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Review article
A diverse group of acid-base balance disorders and disturbances before the initiation of chemotherapy
electrolyte abnormalities have been described in regimens as well as during treatment.
patients with acute leukemia (AL) (1–4). These Disorders of acid-base and electrolytes are also
disturbances are mainly considered to be associated frequently encountered in critically ill patients and
with the leukemic process, organ infiltration, cell in patients with malignant non-hematological dis-
death and/or therapeutic interventions (1, 2, 5, 6). eases, and may be present as metabolic emergencies
Electrolyte and acid-base perturbations may be (10, 11). Although acid-base and electrolyte dis-
present regardless of the blast cell type [acute orders may be a result of the underlying patho-
myelogenous leukemia (AML) or acute lymphocy- physiology (e.g. renal failure, respiratory failure,
tic leukemia (ALL)] or the state of the disease. shock), they may also result from the way we
These abnormalities present a potential hazard in manage these patients (12). Regardless of their
patients with AL, as that of enhancing the cardi- etiology, the presence of these disorders typically
otoxic effects of certain chemotherapeutic regimens. signals the development of an underlying pathol-
In fact, fatal complications, such as sudden death ogy. These disturbances can be severe and are often
due to malignant arrhythmias, have been reported associated with worse outcome (11).
in leukemic patients as an associated synergistic In the following sections, we focus on specific
effect between anti-neoplastic drugs and electrolyte leukemia-related acid-base and electrolyte abnor-
disorders (1, 7–9). Therefore, clinicians should be malities and their interrelations in leukemic patients
vigilant for early detection and appropriate man- (Tables 1 and 2). Large-scale studies with reference
agement of concurrent acid-base and electrolyte to this issue are scarce in bibliography. Sources
449
Filippatos et al.
included MEDLINE and EMBASE (last search remains a poorly illuminated metabolic distur-
update performed on June 6, 2005). The search bance, primarily described in patients with acute
strategy was based on the combination of keywords monocytic and acute myelomonocytic leukemia
Ôacute leukemiaÕ, Ôelectrolyte abnormalitiesÕ, Ôacid- (M4 and M5) (3, 14, 15). In a consecutive series
base disordersÕ, ÔpotassiumÕ, ÔsodiumÕ, ÔmagnesiumÕ, of 22 patients with AL, Lantz et al. (5) demonstra-
and ÔphosphorusÕ. References of retrieved articles ted that leukemic patients had a significantly lower
were also screened. potassium concentration per kilogram of body
weight, per kilogram of lean body mass and total
body water when compared with healthy volunteers
Potassium (P < 0.001). This was evident during disease
relapse as well as during remission.
Hypokalemia
Hypokalemia in AL is of multifactorial origin. It
Hypokalemia is the most pronounced electrolyte has been mainly attributed to lysozymuria-induced
abnormality in patients with AL. Its frequency renal tubular injury with kaliuresis and persists
ranges from 43% to 64% in this population (3–5, despite potassium supplementation (5, 14, 16–18).
13). Although frequently noted, hypokalemia Osserman and Lawlor (19), as early as 1966,
450
Table 2. Clues to diagnosis and management of electrolyte abnormalities in patients with acute leukemia
Abnormality Leukemia subtype Related drug therapy Sings and symptoms Electrocardiographic (ECG) findings Treatment
Hypokalemia Mainly AML, ALL Polymyxine B; amphotericin B; penicillins; Muscular weakness, fatigue, muscle Broadening of T waves, prominent U Potassium orally or intravenously. In cases
aminoglycosides cramps waves, premature ventricular of severe hypokalemia (<2.5 mmol/L) and
contractions associated ECG findings, prompt correction
is advised. In refractory hypokalemia,
magnesium levels should also be measured
Hyperkalemia AML, ALL Cytotoxic drugs causing tumor lysis Muscle weakness, abdominal Peaked T waves of increased A metabolic emergency, as it predisposes to
syndrome; co-trimoxazole distension amplitude, widening of the QRS, life-threatening cardiac arrhythmias.
biphasic QRS-T complexes Calcium gluconate 10%, insulin with
dextrose water, inhaled beta2-agonists,
isotonic sodium bicarbonate, potassium-
binding resins, dialysis (if necessary)
Hyponatremia AML, ALL Vincristine; cyclophosphamide; polymyxine Usually asymptomatic; CNS symptoms Water restriction in cases of SIADH or
B; cytosine arabinoside; co-trimoxazole (in patients with serum sodium levels administration of normal saline in hypovo-
<120 mmol/L) lemic patients. The correction rate of
hyponatremia needs to be no more than
0.5 mmol/L/h.
