Hyponatremia has been observed in up to 46 % of hospitalized cancer patients, and when present, is associated with a poor prognosis compared with euvolemic patients, regardless of tumor type [40–46]. The reported incidence varies greatly, and is affected by the cancer type and the cutoff point for serum used to define hyponatremia. Hyponatremia has been reported most frequently with small cell lung cancer (SCLC) [47]. The syndrome of inappropriate antidiuretic hormone release (SIADH) is the most common cause of hyponatremia in cancer patients, with higher rates among those with SCLC than with other malignancies [48, 49]. Ectopic antidiuretic hormone (ADH) can be produced by tumors, chemotherapeutic agents, pain and nausea, and by other medications commonly prescribed in this population. Even though SIADH is a common cause of hyponatremia in cancer patients, these patients are also at increased risk for hypovolemic hyponatremia from volume contraction due to vomiting, diarrhea, and salt-wasting nephropathy.

There are two important points to keep in mind when approaching disorders of serum sodium: (1) Disorders of serum sodium are essentially disorders of serum osmolarity, and (2) disorders of serum sodium are disorders of relative concentrations of salt and water since serum sodium is expressed in mEq/L. So, even in the patient who has hypovolemic hyponatremia, there is an excess of total body water (TBW) relative to total body sodium .

To elaborate on the first point, disorders of serum sodium can be approached as disorders of serum osmolarity since serum osmolality = 2 Na + Glucose/8 + BUN/2.8. Therefore, in a euglycemic patient, serum sodium essentially equals serum osmolality. Serum osmolality is normally tightly maintained between 280–290 mOsm/L and within 1–2 % in a particular individual. Osmoreceptors located in the anterior hypothalamus detect serum osmolality, and, under physiologic conditions, an increase in serum osmolarity causes release of ADH from the posterior pituitary. In the kidneys, ADH binds to V2 receptors on the basolateral membrane of collecting ducts cells to promote insertion of aquaporin-2 channels to the apical membrane. Increased free water permeability of the apical membrane promotes free water absorption, and consequently, reduces serum osmolality closer to the normal range. ADH also stimulates thirst at higher values of serum osmolality. In the hyperosmolar patient, the end effect of ADH release is increased free water retention. The other physiologic stimulus for ADH release is a decline in plasma volume of  > 7–9 % [50, 51]. These systems are bimodal and importantly, in the absence of an elevated serum osmolality or a significant decrement in plasma volume, ADH should not be released. Therefore, to make the diagnosis of SIADH, the patient should be euvolemic and have a normal serum osmolality .

An algorithm for evaluating these patients is proposed in Fig. 7.2.The first step in evaluating the patient with hyponatremia is to measure the serum osmolality. Hyperosmolar hyponatremia in cancer patients can occur in the setting of procedures like hysteroscopy or transurethral resection of the prostate. During these procedures, large volumes of nonconductive flushing solutions containing glycine are used to create a surgical field within the body cavity. The large volumes of these solutions create elevated pressures within the body cavity. This allows osmotically active particles like glycine to translocate into the venous circulation. Osmotically active particles in the extracellular space cause movement of water from the intracellular to the extracellular space to equalize the osmotic gradient across the cell membrane. As a result, the serum sodium decreases due to dilution. Hyponatremia can occur via the same mechanism when intravenous immune globulin is given in a maltose or sucrose solution, or when patients are hyperglycemic or given mannitol.

A normal serum osmolality in a hyponatremic patient signifies that the patient has pseudohyponatremia. As the moniker suggests, these patients have a normal serum osmolality and normal serum sodium, but, due to the presence of excessive amounts of lipids or paraproteins in circulation, there is a reduction in the fraction of serum that is water and an artificially low serum sodium concentration is measured. With the newer ion specific electrode method, this miscalculation should not be an issue. It is important to identify this category of patients since they require no further therapy for hyponatremia .

