What happens to sodium in SIADH?

Clinical Presentation

The hyponatremia of SIADH is usually asymptomatic.

Symptoms occur most often when the sodium level is less than 120 mEq/L or when a drop in sodium develops rapidly.

Signs and symptoms include nausea, cramps, lethargy, disorientation, agitation, seizures, and coma.

Etiology

Excess ADH leads to retention of free water by the kidney, resulting in expansion of the intravascular space and hyponatremia.

There is no clear unifying cause or pathophysiology.

Most patients appear to have disordered regulation ADH in response to hypo‐osmolality.

CAUSES OF SIADH

SIADH is associated with a great number of illnesses and most often presents as a coincidental biochemical manifestation of the causative disease. The most common causes of SIADH are summarized in Table 21-3. The origin of SIADH is clinically divided into four categories: malignant, pulmonary, pharmacologic, and neurologic causes.

Bartter and Schwartz first described SIADH in association with bronchogenic lung carcinoma. In small cell carcinoma of the lung, SIADH is relatively common, occasionally occurring as the presenting abnormality that prompts a search for the tumor.99 Most neoplasms have been reported to cause SIADH, and the association between malignant disease and SIADH is so strong that a patient presenting with SIADH, general malaise, and unexplained weight loss should be considered to have an underlying malignancy until proven otherwise.

SIADH is commonly associated with intracranial diseases, particularly traumatic brain injury,65-67 in which almost all cases resolve spontaneously with recovery from brain injury. More than 50% of patients with subarachnoid hemorrhage develop hyponatremia in the first week following the bleed, and 70% of these events are due to SIADH.100 SIADH also commonly occurs after hypophysectomy and after surgery for primary brain tumor.

Many drugs are important clinical causes of hyponatremia. The selective serotonin reuptake inhibitors (SSRIs) are thought to cause SIADH by direct stimulation of AVP secretion by serotonin.101 SIADH usually occurs in the first few weeks after SSRIs are introduced, particularly in elderly patients.102 It has been estimated that 12% of hospitalized patients on SSRI therapy develop SIADH.103 Psychotropic medications such as phenothiazines, haloperidol, and tricyclic antidepressants all cause SIADH. Many patients who have conditions treated with psychotropic drugs also have abnormal thirst; if these patients develop drug-induced SIADH, they can develop very significant hyponatremia. For instance, up to 20% of patients with chronic schizophrenia have psychogenic polydipsia, and excess fluid intake can precipitate severe hyponatremia. MDMA (“Ecstasy”) is thought to stimulate both AVP release and thirst as a result of hyperthermia, and this has been implicated in the development of cases of life-threatening hyponatremia.104

SIADH must be distinguished from exercise-associated hyponatremia (EAH),105 in which the electrolyte profile mimics SIADH. The pathophysiology is different, however. EAH occurs in athletes who ingest excessive hypotonic fluid during exercise, with resultant dilutional hyponatremia. Women, marathon runners racing for longer than 4 hours, and athletes of low body mass index are at greatest risk.106 Although some athletes with EAH fail to suppress AVP, EAH probably should be considered to be distinct from SIADH.

5.6 The Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

The syndrome of inappropriate antidiuretic hormone secretion (SIADH, also known as Schwartz–Bartter syndrome) is due to excessive and inappropriate release of antidiuretic hormone (ADH). Usually reduction of plasma osmolality causes reduction of ADH secretion, but in SIADH reduced plasma osmolality does not inhibit ADH release from the pituitary gland, causing water overload. The main clinical features of SIADH include:

Hyponatremia (plasma sodium<131 mmol/L)

Decreased plasma osmolality (<275 mOsm/kg)

Urine osmolality>100 mOsm/kg) and high urinary sodium (>20 mmol/L)

No edema.

Various causes of SIADH are listed in Table 5.1.

