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Diagnostic Approach to the Patient with Hyponatremia and the Cause of Hyponatremia Farahnak Assadi *1, MD 1Pediatrics nephrologist, Professor of Pediatrics, Rush University Medical Center, Chicago, IL, USA Received: 2/8/06 ; Code Number: pe07013 Diagnostic Approach Diagnosis should proceed in a series of sequential steps to ensure that true hyponatremia is present and to establish the pathophysiologic mechanism and cause. The First step in the approach of hyponatremia is to rule out pseudo-hyponatremia due to hyperlipidemia or severe hyperproteinemia. This can be done in one of two ways:
If neither method is available nor either severe hyperlipidemia (usually with lactescent serum) or severe hyperproteniemia are present, you can estimate the contribution of these abnormalities mathematically. In normal subjects, the plasma water is approximately 93 percent of the plasma volume, with fats and proteins accounting for the remaining 7 percent. Thus, a normal plasma sodium level of 142 mEq/L (measured per liter of plasma) represents a concentration in the physiologically important plasma water of 154 mEq/L (142 /0.93 =154). However, the plasma water fraction may fall below 80 percent in patients with marked hyperlipidemia (as in uncontrolled diabetes mellitus) or hyperproteninemia (as in multiple myeloma). In these settings, the plasma water sodium concentration and plasma osmolality are unchanged, but the measured sodium concentration in the total plasma volume will be reduced (since the specimen contains less plasma water). The Second step is to ensure that the hyponatremia represents hypoosmolality and is not due to dilution of the serum sodium by water pulled into the extra cellula fluid (ECF) volume by hypertonicity. The substances which can produce this include glucose and mannitol.
The Third step is to assess the ECF volume status of the patient. Patients with hyponatremia are divided into 3 groups based upon the presence or absence of edema and signs of volume depletion (e.g., hypotension, urine sodium >10 mEq/L). Cause of hyponatremia Causes of hyponatremia can be grouped into three categories based upon the pathophysiologic mechanism. Hyponatremia due to ECF volume loss (true hypovolemia): This is the group of patients with no edema and signs of volume depletion. The hyponatremia in this group is due to both increased proximal tubular reabsorption (limiting delivery to the diluting sites) and increased secretion of ADH. The causes of hypovolemia include: Diarrhea, vomiting, hemorrhage, third spacing, burns, excessive sweating, and use of diuretics, Bartter’s syndrome, osmotic diuresis (glycosuria, mannitol administration, protein load (tube feeding), adrenal insufficiency and cerebral salt wasting. Cerebral salt wasting is a rare syndrome and has been described in patients with cerebral disease (particularly subarachnoid hemorrhage). It mimics the findings in the SIADH, except that salt-wasting is the primary defect with the ensuing volume depletion leading to a secondary rise in ADH release. Patients also may have hypouricemia due to increased urinary uric acid excretion. The etiology is unclear but some studies support the possible role of a circulating factor that impairs renal tubular function. The diagnosis of hyponatremia due to ECF volume depletion can be verified by assessing the response to expansion with normal saline. You can also measure the urine sodium. It is typically less than 10 mEq/L in nonrenal causes of sodium loss. The fractional excretion of sodium (FENa) should be less than 1%. Recognize that intrinsic renal disease or the administration of diuretics in the 24 hrs prior to the measurement can interfere with diluting ability and elevate the urine sodium concentration despite the presence of hypovolemia. Hyponatremia in edema forming states: These are conditions in which the kidney holds onto sodium and water in response to a hemodynamic stimulus. The three major clinical conditions are:
Hyponatremia associated with normal ECF volume: Hyponatremia in the absence of either an edema forming states or true ECF volume depletion is due to either massive water ingestion or more commonly a defect in the ability to excrete a water load. Deficiency in the ability to excrete water is typically due to increased activity of ADH but may be due to insufficient solute intake. Massive water ingestion: If diluting ability is intact, and renal function is normal, the urine osmolality should be below 75 mosml/kg and water ingestion must exceed 15 liters per day in a 60 kg man, to produce sustained hyponatremia. Primary polydipsia is a disorder in which there is a primary stimulation of thirst. It is most often seen in individuals with psychiatric illnesses, particularly those taking antipsychotic drugs in whom the common side effect of a dry mouth leads to increased water intake. Most patients with psychologic polydipsia also have a concentrating defect due to SIADH from the psychosis and present with a urinary osmolality between 100 and 200 mosmol/kg. Increased activity of ADH: If the urine osmolality is >75 mosmol/kg, the causes of increased ADH secretion including the SIADH are usually clinically apparent and include the following:
Insufficient dietary solute intake: Beer drinkers or other malnourished patients, including those with low-protein, high water intake diets, may have a marked reduction in water excretory capacity that is directly mediated by poor dietary intake. If the etiology of hyponatremia is not immediately obvious, one should consider the possibility of anterior pituitary insufficiency with glucocorticoid deficiency. If there is no contraindication to steroid administration, a useful diagnostic test (after drawing a serum cortisol level) is to give the equivalent of 50 to 100 mg cortisone. If the patient is glucocorticoid deficient, a water diuresis will ensue in 30 to 45 minutes. References
Hyponatremia Clinical Quizes Case 1: An 18-years old female (60 kg) presents to the ER with severe pain in her mouth. She had dental work done five days ago and now had developed a tooth abscess. She has been taking a variety of pain pills and has been unable to eat solid food for several days. Past medical history was significant for a postpartum hemorrhage complicated with hypotension 2 years ago. Laboratory data revealed sodium 111 mEq/L, chloride 74 mEq/L, potassium 3.9 mEq/L, CO2 28 mEq/L, BUN 12 mg/dL, creatinine 0.9 mg/dL, calcium 9.5 mg/dL, phosphate 3.6 mg/dL, magnesium 1.9 mg/dL, and albumin 3.9 g/dL. Hematocrit 41%, WBC 5100 cells/uL. Urinalysis showed trace protein, glucose negative, no blood, and no casts, RBC or WBC. Urine sodium was 11 mEq/L and urine osmolality 400 mosmol/kg. Question: What orders would you like to write? A. Restrict free water to <1500 ml/day Question feedback: (A, B and C). It appears that the hyponatremia is due to a combination of reduced intake and ADH secretion in response to ECF volume contraction, pain, and medications. Treatments therefore include restoration of ECF volume with isotonic saline, restriction of free water intake until the other issues are resolved, and drainage of the abscess. ****** Case 2: She is treated with IV fluids, water restriction and removal of the abscessed tooth. Ten days later, she is off all medication and her pain is gone. With restoration of free access to water, however her serum sodium falls to 129 mEq/L with a plasma osmolality of 265 mosmol/kg and a urine osmolality of 685 mosoml/kg. A diagnostic procedure is performed. Question: What was the diagnostic procedure? A. Administration of 100 mg cortisol IV Question feedback: (A) Infarction of the pituitary gland after substantial blood loss during childbirth has long been recognized as a cause of hypopituitarism and is called Sheehan’s syndrome. It occurs as the length of the pituitary gland during pregnancy outstrips the increase in blood supply rendering the gland susceptible to infarction with hypovolemia such as that occurring with hemorrhage during delivery. Severe hypopituitarism can be recognized during the first days or weeks after delivery by the development of lethargy, anorexia, weight loss, and inability to lactate. Less severe hypopituitarism may be manifested by fatigue, amenorrhea, and loss of sexual hair, or hyponatremia but may not be recognized for many years after the inciting event until there is a period of stress. The hyponatremia is due to hypocortisolemia. Normal cortisol levels are necessary to allow Suppression of ADH release by hypo-osmolality. Administration of 100 mg cortisone in this situation is safe and has no side effects. Water diuresis will occur within 15-30 minutes and the response is diagnostic of hypocorticsolism. In this case, the patient recalled that she had had postpartum hemorrhage complicated by hypotension. She responded to IV cortisone with a brisk water diuresis and correction of hyponatremia. ****** Case 3: You are asked to see a 17-years old Caucasian female with acute post-operative hyponatremia. The patient had been in a good health until yesterday when she fell and sustained a compound wrist fracture. It was recommended that surgery be performed immediately. She was started upon low dose unfractionated heparin, a urinary tract catheter was placed and she received prophylactic antibiotics