After excluding the patient with hyperosmolar hyponatremia and pseudohyponatremia, the remaining patients fall into the category of hypoosmolar hyponatremia. Since this group lacks an osmolar stimulus for ADH release, the only physiologic stimulus for ADH release would be a significant decrement in plasma volume. Therefore, determining the volume status in these patients, as well as measuring the urine osmolality and urine sodium, will help to identify the etiology of the dysnatremia, as well as provide information on the appropriate treatment for this group.

Assessing the volume status in cancer patients can be challenging. Edematous patients may actually have intravascular volume depletion if the edema is the result of a pelvic mass compressing the lymphatic system; if it is due to a deep venous thrombosis or to IVC compression; or if the patient has a capillary leak syndrome from the malignancy itself. Patients with liver metastasis as a cause of hepatorenal syndrome can also have significant ascites and edema on examination, but have significant intravascular volume depletion due to vasodilation within the splanchnic circulation. Resting tachycardia can be a misleading sign of volume contraction since these patients experience pain, anxiety, and discomfort. Therefore, when feasible, checking orthostatic blood pressures can provide valuable information on the volume status of these patients.

Since all hyponatremia cases are essentially disorders of relative concentrations of salt and water, with relatively more TBW than salt, knowing the volume status of the patient can help to clarify the pathogenesis of the electrolyte disorder. In the hypervolemic patient, total body salt and TBW are both increased. In the hypovolemic patient, both are decreased but there is relatively more TBW than sodium. In the euvolemic patient, TBW and sodium are fairly normal but these patients do have slightly more TBW than salt, but no appreciable edema .

As stated previously, the diagnosis of SIADH can only be made in a patient who has a normal serum osmolality and normal plasma volume. In patients with SCLC, the tumor itself is the source of inappropriate ADH release. Additional etiologies of inappropriate ADH release in cancer patients include pain, nausea, and chemotherapy. Chemotherapeutic agents can alter central ADH secretion and its effects in the renal tubules. Vincristine and vinblastine are directly toxic to the hypothalamic pituitary axis and disturb the normal osmotic regulation of ADH secretion [52, 53]. Cisplatin and cyclophosphamide both induce ADH release, and the latter also potentiates ADH effect in the kidney. Commonly prescribed medications like tricyclic antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, and opioids stimulate ADH secretion. Nonsteroidal anti-inflammatory medications potentiate ADH effect in the renal tubules [53]. Conditions associated with cancer can also cause SIADH and include CNS or pulmonary diseases, such as subarachnoid hemorrhage, pneumonia, mechanical ventilation, and metastasis of the lungs and brain [51].

In the patient with hypovolemic hyponatremia, a review of the patient’s history and medication list will often reveal the source of their volume deficit. Volume losses from diarrhea, diuretics, or hyperglycemia are easily identified. A cause of hypovolemic hyponatremia that warrants special attention in cancer patients is saltwasting nephropathy. Cisplatin and ifosfamide directly injure renal tubule cells, thereby impairing renal sodium reabsorption [54, 55]. Cerebral salt wasting due to metastatic CNS disease, surgery, and trauma has also been described. Hyponatremia due to either nephrogenic or cerebral salt wasting may be difficult to distinguish from SIADH, since the urine osmolality and urine sodium can be elevated relative to the serum values. Importantly, patients with either type of salt wasting become volume contracted if their urinary losses of salt and water exceed the amount that they are able to ingest orally. Clinically, patients with salt wasting are hypotensive and/or orthostatic on examination, whereas the patients with SIADH appear euvolemic .

The clinical signs and symptoms of hyponatremia are in large part manifestations of increased intracerebral pressure due to brain edema. When the serum sodium and serum osmolality are lower than that within the brain cells, water shifts into the brain cells. Since the skull is a fixed cavity, it cannot expand to accommodate this increase in brain volume. Some clinical signs of increased intracranial pressure include nausea, confusion, vomiting, decline in mental status, ataxia, and seizures. If the brain volume markedly exceeds the skull volume, frank herniation of the brainstem occurs. There are adaptive mechanisms in place to mitigate brain edema in the setting of hyponatremia. When the serum sodium drops too rapidly relative to the ability of the brain to adapt to the change in osmolality, clinical signs and symptoms develop. This explains why one patient presents seizures and another can appear asymptomatic at equivalent serum sodium values.

