogenous sodium load Hypertonic 3% saline or normal (0.9%) saline, antibiotics containing sodium
Hypertonic sodium gain by renal water loss Hypertonic sodium bicarbonate infusion, sodium chloride hypertonic infusion
Gastrointestinal loss Osmotic cathartic agents (lactulose, sorbitol)
ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inflammatory drug; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant
ELECTROLYTE DISTURBANCES IN THE ICU
85SPRING 2012 | INTERNATIONAL JOURNAL OF INTENSIVE CARE
function, the renin–angiotensin–aldosterone system or
transcellular potassium shifting.3
Calcium
Calcium plays a pivotal role in maintaining haemostasis,
cellular membrane stability and bone structure.3,6 Calcium
is also intricately involved in skeletal, myocardial and
smooth muscle function. Although ample amounts of this
electrolyte are found in the human body, the vast majority
(>99%) is stored in the bone.3Serum calcium is largely con-
trolled between the parathyroid hormone and vitamin D
feedback system, with calcitonin, magnesium, epinephrine,
phosphate and interleukins playing minor roles.1The
parathyroid hormone maintains serum calcium concentra-
tions by causing osteoclast-induced release of calcium from
the bone, renal reabsorption of calcium in the kidney and
increased calcium absorption in gastrointestinal tract.3
Ionised serum calcium is the only physiologically active
fraction, while the protein-bound and chelated-complex
forms are inactive. Calculating the true incidence of hypo-
and hypercalcaemia in the ICU population is problematic,
and is done by estimating an ionised calcium concentration
as opposed to using absolute values.3
Cardiac arrhythmias and neurologic dysfunction are
common with calcium disorders.1Tetany may result from
hypocalcaemia, while acute renal failure, anorexia and
death can be associated with hypercalcaemia.1Many med-
ications have been found to induce calcium disorders.
Medications adversely affecting parathyroid hormone lev-
els, vitamin D concentrations, calcium chelation reactions
and bone resorption rates have been proposed as inducing
hypocalcaemia as well as hypercalcaemia.3Diuretics have
also been associated with both hypo- and hypercalcaemia.3
Phosphorus
Phosphorus is the most abundant intracellular anion in the
body, with about 85% of stores found in the bone.26,27Serum
phosphorus concentrations do not accurately correlate to
total body stores (i.e., intracellular concentrations).26,27 The
organic form of phosphate accounts for most of the serum
phosphorus in the human body, while about 33% exists in
the inorganic form.26 It should be noted that inorganic
phosphate may be present in several forms, including
unbound, protein-bound and complexed forms.26 While
phosphorus is necessary for many physiologic functions
within the human body involving the immune system and
➟
Table 2. Medication-induced causes of potassium disturbances
Mechanism Medication
Hypokalaemia
Stimulation of Na+/K+ATPase pump Sympathomimetics (epinephrine, terbutaline, fenoterol, albuterol), insulin,
methylxanthines (theophylline, aminophylline), dobutamine
Inhibition of sodium reabsorption in the loop of
Henle and distal renal tubule Loop and thiazide diuretics
Elevation of the osmolality of the glomerular filtrate Osmotic diuretics
Inhibition of hydrogen ion secretion by the renal
distal tubule Carbonic anhydrase inhibitors
Enhancement of sodium reabsorption at the renal
distal tubule Adrenocortical steroids (mineralocorticoids/glucocorticoids)
Sodium reabsorption and solute diuretic in the
renal collecting duct Natural penicillin, penicillinase-resistant penicillin, aminopenicillins, extended-
spectrum penicillins
Magnesium depletion Aminoglycosides (gentamicin, tobramycin, amikacin), amphotericin B
Inhibition of hydrogen secretion by renal collecting
duct Amphotericin B
Exchange of sodium for potassium within the
intestinal lumen Cation-exchange resin (sodium polystyrene sulphonate)
Hyperkalaemia
Excess potassium administration Citrate, penicillin G, enteral and parenteral nutrition formulations
Competitive inhibition of aldosterone/reduce
sodium absorption in renal distal tubule Spironolactone/amiloride, triamterene, trimethoprim
Inhibition of the Na+/K+ATPase pump Metoprolol, propranolol, labetalol, digoxin
Interference with conversion of angiotensin I into
angiotensin II/induces state of hypoaldosteronism ACE/ARB
Decreases number and affinity of angiotensin II
receptors, reducing aldosterone synthesis Heparin, low molecular-weight heparin
Ion-channel depolarization Succinylcholine
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker
ELECTROLYTE DISTURBANCES IN THE ICU
86 INTERNATIONAL JOURNAL OF INTENSIVE CARE | SPRING 2012
➟
coagulation processes, ATP production is one of its most
vital roles.27 Phosphorus homeostasis is largely regulated
through the kidneys, with the gastrointestinal tract and
bone playing minor roles.27,28
The incidence of clinically significant phosphorus distur-
bances in the ICU is relatively low compared with other elec-
trolyte disorders.3Neurological and muscular dysfunction
are common in hypophosphataemia, and may include res-
piratory depression, seizures, paresthesias and paralysis.1In
addition, gastrointestinal and renal dysfunction can be asso-
ciated with hypophosphataemia.1The most common clini-
cal manifestation of hyperphosphataemia is hypocalcaemia,
as well as the signs and symptoms associated with hypocal-
caemia.3Drug-induced hypophosphataemia may be caused
by pharmacologic agents inhibiting the absorption of dietary
phosphate, increasing renal elimination or affecting tran-
scellular fluctuations.1Medication-related causes contribut-
ing to hyperphosphataemia are primarily through
exogenous phosphorus supplementation.3
Magnesium
Magnesium is the second most common intracellular cation.