and was taken to the OR. Current medications include oxcarbazepine for trigeminal neuralgia, and inderal for hypertension. On examination she appears restless and confused and is complaining of significant pain in her right wrist. Temp is 98, pulse 110, respiratory rate 25. The chest is clear. There is no abdominal distention, tenderness or guarding. There is no organomegaly. There is no edema. The neurological examination is within normal limits except for mild to moderate confusion. Patient’s pre-op laboratory study shows serum sodium 118 mEq/L, potassium 3.9 mEq/L, Chloride 78 mEq/L, CO2 26 mEq/L, BUN 12 mg/dL, creatinine 0.9 mg/dL. Calcium 9.5 mg/dL, phosphate 3.6 mg/dL, magnesium 1.9 mg/dL, and albumin 3.9 g/dL. White blood count 5100 cells/uL, hematocrit 13.0 g/dl. Urinalysis shows trace protein, negative glucose, and no blood, RBC or WBC. Urine sodium is 41 mEq/L, urine osmolality 489 mosmol/kg and plasma osmolality 240 mosmol/kg. Her intake since this AM (over 6 hrs) including the period of surgery and the recovery room was 3 L of D5W. There was little estimated blood loss and she has made 100 ml of urine. The post-op laboratory values are hematocrit 40%, WBC 5,500 cells/uL, BUN 10 mg/dl, creatinine 0.6 mg/dL, sodium 137 mEq/L, potassium 3.5 mEq/L, chloride 103 mEq/L, CO2 27 mEq/L, calcium 9.9 mg/dL, phosphate 3.9 mg/dL, and albumin 2.1 g/dL. Question: What is the likely cause of this condition? A. Postoperative SIADH associated with pain and surgery Question feedback: (A) Major abdominal or thoracic surgery is commonly associated with hypersecretion of ADH, a response that is probably mediated by pain afferents. The length and severity of this condition increases with increasing age. ****** Case 4: The fellow assigned to the case was interested in the problem and was planning to present it at the next conference. Without your knowledge he had a plasma vasopressin level drawn. He now says to you that the vasopressin level was low, NOT high. He wants to know how that can be if the patient has hyponatremia and a concentrated urine. Question: Your answer is which of the following? A. The laboratory made a mistake Question feedback: (C) Hyponatremia associated with oxcarbazepine is not due to SIADH and vasopressin levels are not elevated. Rather, the drug directly enhances absorption of water in the collecting duct possibly by enhancing responsiveness to circulating ADH. ****** Case 5: You are asked to see a 19-years old male with a serum sodium of 123 mEq/L. He was in a good state of health until 4 months ago when he developed a persistent cough. He subsequently experienced 6 kg weight loss. He developed shortness of breath 5 days ago. He has a history of mild hypertension for which he was treated with atenolol 25 mg per day. He has a 24-pack year smoking history. He does not drink alcohol. He denies the use of any other medications or overthe counter supplements. On examination, he appeared cachectic but with no apparent acute distress. BP was 110/72 mmHg without orthostatic; pulse 68; RR 18; T 98.6; Wt 62 kg; Ht 159 cm. Heart had regular rhythm, no murmurs. Chest was dull to percussion with diminished breathing sounds at the right base. There was no edema. The remaining of the PE was normal. A chest X-ray showed a right pleural effusion and he was admitted for further evaluation. Laboratory study showed serum sodium 126 mEq/l, potassium 3.5 mEq/L, Chloride 91 mEq/L, CO2 24 mEq/L, BUN 6 mg/dL, and creatinine 0.7 mg/dL. Calcium 9.1 mg/dL, phosphate 3.2 mg/dL, magnesium 1.9 mg/dL, uric acid 3.5 mg/dL, and albumin 3.6 g/dL. Urine osmolality was 305 mosmol/kg and serum osmolality 250 mosmol/kg. Question 1: What are the causes of hyponatremia that should be considered in this case? (select all that apply)? A. Dilutional hyponatremia due to hyperglycemia Question feedback: (C and E) The diagnosis of SIDH with a primary lung disease is extremely likely in this patient. Rest osmostat typically occurs in chronically ill, malnourished or cachectic patients with tuberculosis and this patient is certainly a candidate. Question 2: How would you make the distinction between SIADH and reset osmostat in this patient? A. Water restriction Question feedback: (C) A patient with reset osmostat will respond to a water load with a water diuresis when the serum sodium concentration falls below the 'reset' level (typically 127-132 mosmol/L). A patient with SIDH will not respond with dilution of the urine. ****** Case 6: A 19-years old male presents to the ER after 5 days of not feeling well. One week ago he began to take his father’s diuretic as he had developed some peripheral edema and abdominal swelling. He claims to have not