The brain’s adaptive mechanisms are essentially aimed at decreasing its water content back to normal by extruding solute. In rat models, Na²⁺and Cl⁻are extruded via the Na²⁺and Cl⁻ channels present in the cell membrane within 30 min of induction of hyponatremia. These electrolyte losses are maximal at around 3 h. After longer periods of persistent hyponatremia, organic osmolytes like glutamate, creatine, and taurine exit the brain cell [56]. These compensatory adaptations explain why rapid correction of chronic hyponatremia leads to rapid egress of water from the brain cells. In mild cases, dehydration of the brain tissue occurs, and in severe cases, osmotic demyelination can occur. The current recommendation is that the serum sodium should not be corrected more than 12 mEq/L within the first 24 h, and generally, at a rate of not more than 0.5 mEq/L/h [51] .

The severely symptomatic hyponatremic patient who are euvolemic or hypervolemic and are present with seizures, impaired mental status, or coma should be managed in consultation with a nephrologist and/or a critical care specialist. These patients require frequent neurological evaluations and monitoring of their serum sodium values while they receive 3 % NS. Importantly, the severely symptomatic patient with hyperosmolar hyponatremia should not receive 3 % NS. Administration of hypertonic solutions in this setting is contraindicated as they worsen the hyperosmolar condition in such patients. These patients may require urgent dialysis. Patients with significant hypovolemia should be treated with boluses of NS until a euvolemic state is achieved. Thereafter, the rate of correction of the serum sodium should not exceed 10–12 mEq/L in a 24 h period.

For patients with hypoosmolar hyponatremia who are minimally symptomatic, the appropriate treatment depends largely on their volume status and on the disease state that is responsible for their volume status. Hypervolemic hyponatremia due to iatrogenic volume overload is best managed by minimizing all intravenous solutions, with or without the addition of diuretics. Patients with congestive heart failure are best managed by minimizing all salt containing intravenous solutions (NS, Normosol, Lactated Ringers, and half NS) and with the use of diuretics. Furosemide is the diuretic of choice in the treatment of hyponatremia, since thiazide type diuretics can actually cause hyponatremia. The aquaretic agents, conivaptan and tolvaptan, have been shown to increase serum sodium by 6–8 mEq/L within a 48 h period without the hypokalemia and accompanying metabolic alkalosis that can result from treatment with diuretics [57].

The management of the asymptomatic patients with euvolemic hypoosmolar hyponatremia is a bit more multidimensional. If nausea, vomiting, and pain are stimulating ADH, then appropriate use of antiemetics and pain medications can diminish these nonphysiologic stimuli for ADH release. Any of the culprit medications that have been implicated as a cause of hyponatremia (see Fig. 7.3) should be discontinued if it is safe to do so. Additional interventions are all aimed at decreasing the relative concentrations of salt and TBW in the patient. Patients can be asked to restrict their fluid intake to 1–1.5 L of free water per day. Patient compliance with fluid restriction can be difficult since they are frequently told to “stay well hydrated” while on chemotherapy and because their pain medications and antidepressants can make them dipsogenic. Therefore, adjunctive pharmacologic therapy is frequently needed. In patients whose blood pressures can tolerate it, furosemide can be used to increase free water losses via the urine. Usual doses in patients with normal renal function are 10–20 mg per day.In euvolemic patients, NaCl tablets can be administered as well. V2 receptor antagonists are the new class of agents which can be used in the management of hypervolemic and euvolemic hyponatremia . V2 receptor antagonists block ADH-mediated insertion of aquaporin channels at the apical membrane of the collecting duct cells. Consequently, free water is lost in the urine. The currently available intravenous and oral formulations in the USA are conivaptan and tolvaptan, respectively. Although tolvaptan is administered orally, the package insert states that the medication needs to be started in the inpatient setting in order to check serial serum sodium values so that overly rapid correction of hyponatremia can be properly identified and managed. In a small study of cancer patients, tolvaptan was shown to be safe and to have superior efficacy in controlling hyponatremia when compared with standard therapy using fluid restriction, diuretics, and salt tablets. No patients overcorrected [58]. Any combination of fluid restriction, NaCl tablets, furosemide, and/or a V2 receptor antagonist can be used to achieve a normal serum sodium value in this group of patients.