Like other electrolytes, serum magnesium concentrations
are poorly reflective of the overall body content.29Total body
stores of magnesium are largely found in the bone, with
smaller amounts located in skeletal muscle, soft tissue and
erythrocytes.29 In addition, serum magnesium exists in sev-
eral forms as ionised, protein-bound and complexed forms
with other substances.30 Magnesium is essential in multiple
organ systems and physiologic processes, including immune
functions and neuromuscular effects.29–31 It is also respon-
sible for the regulation of intracellular ions responsible for
cellular metabolism and conduction.31 Serum magnesium
concentrations are maintained through complex processes
involving the bone, gastrointestinal tract and kidneys, with
involvement of parathyroid hormone, insulin, vitamin D,
vasopressin and calcitonin.30–32 However, serum concentra-
tions are primarily controlled by the kidneys, with about 5%
of renally filtered magnesium being excreted.31
Table 3. Medication-induced causes of calcium disturbances
Mechanism Medication
Hypocalcaemia
Decreased bone resorption Fluoride poisoning, chemotherapeutic agents (cisplatin, carboplatin, 5-fluorouracil
with leukovorin, dactinomycin, cyclophosphamide, ifosfamide, doxorubicin with
cytarabine), bisphosphonates, calcitonin, amphotericin B, cimetidine, ethanol
Calcium chelation or precipitation Foscarnet, citrate, phosphate ingestion (oral, enema, intravenous), edetate
(contrast dye and propofol), albumin, lipid emulsion solutions with total
parenteral nutrition, heparin
Vitamin D deficiency Phenytoin, phenobarbital, ketoconazole, rifampicin, isoniazid, primidone
Decreased parathyroid hormone secretion or action Aspirin, oestrogen, magnesium sulphate, colchicine, propylthiouracil, calcitonin,
loop diuretics
Hypomagnesaemia Aminoglycosides (amikacin, gentamicin, tobramycin, neomycin)
Increased urinary calcium excretion Loop diuretics
Hypercalcaemia
Increased bone reabsorption Vitamin D
Increased calcium absorption Vitamin D, vitamin A
Decreased urinary calcium excretion Loop diuretics
Miscellaneous Oestrogen, tamoxifen, thiazide diuretics, lithium
Table 4. Medication-induced causes of phosphate disturbances
Mechanism Medication
Hypophosphatemia
Malabsorption Antacids (aluminium- or magnesium-containing), sucralfate, phosphate binders
(calcium-containing products)
Transcellular shift Aspirin (overdose), albuterol, catecholamines (epinephrine, dopamine), insulin
(exogenous), sodium bicarbonate
Urinary excretion Acetaminophen (overdose), chemotherapeutic agents (ifosfamide, cisplatin,
cyclophosphamide, doxorubicin), diuretics (thiazides, loop, osmotic, carbonic
anhydrase inhibitors), glucocorticoids, theophylline (overdose)
Hyperphosphataemia
Excess phosphate administration Phosphate-containing enema/laxative, phosphate (exogenous, intravenous or
oral sources)
ELECTROLYTE DISTURBANCES IN THE ICU
87SPRING 2012 | INTERNATIONAL JOURNAL OF INTENSIVE CARE
➟
The clinical manifestations of hypomagnesaemia include
muscle weakness, respiratory depression and neurologic
abnormalities (seizures and coma).1,3 Hypermagnesaemia
can cause nausea, vomiting, loss of deep tendon reflexes and
hypotension. Both hypo- and hypermagnesaemia can lead
to cardiac arrhythmias.1,3 Several medications contribute to
hypomagnesaemia, possibly by affecting the kidney’s abil-
ity to reabsorb magnesium as well as by causing transcellu-
lar shifts.3However, the exact mechanisms of drug-induced
hypo- and hypermagnesaemia remain unknown.3
MANAGEMENT AND MONITORING
The management of drug-induced electrolyte disorders
varies significantly depending upon the known or suspect-
ed electrolyte and the severity of symptoms.3Unfortunately,
few prospective clinical trials have investigated treatment
strategies for electrolyte disturbances.1Therefore, the man-
agement of electrolyte imbalances has been historically based
upon clinical experience and expert opinion.1Although an
extensive clinical management pathway for all electrolyte
disorders is beyond the scope of this article, treatment is typ-
ically supportive with close monitoring.1Several drug ther-
apy options are available for each specific electrolyte.1
However, the decision-making process must take into
account key factors in determining optimal management.
