Causes of hyponatremia

Causes of hyponatremia

Fluid and Electrolytes F . Mamdouhi M . D Mashhad University of Medical Sciences :: : : 290-275: : : : :: :

: : : : The major ECF particles are Na+ and its accompanying anions Cl and HCO3. The predominant ICF osmoles are K+ and organic phosphate esters (ATP, creatine phosphate, and phospholipids). REGULATION OF

PLASMA OSMOLALITY The normal plasma osmolality (Posm ) is 280 to 295 mosmol/kg. It usually is held within narrow limits as variations of only 1 to 2 percent initiate mechanisms to return the Posm to normal. These alterations in osmolality are sensed by receptor cells in the hypothalamus which affect water intake (via thirst) and water excretion (via ADH, which increases water reabsorption in

the collecting tubules). The osmolality of human body fluid is between 280 and 295 mosmol/kg and regulated by : Vasopressin secretion water ingestion, and renal water transport. Osmolality

Hypoosmolality and hyperosmolality can produce serious neurologic symptoms and death, primarily due to water movement into and out of the brain, respectively. To prevent this, the plasma osmolality (Posm ), which is primarily determined by the plasma Na+ concentration, is normally maintained within narrow limits by appropriate variations in water intake and water excretion. This regulatory system is governed by osmoreceptors in the hypothalamus that influence both thirst and the secretion of antidiuretic hormone (ADH).

Vasopressin (AVP) is synthesized in the hypothalamus. the distal axons of those neurons project to the posterior pituitary or neurohypophysis, from which AVP is released into the circulation. AVP has a half-life in the circulation of only 1020 min.

AVP secretion is stimulated as systemic osmolality increases above a threshold level of 285 mosmol/kg, Thirst sensation and thus water ingestion also are activated at 285 mosmol/kg. Changes in blood volume and blood pressure are also direct stimuli for AVP release and thirst. osmoregulation is almost

entirely mediated by changes in WATER BALANCE WATER BALANCE Water intake Obligatory water output :

: : : : GI : : : : : : : : : GI: NG tube

Gastrointestinal losses Only small amounts of water are normally lost in the stool, averaging 100 to 200 mL/day. However, gastrointestinal losses are increased to a variable degree in patients with vomiting or diarrhea. The effect of these losses on the plasma Na+

concentration depends on the sum of the Na+ and K+ concentrations in the fluid that is lost. : : ( )

: : : : : : :

obligatory renal water The obligatory renal water loss is directly related to solute excretion. If a subject has to excrete 800 mosmol of solute per day (mostly Na+ and K+ salts and urea) to remain in the steady state, and the maximum Uosm is 1200 mosmol/kg, then the excretion of the 800 mosmol will require a minimum urine volume of 670 mL/day.

: Insensible losses The evaporative losses play an important role in thermoregulation; the heat required for evaporation,

0.58 kcal/1.0 mL of water, normally accounts for 20 to 25 percent of the heat lost from the body, with the remainder occurring by radiation and convection. The net effect is the elimination of the heat produced by body metabolism, thereby preventing the development of hyperthermia. Sensible loss Sweat is a hypotonic fluid (Na+ concentration equals

30 to 65 meq/L) It also contributes to thermoregulation, as the secretion and subsequent evaporation of sweat result in the loss of heat from the body. In the basal state, sweat production is low, but it can increase markedly in the presence of high external temperatures or when endogenous heat production is enhanced, as with exercise, fever, or hyperthyroidism. As an example, a subject exercising in a hot, dry climate can lose as much as 1500 mL/h as sweat

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. : : : 3/2 : : -25 %30 : %5 - - : : ---: : : 135 :: -1: :

-2: Hyponatremia In almost all cases, hyponatremia results from the intake and subsequent retention of water. A water load will be rapidly excreted as the dilutional fall in plasma osmolality suppresses the release of antidiuretic hormone (ADH), thereby allowing the excretion of a dilute urine. The maximum rate of water excretion on a regular

diet is over 10 liters per day. :: -1 : : : : : -2 : : :