Hypernatremia Mainly AML, ALL Amphotericin B Orthostatic hypotension and oliguria Water drinking and/or administration of
(when dehydration exists). CNS hypotonic solutions intravenously in more
symptoms (in severe cases) severe cases. Vasopressin analog DDAVP
may be considered in rare cases of central
diabetes insipidus
Hypomagnesemia AML, ALL Prednisone; aminoglycosides; amphotericin; Weakness, muscle cramps; in severe Prolonged PR and QT intervals Elemental magnesium orally (250–500 mg
pentamidine cases, neurologic symptoms (lethargy, two to four times daily). In cases of severe
tremor, nystagmus, ataxia, tetany, and hypomagnesemia, intravenous fluids
seizures) containing magnesium chloride or
magnesium sulfate. Infusion rate should be
adjusted to maintain serum magnesium at
levels no more than 1.25 mmol/L
Hypermagnesemia AML, ALL Cytotoxic drugs, causing tumor lysis Seen if serum magnesium level is Prolonged PR, QRS and QT intervals; Avoid magnesium preparations in patients
syndrome >1.65 mmol/L: neuromuscular complete heart block and asystole with renal failure. Severe symptomatic
abnormalities (muscle weakness, hypermagnesemia should be treated with
decreased deep tendon reflexes, 10% calcium gluconate, 10–20 mL over
lethargy) and respiratory failure 10 min intravenously
Hypophosphatemia AML, ALL In severe cases (serum phosphorus Asymptomatic hypophosphatemia requires no
>1 mg/dL, 0.3 mmol/L): muscular therapy except correction of underlying
abnormalities (weakness, rhabdomy- cause. Phosphate supplementation is
olysis), impaired diaphragmatic function, needed only if serum phosphorus is below
neurologic abnormalities (confusion, 1 mg/dL (0.3 mmol/L)
stupor, seizures, coma), hemolysis and
platelet dysfunction (rarely)
Hyperphosphatemia AML, ALL Cytotoxic drugs causing tumor lysis See hypocalcemia Correction of hypovolemia and coexistent
syndrome; liposomal amphotericin B impairment of renal function; management
of the tumor lysis syndrome (see text); oral
phosphate binders (calcium carbonate,
0.5–1.5 g three times daily with meals)
451
Leukemia-associated electrolyte disorders
Filippatos et al.
insufficiency
appears in serum, nasal and lacrimal secretions and
various body fluids (14). High serum and urinary
lysozyme levels have been demonstrated in patients
with disorders characterized by proliferation of
granulocytes and macrophages (20), such as AL
Cyclosporine as treatment prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation has been associated with a wide array of metabolic disturbances (128). (primarily M4 and M5) (19, 21, 22), multiple myel-
Electrocardiographic (ECG) findings
Cyclosporine1
452
Leukemia-associated electrolyte disorders
of the RAAS by paraneoplastic production of action, however, is short lived, and treatment may
renin-like substances might contribute to the need to be repeated. Insulin promotes the intracel-
observed hypokalemia in AL patients. lular shift of potassium, and is administered with
Finally, in some cases factitious hypokalemia has dextrose to prevent hypoglycemia. Inhaled beta2-
been described in leukemic patients as the result of agonists may also produce an intracellular shift of
the uptake of potassium by immature leukemic potassium. Isotonic sodium bicarbonate can be
cells, when plasma has not been separated imme- used to reduce metabolic acidosis and also to shift
diately after venipuncture (29). potassium intracellularly. However, sodium bicar-
The safest way to treat mild to moderate potas- bonate should be administered judiciously in
sium deficiency is with oral potassium. All potas- patients with acute renal failure as it can lead to
sium formulations are easily absorbed. Intravenous inappropriate volume expansion. Potassium-bind-
potassium replacement is indicated for patients ing resins, such as sodium polystyrene sulfate,
with severe hypokalemia and for those who cannot exchange sodium for potassium cations in the
take oral supplementation (30, 31). In addition to gastrointestinal tract. As resins typically require a
potassium administration discontinuation of drugs longer time to effect removal, faster methods of
causing hypokalemia and correction of magnesium lowering potassium such as dialysis may be
deficiency may be needed (32). required, especially in the setting of acute renal
failure (39).