Table 5.1. Causes of SIADH*

Type of DiseaseSpecific Disease/CommentsPulmonary diseasesPneumonia, pneumothorax, acute respiratory failure, bronchial asthma, atelectasis, tuberculosis.NeurologicalMeningitis, encephalitis, stroke, brain tumor infection.MalignanciesLung cancer especially small cell carcinoma, head and neck cancer, pancreatic cancer.HereditaryTwo genetic variants, one affecting renal vasopressin receptor and another affecting osmolality sensing in hypothalamus have been reported.Hormone therapyUse of desmopressin or oxytocin can cause SIADH.DrugsCyclophosphamide, carbamazepine, valproic acid, amitriptyline, SSRI, monoamine oxidase inhibitors and certain chemotherapeutic agents may also cause SIADH.

19.2.3.5 Epidemiology of SIADH

SIADH is one of the most common causes of hyponatremia in the hospital setting and frequently leads to severe hyponatremia (plasma Na < 120 mEq/l) (Anderson et al., 1985). Following its initial description in 1957, it has become apparent that SIADH is a common occurrence in an ever growing number of disease states (Table 19.4). SIADH most often occurs due to central nervous system disorders, pulmonary disorders, malignancies and medications (Zerbe et al., 1980). SIADH has been implicated in a variety of conditions that deserve special emphasis.

Table 19.4. Causes of SIADH

Central nervous system disordersMalignanciesInfection: meningitis, encephalitisCarcinomasBrain tumorsBronchogenicVascular abnormalitiesOat cell of the lungPsychosisStomachHydrocephalusDuodenumCongenital malformationsPancreasPost-pituitary surgeryProstateHead traumaUreterSubarachnoid hemorrhageBladderCerebrovascular accidentThymomaCavernous sinus thrombosisMesotheliomaGuillain–Barré syndromeEndometriumMultiple sclerosisNeuroblastomaDelerium tremensOropharynxAmyotrophic lateral sclerosisAcute intermittent porphyriaLymphomasSarcomaPulmonary disordersMedicationsPneumoniaVincristineTuberculosisIntravenous cytoxanAspergillosisCarbamazepineAsthmaOxcarbazepineCystic fibrosisNarcoticsPositive pressure ventilationSeritonin reuptake inhibitorsPneumothoraxTricyclic antidepressantsNicotine3,4-methylenedioxymethamphetamine (ecstasy)Non-steroidal anti-inflammatory drugs

A condition similar to SIADH is seen in the postoperative setting, especially following orthopedic and head and neck surgery. Hospital acquired hyponatremia is commonly seen in the postoperative setting (Chung et al., 1986). Postoperative patients develop hyponatremia due to a combination of non-osmotic stimuli for ADH release, such as narcotics, subclinical volume depletion, pain, nausea, stress, edema-forming conditions and administration of hypotonic fluids. ADH levels are universally elevated postoperatively when compared to preoperative values (Wilson et al., 1988; Grant et al., 1991). Premenopausal females are most at risk for developing hyponatremic encephalopathy postoperatively (Ayus et al., 1992).

SIADH

SIADH is a disorder in which there is increased ADH secretion despite low plasma osmolality. Water retention results in hyponatremia and serum hypo-osmolality. Suppression of aldosterone secretion and increased secretion of atrial natriuretic peptide in response to high intravascular volume lead to increases in urinary sodium excretion. The main causes of SIADH are shown in Table 2.5. Most patients with SIADH do not have specific clinical features unless the hyponatremia is severe (Na+ <125 mmol/L); however, mild hyponatremia has been associated with falls, inattention, and gait impairment in elderly populations [37]. Symptoms of moderately severe hyponatremia include anorexia, nausea, vomiting, and headaches. With profound hyponatremia (Na+ <110) or with rapidly developing hyponatremia, confusion, convulsions, hemiparesis, and coma become evident.

Table 2.5. Major causes of SIADH.