Pseudohyponatremia Is associated with a normal plasma osmolality, refers to those disorders in which marked elevations of substances, such as lipids and proteins, result in a reduction in the fraction of plasma that is water. In normal subjects, the plasma water is

approximately 93 percent of the plasma volume. A normal plasma sodium concentration of 142 meq/L (measured per liter of plasma) actually represents a concentration in the physiologically important plasma water of 154 meq/L (142 0.93 = 154). Ion-selective electrodes have been used to directly measure the plasma water sodium concentration in this setting but have variable

accuracy. HYPONATREMIA WITH A HIGH PLASMA OSMOLALITY Hyponatremia with a high plasma osmolality is most often due to hyperglycemia. A less common cause is the administration and retention of hypertonic mannitol. The rise in plasma osmolality induced by glucose or mannitol pulls water out of the cells, thereby lowering the

plasma sodium concentration by dilution. Physiologic calculations suggest that the plasma sodium concentration should fall by 1 meq/L for every 62 rmg/dL rise in the plasma concentration of glucose or mannitol (which have the same molecular weight). The 1:62 ratio applied when the plasma glucose concentration was less than 400 mg/dL. At higher glucose concentrations, the ratio of

1:42 provided a better estimate of this association than the usual 1:62 ratio Normal Plasma Osmolality Isosmotic hyponatremia can be produced by the addition of an isosmotic (or near isosmotic) but non-sodium-containing fluid to the extracellular space. This problem primarily occurs with the use of nonconductive glycine or sorbitol flushing

solutions during transurethral resection of the prostate or bladder or irrigation during laparoscopic surgery, since variable quantities of this solution are absorbed. DISORDERS IN WHICH ADH LEVELS ARE ELEVATED The two most common causes of hyponatremia are: effective circulating volume depletion and

the syndrome of inappropriate ADH secretion, disorders in which ADH secretion is not suppressed. Effective Circulating Volume Depletion Significantly decreased tissue perfusion is a potent stimulus to ADH release. This response is mediated by baroreceptors in the

carotid sinus and can overcome the inhibitory effect of hyponatremia on ADH secretion. Heart Failure and Cirrhosis Even though the plasma volume may be markedly increased in these disorders, the pressure sensed at the carotid sinus baroreceptors is reduced due to the fall in cardiac output in heart failure and to peripheral vasodilatation in cirrhosis. The rise in ADH levels tend to vary with the severity of

the disease, making the development of hyponatremia an important prognostic sign. Syndrome of Inappropriate ADH Secretion Persistent ADH release and water retention can also be seen in a variety of disorders that are not associated with hypovolemia. These patients have a stable plasma sodium

concentration between 125 and 135 meq/L. Hormonal Changes Hyponatremia can occur in patients with adrenal insufficiency (in which it is lack of cortisol that is responsible for the hyponatremia) and with hypothyroidism. The release of HCG during pregnancy may be responsible for the mild resetting of the osmostat downward, leading to a fall in the plasma sodium

concentration of about 5 meq/L. DISORDERS IN WHICH ADH LEVELS MAY BE APPROPRIATELY SUPPRESSED There are two disorders in which hyponatremia can occur despite suppression of ADH release: advanced renal failure primary polydipsia

Advanced Renal Failure The relative ability to excrete free water (free water excretion divided by the glomerular filtration rate) is maintained in patients with mild to moderate renal failure. Thus, normonatremia is usually maintained in the absence of oliguria or advanced renal failure.

Advanced Renal Failure In the latter setting, the minimum urine osmolality rises to as high as 200 to 250 mosmol/ kg despite the appropriate suppression of ADH. The osmotic diuresis induced by increased solute excretion per functioning nephron is thought to be responsible for the inability to dilute the urine. Primary Polydipsia Is a disorder in which there is a primary

stimulation of thirst. It is most often seen in anxious and in patients with psychiatric illnesses, particularly those taking antipsychotic drugs in whom the common side effect of a dry mouth leads to increased water intake. Polydipsia can also occur with hypothalamic lesions (as with infiltrative diseases such as sarcoidosis) which directly affect the thirst centers

Primary Polydipsia The plasma sodium concentration is usually normal or only slightly reduced in primary polydipsia, since the excess water is readily excreted. These patients may feel asymptomatic or may present with complaints of polydipsia and polyuria. In rare cases water intake exceeds 10 to 15 L/day

and fatal hyponatremia may ensue. Symptomatic hyponatremia can also be induced with an acute 3 to 4 liter water load (as may rarely be seen in anxious patients preparing for a radiologic examination or for urinary drug testing) Symptomatic and potentially fatal hyponatremia has also been described after ingestion of the designer amphetamine ecstasy

