Endocrinology
A 57 year old man with history of small cell lung cancer is brought to the Emergency Department with weakness, nausea and vomiting. He is alert with a normal neurological examination. His blood results are:
- Haemoglobin: 123 g/L
- White cell count: 10.3 x 109/L
- Sodium: 129 mmol/L
- Potassium: 3.5 mmol/L
- Urea: 6.3 mmol/L
- Creatinine: 83 μmol/L
What is the recommended management for this patient?
Answer:
The patient with small cell lung cancer is demonstrating signs and symptoms of hyponatremia. Lung cancers, especially small cell cancer, can lead to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). For relatively asymptomatic patients with sodium values of 115 to 135 mmol/L, a trial of free water restriction to less than 0.8 L/day to 1.25 L/ day should be attempted. As the hypo-osmolality in SIADH results from a relative abundance of water in the intracellular and extracellular volumes and is maintained by a reduced ability to excrete water, the restriction of free oral water intake is usually the most effective therapy.Syndrome of Inappropriate Antidiuretic Hormone Secretion
Endocrinology / Nephrology / Oncology & Palliative Care
Last Updated: 17th January 2023
Syndrome of inappropriate antidiuretic hormone (SIADH) is defined as euvolaemic, hypotonic hyponatraemia secondary to impaired free water excretion, usually from excessive antidiuretic hormone (ADH) release.
Pseudohyponatraemia due to hyperglycaemia, hyperlipidaemia, or hyperproteinaemia should be ruled out first. Renal failure, adrenal insufficiency, and appropriate release of ADH secondary to extracellular volume depletion (hypovolaemia, due to gastrointestinal or renal loss) or intravascular volume depletion (hypervolaemia due to congestive heart failure, cirrhosis of the liver, or nephrotic syndrome) must be ruled out in order to diagnose SIADH.
Causes
The potential causes of SIADH include increased ADH release or responsiveness. These may be due to:
- Malignancy:
- Lung, gastrointestinal, or genitourinary cancers; lymphomas; or sarcomas
- Neurological:
- CNS infections, brain trauma, haemorrhage, multiple sclerosis, Guillain-Barre syndrome, and acute intermittent porphyria
- Pulmonary:
- Pulmonary infections and lung cancers, especially small cell lung cancer
- Drugs:
- SSRIs, amiodarone, carbamazepine, chlorpromazine, amitriptyline, NSAIDs, and many chemotherapeutic agents such as cyclophosphamide, vincristine, and vinblastine
Diagnosis
Laboratory tests are used to confirm the following diagnostic criteria:
- Hypotonic hyponatraemia
- Low serum sodium (< 135 mmol/L) confirms hypotonic hyponatraemia
- Low serum osmolality (< 275 mOsmol/kg) confirms hypotonic hyponatraemia
- Relatively concentrated urine:
- High urine osmolality (> 100 mOsm/kg) indicates raised ADH levels when present in conjunction with low serum sodium and osmolality
- Euvolaemic hyponatraemia:
- High urine sodium (> 30 mmol/L) in euvolaemic patient is consistent with SIADH
- High fractional excretion of sodium and urea (>1% and >55%) confirms euvolaemic state
- Low serum urea (< 3.6 mmol/L) indicates mild volume expansion consistent with SIADH
- Low serum uric acid levels (<238 micromol/L) mild volume expansion consistent with SIADH
- Exclusion of endocrinopathy (to rule out hypothyroidism and Addison's, both of which can cause euvolaemic hyponatraemia):
- Normal serum TSH
- Normal serum cortisol
Further investigations may include a diagnostic trial with normal saline infusion. This is only performed in patients with suspected volume depletion and should not be used in symptomatic hyponatraemic patients. In SIADH, serum sodium level does not improve after a normal saline infusion (1-2 L of normal saline) is administered.
Rarely, plasma ADH level may be measured. This test may not be readily available and is only indicated in patients with non-diagnostic laboratory results or absence of SIADH aetiologies.
Management
- Hyponatraemia with severe neurological symptoms
- Severe neurological symptoms, such as altered mental status, seizure, and coma, are always treated with hypertonic saline (3% sodium chloride solution), with close monitoring to avoid overcorrection of serum sodium.
- Serum sodium levels should be checked every 2 hours, with a goal of increasing serum sodium by 1 to 2 mmol/L/hour until neurological symptoms resolve. Subsequently, correction is slowed to elevate serum sodium by no more than 8 to 10 mmol/L in a 24-hour period thereafter.
- Furosemide may be used in addition to hypertonic saline, especially if the patient is at risk for volume overload. Furosemide helps to correct hyponatraemia by increasing free water excretion. If furosemide is used in addition to intravenous hypertonic saline, infusion rates may need to be reduced, so as to avoid overcorrection of hyponatraemia. Hypokalaemia is monitored and corrected with intravenous potassium replacement.
- Central pontine myelinolysis (osmotic demyelination syndrome) may occur with rapid correction of serum sodium in excess of 12 mmol/L/day. Central pontine myelinolysis occurs with overcorrection of hyponatraemia where solute-poor cerebral cells are subject to shrinkage. It is characterised by demyelination of pontine, basal ganglion, and cerebellar regions, with resultant neurological symptoms, including behaviour disturbances, lethargy, dysarthria, dysphagia, paraparesis or quadriparesis, and coma. Seizures may also be seen but are less common.
- Investigation for an underlying disorder (e.g. malignancy, infection, pain, nausea, stress, SIADH-associated medicine, or administration of hypotonic fluid) is required. These disorders are treated and any causative medicines discontinued. All hypotonic fluids are also stopped.
- Acute hyponatraemia, once corrected and any cause of SIADH removed, may be self-limiting. It may be necessary to continue free fluid restriction (of 1-1.5 L/day) after hypertonic saline therapy is discontinued. Serum sodium is monitored daily until it stabilises.
- Following successful therapy with intravenous hypertonic saline, a vasopressin receptor antagonist (vaptan) may be required for chronic SIADH. Vasopressin receptor antagonists (vaptans) compete with ADH for binding at the V2 receptor on the basolateral side of the principal cell and inhibit water channel insertion and free water absorption. Close monitoring, especially in the first 24 hours of oral therapy, is required. Fluid restriction should be removed, because polyuria commonly occurs.
- Hyponatraemia with mild to moderate symptoms
- Mild to moderate symptoms include nausea, vomiting, or headache.
- In acute SIADH patients, treatment is with fluid restriction of 1 to 1.5 L/day.
- Vasopressin receptor antagonists (vaptans) are used for chronic SIADH patients.
- In both cases, investigation and management of any underlying disorder is also undertaken and any causative medication discontinued.
- Asymptomatic patients are managed with fluid restriction of 1 to 1.5 L/day and investigation and management of any underlying cause.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