First, the symptom severity will likely guide the clinician
in choosing therapy options. For example, a patient expe-
riencing potentially life-threatening cardiac arrhythmias
because of elevated serum potassium concentrations may
require several medications (e.g., calcium gluconate,
insulin) to treat the acute disorder, while an asymptomat-
ic patient with elevated serum potassium concentration of
5.0 mEq/L may only require close monitoring. The clini-
cian must also consider the rate of electrolyte correction.
Aggressive treatment strategies used in potentially life-
threatening conditions (e.g., 3% sodium chloride infusion
rate for symptomatic hyponatraemia) may be associated
with an increased risk of adverse drug events. Concomitant
disease states (e.g., chronic kidney disease, heart failure)
should be acknowledged by the healthcare provider in
determining which medications will be used to manage the
electrolyte disorder, as well as in deciding the optimal elec-
trolyte dosing replacement strategy in patients with defi-
cient serum electrolyte concentrations. Lastly, medication
costs should be considered. Newer therapies are typically
more expensive than more established medications. The
clinician must evaluate the cost of a more expensive agent
and the potential impact on clinical outcomes. For exam-
ple, sevelamer and lanthanum carbonate are acceptable
treatment options compared with other phosphate-bind-
ing agents (aluminium- and magnesium-containing phos-
phate binders). The clinician should assess clinical efficacy,
safety and cost in deciding a drug’s role in the overall man-
agement plan.
The management of acute electrolyte disorders in the ICU
requires discontinuation of the suspected or known agents
causing or contributing to the abnormality. Alternative
medications should be considered in patients who require
acute management or long-term drug therapy for their dis-
ease state. Supportive measures are often required for
patients who present symptoms and revolve around the spe-
cific clinical manifestations. Management also includes
close monitoring of the patient’s symptoms, as well as lab-
oratory data for drug-induced electrolyte disorders.
PREVENTION
Electrolyte disorders may be avoided through increased
awareness of the medications associated with each disorder.
Unfortunately, ICU patients may be at an increased risk of
developing certain electrolyte abnormalities (e.g., patients
with chronic kidney disease might be treated with several med-
ications associated with hyperkalaemia). Increased vigilance
towards specific intravenous fluids and nutrition require-
ments in ICU patients is essential in minimising or complete-
ly eliminating the risk of developing electrolyte disturbances.
Critically ill patients with non-drug- and drug-induced fac-
tors associated with electrolyte abnormalities should be close-
ly monitored to prevent clinical complications.
CONCLUSION
Drug-induced electrolyte disorders are common in ICU
patients. Several medications can cause or contribute to
these abnormalities. Medications induce electrolyte com-
plications mostly by manipulating the normal physiology
of electrolyte regulation related to the drug’s mechanism of
action. Although the incidence and risk each medication
carries for the development of electrolyte disturbances may
be unclear, recognition of potential drug-induced causes in
ICU patients is essential for the overall management.
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Table 5. Medication-induced causes of magnesium disturbances
Mechanism Medication
Hypomagnesaemia
Increased renal excretion Aminoglycosides (gentamicin, tobramycin, amikacin, neomycin), amphotericin
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CORRESPONDENCE TO:
Mitchell S. Buckley
Clinical Pharmacy Specialist
Department of Pharmacy
Banner Good Samaritan Medical Center
1111 E. McDowell Rd
Phoenix, AZ 85006
USA
E-mail: mitchell.buckley@bannerhealth.com