Hypernatremia can be conceptualized in a manner similar to hyponatremia in that establishing the relative concentrations of salt and water in the patient and the volume status of the patient yields the correct diagnosis. Patients receiving exogenous sodium (hypertonic saline, IV NS, oral NaCl tablets, IV sodium bicarbonate) tend to be volume overloaded and/or hypertensive because they have an excess of salt relative to free water. Patients who have lost free water in excess of salt are volume depleted and/or hypotensive. Examples of such cases include free water losses from the kidney (diuretics), skin (high fevers, excessive sweating), respiratory tract (ventilated patients), and from the GI tract (diarrhea, vasoactive intestinal peptide producing tumors, or VIPomas). In all of these cases, if the patient cannot match or exceed the free water losses, the serum sodium concentration rises.

Because of ADH’s tight control of serum osmolarity within a very narrow range, when serum sodium increases (for example from 140–150 mEq/L) thirst is stimulated and individuals “drink themselves” back to a normal serum sodium. Therefore, hypernatremia develops when there is a defect in the synthesis or release of AVP from the pituitary (central diabetes insipidus, CDI) or unresponsiveness of the renal tubule to AVP (nephrogenic DI). The most common etiologies of CDI are neurosurgery, trauma, primary or metastatic tumors, and infiltrative diseases [59]. Leukemic infiltration of the pituitary stalk in patients with acute leukemias has also been reported to cause CDI [60, 61]. Most patients with CDI or NDI have a normal thirst mechanism and are also present with polydipsia. In the general adult population, the most common causes of NDI are chronic lithium use, hypokalemia and hypercalcemia [59]. In cancer patients, obstructive uropathy from masses at the bladder neck or ureter can also cause ADH unresponsiveness. Amyloid deposition along the basement membrane of medullary collecting ducts has been associated with unresponsiveness to AVP [62]. Chemotherapeutic agents and medications commonly used for the management of infectious complications following chemotherapy and bone marrow transplantation that have been associated with NDI include cidofovir, indinavir, tenofovir, foscarnet, amphotericin, ifosfamide, cyclophosphamide, methotrexate, and ofloxacin [63–67]. A water deprivation test can help to distinguish CDI from NDI and a detailed explanation of this test can be found elsewhere [59] .

Hypervolemic or euvolemic hypernatremia can be managed with discontinuing exogenous salt containing IVFs and by correcting the free water deficit orally with free water or intravenously with 5 % dextrose water. There are numerous online calculators to measure the water deficit, or the following equation can be used:

To avoid brain edema, which can occur if the deficit is corrected too rapidly, only half of the calculated water deficit should be administered within the first 24 h. The serum sodium should not be corrected more than 12 mEq/L over the initial 24 h. When correcting hypovolemic hypernatremia, the best approach is to re-expand and the intravascular volume with 0.9 % or 0.45 % NS until the patient is no longer orthostatic. For patients with ongoing GI, renal, and insensible fluid losses, a portion of these losses should be added to the calculated deficit. Concomitant hypercalcemia and hypokalemia needs to be corrected as both conditions are associated with unresponsiveness of the renal tubules to AVP .

Among the general hospital population, hypomagnesemia has been observed in up to 15 % of patients [68, 69]. The incidence of hypomagnesemia appears to be higher among hospitalized cancer patients, especially critically ill cancer patients, with reported frequencies of 17 and 46 %, respectively [70–73]. Hypomagnesemia, when present, may be associated with poorer clinical outcomes. One study that looked at hypomagnesemic and normomagnesemic groups with comparable APACHE II scores found that the mortality rates of the hypomagnesemic medical ICU and non-ICU groups were approximately twice the rate of the normomagnesemic groups [74]. Of note, hypomagnesemia may actually be underreported since the serum magnesium level is not reported as part of the routine chemistry panel .