The principles of management of tumor lysis
Hyperkalemia
syndrome should address three critical areas: hydra-
Some AL patients, especially those who are newly tion, metabolic abnormalities, and supportive treat-
diagnosed, show elevated serum potassium, phos- ment of renal failure. Hydration should begin 2 d
phorus and magnesium levels (1). This could be due prior to, and continue 2–3 d after, chemotherapy.
to the accumulation of these electrolytes as a result of Volume expansion with isotonic saline reduces
urate nephropathy as well as renal failure as a result serum concentrations of uric acid, phosphate, and
of leukemic infiltration of the kidneys and/or severe potassium. Asymptomatic hypocalcemia should not
leukostasis with consequent microvascular insuffi- be treated due to the risk of exacerbating calcium
ciency (33–36). Furthermore, the increase of these phosphate precipitation. Intravenous calcium gluc-
ions could be a result of their release from malignant onate is indicated for symptomatic hypocalcemia.
cells following cytotoxic therapy. This phenomenon Hypocalcemia usually resolves with treatment of the
is known as the Ôtumor-lysis syndromeÕ, which is an concomitant hyperphosphatemia. Finally, the cor-
oncologic emergency that is characterized by severe nerstone of prevention and treatment of hyperuri-
metabolic derangements, such as hyperkalemia, cemia includes both inhibiting the formation of uric
hyperphosphatemia, hypocalcemia and hyperuri- acid (allopurinol) as well as increasing its renal
cemia. It typically occurs in patients with lympho- clearance (urine alkalinization) (39).
proliferative malignancies who are exposed to
chemotherapy, radiation, or corticosteroids, but
can occur spontaneously in the absence of treatment Sodium
(37). Patients with pre-existing acute or chronic renal
Hyponatremia
insufficiency are predisposed to developing the
syndrome and are more vulnerable to its effects. Low serum sodium levels are infrequently noticed
Hyperkalemia may appear from 6 to 72 h after the in patients with AL. It has been reported to affect
initiation of chemotherapy (38) and is the most about 10% of leukemic patients (3, 4). Hypo-
serious manifestation of tumor-lysis syndrome. Cell volemic hyponatremia appears to be the most
lysis results in the liberation of large amounts of common cause of hyponatremia in most series.
intracellular potassium into the extracellular fluid. This is usually the result of volume contraction (e.g.
Chronic kidney disease, acute renal failure, or gastrointestinal fluid losses due to vomiting or
concurrent acidosis may exacerbate hyperkalemia diarrhea) noted in leukemic patients at the time of
as the excretory capacity of the kidney can be disease presentation or during treatment (3).
overwhelmed by transcellular shifts due to potas- Hyponatremia in AL patients is rarely associated
sium release from lysing cells as well as acidosis (39). with the presence of the syndrome of inappropriate
The major goals of the treatment of acute anti-diuretic hormone (ADH) secretion (SIADH)
hyperkalemia are cardiac membrane stabilization, (40). Even though neoplasias are among the com-
intracellular shift of potassium, and reduction of monest causes of SIADH (41, 42), hyponatremia
total potassium load. Membrane stabilization is and hypochloremia secondary to SIADH have been
achieved with 10% calcium gluconate to prevent infrequently reported in the setting of AL relating
life-threatening cardiac arrhythmias. Its duration of either to the leukemic process per se (1) or to high
453
Filippatos et al.