(methylenedioxymethamphetamine or MDMA) Both a marked increase in water intake and inappropriate secretion of ADH may contribute. Low Dietary Solute Intake Beer drinkers or other malnourished patients may have a marked reduction in water excretory capacity. Normal subjects excrete 600 to 900 mosmol/kg of

solute per day (primarily Na, K salts and urea); thus, if the minimum urine osmolality is 60 mosmol/kg, the maximum urine output will be 10 to 15 L/day . Beer contains little or no Na, K , or protein, and the carbohydrate load will suppress endogenous protein breakdown and therefore urea excretion. Diagnosis of Hyponatremia Hyponatremia in virtually all patients reflects

water retention due to an inability to excrete ingested water. In most cases, this defect represents the persistent secretion of ADH, although free water excretion can also be limited in advanced renal failure independent of ADH. In the absence of renal failure, the differential diagnosis begins with the history and physical examination, looking for one of the causes of

excess ADH secretion: effective circulating volume depletion (including gastrointestinal or renal losses, congestive heart failure, and cirrhosis); the syndrome of inappropriate ADH secretion (SIADH); adrenal insufficiency or hypothyroidism. DIAGNOSIS Three laboratory findings also may provide

important information in the differential diagnosis of hyponatremia: the plasma osmolality; the urine osmolality; the urine sodium concentration. Plasma Osmolality The plasma osmolality is reduced in most hyponatremic patients, because it is primarily determined by the plasma sodium

concentration and accompanying anions. In some cases the plasma osmolality is either normal or elevated. Since there is no hypoosmolality and therefore no risk of cerebral edema due to water movement into the brain, therapy directed at the hyponatremia is not indicated in any of these disorders with the exception of glycine administration.

In this setting, the plasma osmolality may fall with time as the glycine is metabolized. Urine Osmolality The normal response to hyponatremia (which is maintained in primary polydipsia) is to completely suppress ADH secretion, resulting in the excretion of a maximally dilute urine with an osmolality below 100 mosmol/kg and a specific gravity < or =1003. Values above this level indicate an inability to

normally excrete free water that is generally due to continued secretion of ADH. : - : : :

: : : < 100 :

: : - : Na < 20 : :

: ECF SIADH : <10 Na -

: : : :SIADH : : : :

hyponatremia due to the SIADH is characterized by the following set of findings: A fall in the plasma osmolality An inappropriately elevated urine osmolality (above 100 mosmol/kg and usually above 300 mosmol/kg) A urine sodium concentration usually above 40 meq/L.

A relatively normal plasma creatinine concentration Normal adrenal and thyroid function. : :SIADH

: +: Uosm<100 UNa<40 : - : - : : :

Plasma Uric Acid and Urea Concentrations The initial water retention and volume expansion in the SIADH leads to another frequent finding that is the opposite of that typically seen with volume depletion: hypouricemia (plasma uric acid concentration less than 4 mg/dL ) due to increased uric acid excretion in the urine. It is presumed that the early volume expansion diminishes proximal sodium reabsorption,

leading to a secondary decline in the net reabsorption of uric acid. Cerebral Salt Wasting All of the changes in electrolyte balance observed in the SIADH have also been described in the putative syndrome of cerebral salt-wasting. This disorder is characterized by a high urine sodium concentration that is due to defective tubular reabsorption (mediated by the release of

a natriuretic hormone, perhaps brain natriuretic peptide) and an elevation in ADH and the subsequent development of hyponatremia due to the associated volume depletion. Symptoms of Hyponatremia The symptoms that may be seen with hyponatremia or hypernatremia are primarily neurologic and are related both to the severity and in particular to the

rapidity of onset of the change in the plasma sodium concentration. Symptoms of Hyponatremia The symptoms directly attributable to hyponatremia primarily occur with acute and marked reductions in the plasma sodium concentration and reflect neurologic dysfunction induced by cerebral edema . In this setting, the associated fall in plasma

osmolality creates an osmolal gradient that favors water movement into the cells, leading in particular to brain edema. The presence of cerebral overhydration generally correlates closely with the severity of the symptoms. Nausea and malaise are the earliest findings, and may be seen when the plasma sodium concentration falls below 125 to 130

meq/L. This may be followed by headache, lethargy, and obtundation and eventually seizures, coma and respiratory arrest if the plasma sodium concentration falls below 115 to 120 meq/L. Hyponatremic encephalopathy may be reversible, although permanent neurologic damage or death can occur, particularly in

premenopausal women. Overly rapid correction also may be deleterious, especially in patients with chronic asymptomatic hyponatremia. : : : : : : : : : : : 125