The incidence and severity of hypomagnesemia is particularly high among patients who receive treatment with cisplatin and monoclonal antibodies directed against the epithelial growth factor receptor (eEGFR) domain (cetuximab, panitumumab) . In a recent meta-analysis of the incidence of hypomagnesemia with cetuximab therapy, the incidence of all grade hypomagnesemia was 37 %. Panitumumab-induced hypomagnesemia was reported in 90 % of patients treated at one center [75]. Not infrequently, treatment with these agents has to be interrupted or stopped as a consequence of severe magnesium depletion. While patients receiving anti-EGFR therapy seem to respond to magnesium supplementation and maintain normal magnesium levels after the drug is stopped, a proportion of patients with ifosfamide- and cisplatin-related hypomagnesemia can have persistently low levels for years after cessation of drug treatment [76]. The incidence and severity of hypomagnesemia due to cisplatin and anti-EGFR therapy appear to be related to duration of exposure to these agents[77]. Other cancer drugs that can cause hypomagnesemia include cyclosporine, tacrolimus, pegylated liposomal doxorubicin, and interleukin-2. Other medications frequently given to cancer patients that can cause or potentiate hypomagnesemia include diuretics, aminoglycosides, amphotericin B, pentamidine, gentamicin, and proton pump inhibitors [69]. Proton pump inhibitors have been associated with hypomagnesemia (gastrointestinal loss of Mg) after prolonged use, usually more than a year [78–80].

Less than 2 % of the total body magnesium is present in the extracellular space, and only two third of this amount is unbound to albumin (free) and is active. The remainder of total body magnesium resides in bones and soft tissues, with the bones being the principal source of magnesium. The kidneys and the GI tract are the major organs of magnesium absorption and elimination from the body. Although magnesium depletion from GI losses can occur from upper or lower tract losses, lower tract secretions contain much larger magnesium content than upper tract secretions. (15 mEq/L in the lower tract versus 1 mEq/L in the upper tract) [81]. Thus, hypomagnesemia is more common with diarrhea, malabsorption, and short bowel resection compared with vomiting or nasogastric suction .

Magnesium elimination from the body occurs predominantly in the kidneys. In the setting of magnesium depletion, the kidneys fastidiously conserve magnesium, with the main site of magnesium reabsorption being the thick ascending limb of the loop of Henle. Magnesium handling in the kidney is slightly different than for other electrolytes in that the threshold for urinary excretion of magnesium is very close to the normal serum concentration of this electrolyte. Consequently, if a hypomagnesemic patient is receiving an IV bolus of magnesium and the serum magnesium rises abruptly, the kidneys quickly eliminate magnesium. For this reason, it is recommended that magnesium infusions should be given slowly to improve magnesium absorption and minimize renal elimination.

Hypokalemia and hypocalcemia can coexist with hypomagnesemia, so there is overlap between some of the clinical signs and symptoms of hypomagnesemia and deficiencies of these other electrolytes. Neuromuscular symptoms of magnesium deficiency include generalized weakness, tetany, seizures, delirium, and coma. Cardiac manifestations include EKG changes (widening of the QRS complex, flattening of the T wave) and ventricular and atrial arrhythmias .

The severity of the clinical manifestations of hypomagnesemia and the extent of the deficiency determines the appropriate dose and route for magnesium repletion. In the setting of ventricular arrhythmias or EKG abnormalities, IV magnesium sulfate 1–2 g can be given as a bolus followed by a slow infusion once hemodynamic stability is achieved. For severe asymptomatic hyponatremia (serum magnesium less than or equal to 1 mg/dl or 0.4 mmol/L, 4–8 g of magnesium sulfate can be infused slowly over 12–14 h. For less significant deficiencies (serum magnesium levels > 1.2 mg/dl or 0.5 mmol/L) oral magnesium can be used, preferably using a sustained release preparation .