dose cytosine arabinoside chemotherapy (43). Nev- reported that low serum magnesium levels may
ertheless, the most relevant context in the everyday be detected in as many as 30% of AL patients
clinical practice for the presence of SIADH is an (3). An increased transcellular magnesium shift
underlying infection of the respiratory or central from the extracellular to the intracellular space
nervous system (CNS) (44, 45) or disease-related significantly contributes to the decreased serum
CNS involvement due to leukemic infiltration (46). magnesium levels, especially in patients with
Salt-losing nephropathy can also be diagnosed as marked leukocytosis as well as in patients with
the cause of hyponatremia in patients with evidence alkalemia (58, 59). Furthermore, increased gas-
of mild renal function decline, abnormal urine trointestinal magnesium loss is probably the main
sediment findings, and hypovolemia (47). In these pathogenetic mechanism of hypomagnesemia in
patients a meticulous history of any underlying patients with acute or chronic diarrhea as a
renal disease or analgesic abuse should be obtained. consequence of cytotoxic chemotherapy or neu-
In the absence of the above potential causes, a tropenia-related gastrointestinal infections (60,
leukemia-induced tubular defect may be implicated 61). However, hypomagnesemia coexisting with
as the cause of renal sodium wasting (3). inappropriate magnesiuria has been described in
Treatment of hyponatremia includes water a significant proportion of patients, suggesting
restriction and/or administration of 0.9% saline that increased magnesium urinary losses may play
with furosemide. The correction rate of hyponatre- a key role in the pathogenesis of magnesium
mia need to be no more than 0.5 mmol/L/h in order depletion (3).
to avoid central pontine myelinolysis (48, 49). Inappropriate magnesiuria can be due to leuke-
mia-induced and/or lysozyme-induced tubular dys-
function. It is well known that in patients with AL
Hypernatremia
renal impairment may be associated with either
Elevated serum sodium levels have been reported in glomerular or tubular dysfunction (1, 16, 18).
some rare cases of AL. Nakamura et al. (50) have Indeed, active urinary sediment has been associated
ascribed hypernatremia to the leukemia-induced with increased urinary magnesium loss (3). More-
central diabetes insipidus (DI). Central DI is a over, it has been shown that leukemic cell products
rarely observed complication of hematological other than lysozyme are also linked to renal
malignancies, including myelodysplastic syndrome tubular injury and increased electrolyte excretion
and acute myeloid leukemia (51). Indeed, central (16). Finally, metabolic acidosis and phosphate
DI has been reported in AML patients with specific depletion observed in some hypomagnesemic
cytogenetic abnormalities, such as abnormalities of patients may be held responsible for the inappro-
chromosomes 3 and 7 (monosomy 7) (52–54). The priate magnesiuria as a result of reduced magnes-
proposed mechanism for the development of cen- ium reabsorption in the loop of Henle as well as in
tral DI is an inability of the hypothalamo-neuro- the distal tubule (62, 63).
hypophyseal fibers to secrete ADH, probably A renal wastage of magnesium may be associated
because of infiltration by leukemic cells. Typical with cyclical prednisone therapy (64–66), treatment
symptoms are polydipsia, polyuria, and marked with aminoglycoside antibiotics, such as amikacin
thirst. However, when the hypothalamic thirst (66–68), amphotericin (69–71) and pentamidine
center is damaged, central DI gives rise to Ôhypo- (72, 73).
dipsic hypernatremiaÕ and dehydration (55). In some patients with AL no apparent cause for
Interestingly, Dickenmann and Brunner (56) hypomagnesemia (some times severe) can be found.
have claimed free-water loss by urea-induced This pronounced fall in serum magnesium levels in
osmotic diuresis to be the cause of hypernatremia these patients could be due to low magnesium
in a patient with AL. In this case, the excretion of intake related to malnutrition and/or a grave
large amounts of urea was induced by severe disease course (3).
metabolic stress with high protein turnover requi- In patients with mild hypomagnesemia, mag-
ring large urine volume excretion. nesium oxide is given orally at a dose of 250–
Treatment of hypernatremia consists of encour- 500 mg two to four times daily to replenish
aging water drinking and/or administration of 5% magnesium stores. Treatment of severe hypo-
dextrose in water (i.e. hypotonic solutions) intra- magnesemia consists of discontinuation of drugs
venously in more severe cases (57). causing this abnormality and the use of intra-
venous fluids containing magnesium as chloride or
sulfate ion. In this case, serum magnesium levels
Magnesium
must be monitored and dosage adjusted to keep
Hypomagnesemia is a relatively common electro- the concentration from rising above 1.25 mmol/L
lyte abnormality in leukemic patients. It has been (74).