: : : : : 120-115 : : : : 115 -1 + : : : - -2 + : : :

: + + - : -3 :SIADH : :

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: : : Na deficit (mmol) = 0.6 x wt(kg) x (desired [Na] - actual [Na]) 60 kg women, serum Na 107, seizure recalcitrant to benzodiazepines. Na defecit = 0.6 x (60) x (120 107) = 468 mEq Want to correct at rate 1.5 mEq/L/h: 13/1.5 = 8.7h 468 mEq / 8.7h = 54 mEq/h 3% NaCl has 513 mEq/L of Na

54 mEq/h = x 513 mEq 1L x = rate of 3% NaCl = 105 cc/h over 8.7h to correct serum Na to 120 mEq/h Note: Calculations are always at best estimates, and anyone getting hyponatremia corrected by IV saline (0.9% or 3%) needs frequent serum electrolyte monitoring (q1h if on 3% NS). :

> : :: > 145 : = : : : : - : - : Causes of Hypernatremia Hypernatremia is a relatively common problem that can be produced either by the administration

of hypertonic sodium solutions or, in almost all cases, by the loss of free water. It should be emphasized that persistent hypernatremia does not occur in normal subjects, because the ensuing rise in plasma tonicity stimulates both the release of ADH and, more importantly, thirst. The net effect is that hypernatremia primarily occurs in those patients who cannot express thirst normally:

infants and adults with impaired mental status. The latter most often occurs in the elderly , who also appear to have diminished osmotic stimulation of thirst. Hospitalized persons, whether old or young, can become hypernatremic iatrogenically as a result of inadequate fluid prescription or impaired thirst. Hypernatremia due to water loss is called dehydration.

This is different from hypovolemia in which both salt and water are lost. UNREPLACED WATER LOSS The loss of solute-free water will, if unreplaced, lead to an elevation in the plasma sodium concentration. It is important to recognize that the plasma sodium concentration and plasma tonicity are determined by the ratio between total body solutes and the

total body water. Thus, it is the sum of the sodium and potassium concentrations that determines the effect that loss of a given amount of fluid will have. Patients with secretory diarrheas (cholera, vipoma) have a sodium plus potassium concentration in the diarrheal fluid that is similar to that in the plasma. Loss of this fluid will lead to volume and

potassium depletion, but will not directly affect the plasma sodium concentration. In contrast, many viral and bacterial enteritides and the osmotic diarrhea induced by lactulose (to treat hepatic encephalopathy) or charcoal-sorbitol (to treat a drug overdose). Similar considerations apply to urinary losses during an osmotic diuresis induced by

glucose, mannitol, or urea. With these considerations in mind, the sources of free water loss that can lead to hypernatremia if intake is not increased include: Insensible and Sweat Losses Insensible water loss from the skin and respiratory tract by evaporation and sweat

are dilute fluids, the loss of which is increased by fever, exercise, and exposure to high temperatures. Gastrointestinal losses As mentioned above, some gastrointestinal losses, particularly osmotic diarrheas, will promote the development of hypernatremia because the sodium plus potassium concentration

is less than that in the plasma. Central or Nephrogenic DiabetesInsipidus Decreased release of ADH or renal resistance to its effect cause the excretion of a relatively dilute urine. Most of these patients have a normal thirst mechanism . As a result, they typically present with polyuria and polydipsia. However, marked and symptomatic

hypernatremia can occur if a central lesion impairs both ADH release and thirst. Osmotic Diuresis An osmotic diuresis due to glucose, mannitol, or urea causes an increase in urine output in which the sodium plus potassium concentration is well below that in the plasma because of the presence of the nonreabsorbed organic solute. Patients with diabetic ketoacidosis or nonketotic

hyperglycemia typically present with marked hypertonicity, although the plasma Na concentration may not be elevated due to hyperglycemia-induced water movement out of the cells. Hypothalamic Lesions Affecting Thirst or Osmoreceptor Function Hypernatremia can also occur in the absence of increased water losses if there is primary

hypothalamic disease impairing thirst (hypodipsia). Two different mechanisms have been described, which in adults, are most often due to tumors, granulomatous diseases (eg, sarcoidosis), or vascular disease. SODIUM OVERLOAD Acute and often marked hypernatremia (in which the plasma sodium concentration can exceed 175 to 200 meq/L) can also be

induced by the administration of hypertonic sodium-containing solutions. Examples include accidental or nonaccidental salt poisoning in infants and young children, the infusion of hypertonic sodium bicarbonate to treat metabolic acidosis, hypertonic saline irrigation of hydatid cysts. The hypernatremia in this setting will correct

spontaneously if renal function is normal, since the excess sodium will be rapidly excreted in the urine. Too rapid correction should be avoided if the patient is asymptomatic; these patients, however, are less likely to develop cerebral edema during correction, since the hypernatremia is generally very acute with little time for cerebral adaptation. :