eaten in 6 days and his only intake was beer. He had been told to have chronic hyponatremia several months ago with a serum sodium consistently in the range of 128-132 mEq/L. Urine osmolality was 445 mosmol/kg. Workup revealed normal renal and adrenal function. Chest x-ray was normal. He was on no medications. He was given a diagnosis of SIADH and was subsequently lost to follow-up. Blood pressure was 100/70 mmHg. Lab studies were: sodium 106 mEq/L, potassium 3.4 mEq/L, chloride 78 mEq/L, CO2 22 mEq/L, BUN 10 mg/dL, creatinine 1.0 mg/dL, urine sodium 10 mEq/L and urine osmolality 686 mosmol/L. Question: What was the likely sequence of events leading to severe hyponatremia in this patient? A. Worsening SIADH Question feedback: (B) He likely had a severe limitation on his ability to excrete free water due to a chronic problem with superimposed volume concentration from the diuretics and low solute intake associated with massive beer intake. ****** Case 7: He was given 2 liters of normal saline over the next 4 hrs after which he began to excrete clear urine with a sp of 1.002. He excreted 6 liters over the next 10 hrs at which point his serum sodium was 129 mEq/L. His fluid therapy was changed to 5%DW because of the fear of too rapid correction of his hyponatrema. At that point it was noted that his urine osmolality was 453 mosmol/kg. Question: What was the likely sequence of events? A. Reset osmostat complicated by volume contraction and beer drinker potomania Question feedback: (A) The patient had a reset osmostat accounting for his chronic hyponatremia. Superimposed volume contraction and potomania prevented his ability to excrete the water load. When he was repleted with saline, this corrected the volume contraction and provided solute to allow free water to be excreted. When his serum osmolality exceeded his 'reset'point, he began to respond by concentrating his urine. ****** Case 8: You are asked to see a 2-years old boy because of a congestive heart failure. His medications include digoxin and furosemide. On examination, he is lethargic and in mild respiratory distress, with a blood pressure of 100/54 mm Hg and irregular pulse of 104. Rales are present in ¼ of the upper lobe of his lung fields, and there is 2+ ankle edema. Lab studies reveals the following: sodium 125 mEq/L, potassium 3.3 mEq/L, chloride 95 mEq/L, CO2 24 mEq/L, BUN 11 mg/dL, creatinine 0.8 mg/dL, fasting blood glucose 90 mg/dL, serum osmolality 230 mosmol/kg and urine osmolality 600 mosomol/kg. Question: Which of the following statement concerning his hyponatremia are true? A. She most likely has SIADH Question feedback: (C and D) In state of congestive heart failure, a decrease in cardiac output (effective volume depletion) initiates a baroreceptor response which triggers the renal response via secretion of the three “hyponatremia” hormones (renin-angiotensin II system, antidiuretic hormone (ADH), and norepinephrine). The severity of the defect in water excretion (due to the neurohumoral activation) and of the associated reduction in the plasma sodium concentration parallels the severity of the heart disease. Patient survival is significantly reduced (in comparison to normonatremic patients) once the plasma sodium concentration falls below137 mEq/L. A low plasma sodium concentration below represents near end-stage disease. ****** Case 9: A 50-kg male has SIADH due to a tumor; the plasma sodium is in a steady state and 120 mEq/L, and plasma potassium is 4.0 mEq/L. there are no symptoms attributable to hyponatremia. Assume that the ECF volume is normal and that the patient is consuming a usual diet. Question: How much water restriction would correct the hyponatremia? A. 4.3 liters Question feedback: (B) Physiologically, in patients with SIDH, the total body sodium (TBNa) is normal but the total body water (TBW) is increased proportionately to the fall in plasma sodium (PNa) concentration, due to overproduction of ADH. Because TBNa is the product of TBW x PNa concentration, the excess water gain in SIADH can be estimated using the following equation: TBNa (TBW x PNa) in normal subjects = TBNA (TBW x PNa) in SIADH patient or (50kg x 0.6) x 135mEq/L = (TBW x 120 mEq/L) or TBW in SIADH patient = 50 kg x 0.6 [30 liters] x 135 mEq/L : 120 mEq/L or TBW in SIADH patient = 33.750 liters The excess water gain in patient with SIADH can now be calculated from the difference between normal subject and SIADH patient TBW or Water gain in patient with SIADH = SIADH TBW – Normal TBW or Water gain = (33.750 liters) - (30.00 liters) or Water gain in SIADH patient = 3.375 liters Copyright 2007 - TUMS PUBLICATIONS |
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