454
Leukemia-associated electrolyte disorders
455
Filippatos et al.
calcium absorption with a resulting hypercalciuria alkalosis, and (iii) patients with severe lower
(107, 108). Hypercalciuria has also been demonstra- respiratory infection and hypoxemia presented with
ted in children with acute lymphoblastic leukemia a combination of respiratory acidosis and meta-
and low levels of vitamin D and osteocalcin (66, 109). bolic alkalosis (3).
Finally, hypocalcemia has been observed during In the clinical setting of acid-base disequilibri-
treatment with aminoglycoside antibiotics (indu- um in patients with AL, restoration of hypovole-
cing hypermagnesiuria and hypercalciuria) (68), mia, effective treatment of underlying infections,
pentamidine (73) and cytotoxic agents (due to the and correction of concurrent metabolic distur-
precipitation of the calcium phosphate complex bances are cardinal constituents of the patientsÕ
following cell lysis-induced increase of phosphate remedy.
concentrations) (39). In cases of severe sympto-
matic hypocalcemia calcium gluconate 10% (10–
Drug-induced abnormalities (Table 3)
20 mL) administered intravenously over 10–15 min
and then calcium infusion is indicated. Concurrent Therapeutic interventions, including abnormal
hypomagnesemia must be corrected (90). cell-targeting agents as well as drugs used to
treat infections, represent well-established causes
of potentially hazardous metabolic disturbances in
Acid-base balance
patients with AL. As mentioned above, sponta-
Patients with AL often exhibit acid-base balance neous or therapy-induced Ôtumor-lysis syndromeÕ
disorders. In a study by Mir and Delamore (2), may result in hyperuricemia, hyperphosphatemia,
metabolic alkalosis was detected in 35% of hyperkalemia and hypocalcemia and may preci-
patients, and acidemia in another 10%. Metabolic pitate renal failure (110). Following vincristine
alkalosis was probably related to volume depletion and cyclophosphamide administration, changes
and hypokalemia, while acidemia developed in the such as acute or prolonged hyponatremia are
presence of renal failure. Respiratory alkalosis due frequently seen and are probably due to SIADH
to respiratory infection and hypoxemia has also (6); polymyxine B-induced nephrotoxicity is asso-
been described (3). ciated with hyponatremia, hypocalcemia and
In several studies, a large number of leukemic hypokalemia (1); trimethoprime-sulfamethoxazole
patients developed mixed acid-base disorders. Spe- (co-trimoxazole) induces hyperkalemia with meta-
cial attention should be drawn to the correct and bolic acidosis, and hyponatremia (111–115);
careful interpretation of acid-base and electrolyte amphotericin B use is related to hypokalemia,
parameters in order to disclose and elucidate the hypomagnesemia, hyperphosphatemia, and
underlying mechanisms of these mixed acid-base hypernatremia (70, 87, 116–119). Hypocalcemia
disorders. An underlying infection may play a seen after l-asparaginase treatment has been
prominent role in the development of these ascribed to the induction of hypoparathyroidism,
derangements. For example, in a series of 66 AL while (sometimes severe) hypokalemia is encoun-
patients: (i) patients with septicemia exhibited a tered after the administration of large doses of
combination of respiratory alkalosis (due to hyper- antibiotics (antipseudomonal penicillins, such as
ventilation) and metabolic acidosis (possibly due to piperacillin and ticarcillin) owing to a non-reab-
lactic acidosis), (ii) patients with acute diarrheal sorbable anion effect in the distal tubule or
illness showed a combination of diarrhea-induced changes in membrane ionic transport of all cells
hyperchloremic metabolic acidosis and respiratory (1, 67, 120, 121).
456
Leukemia-associated electrolyte disorders
Cardiotoxicity associated with the use of anthra- leukemia may be a clue for renal damage in long-term per-
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