: : :: : : -: : : : : : : : DI

Even with optimal therapy, the mortality rate is extremely high in adults with a plasma sodium concentration that has acutely risen to above 180 meq/L. For reasons that are not well understood, severe hypernatremia is often better tolerated in young children. Diagnosis of Hypernatremia

Hypernatremia represents a relative deficit of water in relation to solute. Although it can be induced by the administration of Na in excess of water (as with hypertonic sodium bicarbonate during a cardiac arrest), a high plasma Na concentration most often results from free water loss. DIAGNOSIS

The cause of the hypernatremia is usually evident from the history. If, however, the etiology is unclear, the correct diagnosis can usually be established by evaluation of the integrity of ADH-renal axis via measurement of the urine osmolality. A rise in the plasma sodium concentration is a potent stimulus to ADH release as well as to thirst; furthermore, a plasma osmolality above 295

mosmol/kg (which represents a plasma sodium concentration above 145 to 147 meq/L) generally leads to sufficient ADH secretion to maximally stimulate urinary concentration. Thus, if both hypothalamic and renal function are intact, the urine osmolality in the presence of hypernatremia will be above 700 to 800 mosmol/kg. In this setting:

unreplaced insensible or gastrointestinal losses, sodium overload, or rarely a primary defect in thirst Measurement of the urine sodium concentration may help to distinguish between these disorders. it should be less than 25 meq/L when water

loss and volume depletion are the primary problems, but is typically well above 100 meq/L following the ingestion or infusion or a hypertonic sodium solution. The urine osmolality is lower than that of the plasma, then either central (ADH-deficient) or nephrogenic (ADH-resistant) diabetes insipidus is present. These conditions can be distinguished simply by

administering exogenous ADH. The urine osmolality will rise, usually by 50 percent or more, in central DI but will have little or no effect in nephrogenic DI. The history is also often helpful in this setting, since severe nephrogenic DI in adults is uncommon in the absence of chronic lithium use or hypercalcemia. : ECF

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: < 750 : : : : DDAVP : -

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: - : : : : : : - NSAIDs

Treatment of DI AVP, Aqueous vasopressin (Pitressin) Only parenteral form, 5-10 U SC q2-4h Lasts 2-6h Can cause HTN, coronary vasospasm Chlorpropamide (OHA which stimulates AVP secretion)

100-500 mg po OD-bid Only useful for partial DI, can cause hypoglycemia HTCZ (induces volume contraction which diminishes free water excretion) 50-100 mg OD-bid Mainstay of Rx for chronic NDI Amiloride (blunts Lithium uptake in distal tubules & collecting ducts) 5-20 mg po OD-bid Drug of choice for Lithium induced DI

Indomethacin 100-150 mg po bid-tid (PGs antagonize AVP action) Clofibrate 500 mg po qid (augments AVP release in partial CDI) Clinical Manifestations of Hypernatremia The rise in the plasma sodium concentration and osmolality causes acute water movement out of the brain; this decrease in brain volume can cause rupture of the cerebral veins, leading to

focal intracerebral and subarachnoid hemorrhages and possible irreversible neurologic damage. The clinical manifestations of this disorder begin with lethargy, weakness, and irritability, and can progress to twitching, seizures, and coma. Values above 180 meq/L are associated

with a high mortality rate, particularly in adults. Correction of chronic hypernatremia must occur slowly to prevent rapid fluid movement into the brain and cerebral edema, changes that can lead to seizures and coma. Although the brain cells can rapidly lose potassium and sodium in response to this cell swelling, the

loss of accumulated osmolytes occurs more slowly, a phenomenon that acts to hold water within the cells. The delayed clearance of osmolytes from the cell can predispose to cerebral edema if the plasma sodium concentration is lowered too rapidly. As a result, the rate of correction in

asymptomatic patients should not exceed 12 meq/L per day, which represents an average of 0.5 meq/L per hour. free-water deficit= 0.4(0.5) x w x{ (Na p 140) 140} 50-kg woman with a plasma Na+ concentration of 160 mmol/L has an estimated free-water deficit of 2.9 L {[(160 140) 140] x (0.4 x 50)} 160-140= 20