NeoplasiaCarcinoma of bronchus, duodenum, pancreas, nasopharynx, ureter, or prostate; leukemia; thymoma; mesotheliomaPulmonary disordersPneumonia, tuberculosis, lung abscess, positive pressure ventilation, chronic obstructive airway diseaseCentral nervous system disordersEncephalitis, meningitis, head injury, Guillain–Barré syndrome, acute intermittent porphyria, brain abscess, brain tumor, subdural hematoma, subarachnoid hemorrhage, vasculitisDrugsChlorpropamide, vincristine, cyclophosphamide, phenothiazines, tricyclic antidepressants, SSRIs, ACEIs, carbamazepine, amiodaroneOtherAcquired immunodeficiency syndrome, strenuous exercise, idiopathic

The biochemical features that favor the diagnosis of SIADH include hyponatremia, low serum osmolality (<275 mOsm/kg), urine Na+ >40 mmol/L, and inappropriately elevated urine osmolality (>100 mOsm/kg) in the setting of low plasma osmolality [38]. Supplemental findings include a serum uric acid of <4 mg/dL and blood urea nitrogen <10 mg/dL. Adrenal insufficiency, hypothyroidism, and diuretic use should be excluded before making the diagnosis of SIADH.

Hyponatremia With Normal Total Body Sodium: Syndrome of Inappropriate Antidiuretic Hormone

In SIADH, nonosmotic AVP secretion and thirst are present despite normal perfusion.29,68,69 The combination of nonosmotic AVP secretion and no hemodynamic activation of the RASS/sympathetic nervous system can result in a very negative EFWC: UNa + UK ≫ SNa. This puts the patient at high risk of hyponatremia when hypotonic fluids, such as water, 5% dextrose, or half-strength Darrow's solution with 5% dextrose, are prescribed or ingested.70 When urine sodium concentration is high, infusion of 0.9% NaCl can result in a worsening of the hyponatremia because the sodium is excreted in a smaller volume than that infused and electrolyte-free water is retained (“desalination”).12 Failure to increase SNa with 0.9% NaCl is a practical way to distinguish SIADH from hyponatremia with reduced ECV.

In the critically ill, SIADH may be due to various drugs (see Table 56.1) and diseases (see Table 56.2). Causes of SIADH may be divided rationally into (1) self-limiting mechanisms (common in the hospitalized patient), with an inherent risk of overcorrection when the AVP stimulus is abolished (e.g., cessation of nausea), and (2) persistent conditions (e.g., paraneoplastic phenomenon) that, in the absence of arginine V2-receptor antagonist treatment, rarely will be overcorrected.6

The conventional criteria for SIADH are plasma hypo-osmolality (P-Osm < 275 mOsm/kg) without maximally diluted urine (urine osmolality > 100 mOsm/kg, usu­ally >300 mOsm/kg); high urine sodium concentration (>40 mmol/L); normal circulation; and normal renal, thyroid, and adrenal function.29,71 However, in the critically ill patient, other hyponatremia mechanisms are likely to coexist (e.g., renal impairment, use of diuretics) and must be detected and corrected. When persistent SIADH is the likely diagnosis, the cornerstone is investigation and treatment of its underlying causes (e.g., cancer).

In critical illness, correction of the hyponatremia is achieved primarily by restriction of hypotonic water and infusion of hypertonic saline (e.g., 0.1–0.4 mmol/kg/hr). In the persistent form of SIADH, V2-receptor antagonist treatment may be the most effective option; however, treatment most be monitored to avoid overcorrection and dehydration. EFWC often can be increased with loop diuretics or osmotically by supplemental salt or urea treatment.72

Excessive Antidiuretic Hormone

Patients with SIADH resulting from malignancy have the usual problems present in malignancy, such as anemia and malnutrition, often with fluid and electrolyte imbalance as well. Perioperatively, they usually have low urine output, high urine osmolality, low serum osmolality, and delayed awakening from anesthesia or awakening with mental confusion.

Where does sodium go in SIADH?

What happens to sodium when ADH is released?

What happens to urine sodium in SIADH?

What electrolytes does SIADH affect?