20 x 0.5 = 40 h 2900 40= 73 : : : 3/5 : 5 150: Na-K-ATPase : 40: 120

: : 10:%60-50 : : : 90% : . : CCD principal cell : : : : : : : Na K-ATPase

: Causes of Hypokalemia Hypokalemia is a common clinical problem. Potassium enters the body largely stored in the cells, and then excreted in the urine. Decreased intake, increased translocation into the cells, or, most often, increased losses in the urine (or gastrointestinal tract or sweat) all can lead to potassium depletion.

: : : DECREASED POTASSIUM INTAKE The normal range of potassium intake is 40 to 120 meq per day, most of which is then excreted in the urine.

The kidney is able to lower potassium excretion to a minimum of 5 to 25 meq per day in the presence of potassium depletion. INCREASED ENTRY INTO CELLS The normal distribution of potassium between the cells (which contains approximately 98 percent of exchangeable potassium) and the extra cellular fluid is maintained by the Na-K-ATPase

pump in the cell membrane. In some cases, however, there is increased potassium entry into cells, resulting in transient hypokalemia. Elevation in Extracellular pH Either metabolic or respiratory alkalosis can promote potassium entry into cells. Hydrogen ions leave the cells to minimize the change in extracellular pH; the necessity to

maintain electro neutrality then requires the entry of some K (and Na) into the cells. This direct effect is relatively small, as the plasma potassium concentration falls less then 0.4 meq/L for every 0.1-unit rise in pH . Increased Availability of Insulin Insulin promotes the entry of K into skeletal muscle and hepatic cells, apparently by increasing the activity of the Na-K-ATPase

pump. The plasma potassium concentration can also be reduced by a carbohydrate load. Elevated Adrenergic Activity Catecholamines, acting via the B-adrenergic receptors , can promote potassium entry into the cells, primarily by increasing Na-KATPase activity. As a result, transient hypokalemia can be

caused in any setting in which there is stressinduced release of epinephrine, as with acute illness, coronary ischemia, or theophylline intoxication. lower Gastrointestinal Losses Hypokalemia is most common when the losses occur over a prolonged period as with a villous adenoma or a vasoactive intestinal peptide secreting tumor (VIPoma).

INCREASED URINARY LOSSES Urinary potassium excretion is mostly derived from potassium secretion in the distal nephron, particularly by the principal cells in the cortical collecting tubule. This process is primarily influenced by two factors: aldosterone and the distal delivery of sodium and water. Thus, urinary potassium wasting generally

requires increases in either aldosterone or distal flow, while the other parameter is at least normal or increased. Diuretics Any diuretic that acts proximal to the potassium secretory site acetazolamide, loop diuretics, and thiazide-type diuretics will both increase distal delivery and, via the induction of volume depletion, activate the renin-angiotensinaldosterone system.

As a result, urinary potassium excretion will increase, leading to hypokalemia if these losses are greater than intake. Primary Mineralocorticoid Excess Urinary potassium wasting is also characteristic of any condition associated with primary hypersecretion of a mineralocorticoid, as with an aldosterone-producing adrenal adenoma.

These patients are almost always hypertensive. Loss of Gastric Secretions This problem is usually suggested from the history. If, however, the history is not helpful, the differential diagnosis of a normotensive patient with hypokalemia, urinary potassium wasting, and metabolic alkalosis includes: surreptitious vomiting or diuretic use and

Hypokalemic Periodic Paralysis Is a rare disorder of uncertain cause characterized by potentially fatal episodes of muscle weakness or paralysis which can affect the respiratory muscles . Acute attacks, in which the sudden movement of potassium into the cells can lower the plasma potassium concentration to as low as 1.5 to 2.5

Hypokalemic Periodic Paralysis The recurrent attacks with normal plasma potassium levels between attacks distinguish periodic paralysis. Hypokalemic periodic paralysis are often precipitated by rest after exercise, stress, or a carbohydrate meal, events that are often associated with increased release of epinephrine or insulin.

Hypokalemic Periodic Paralysis The hypokalemia is often accompanied by hypophosphatemia and hypomagnesemia. May be familial with autosomal dominant inheritance (in which the penetrance may be only partial) or may be acquired in patients with thyrotoxicosis. The oral administration of 60 to 120 meq of potassium chloride usually aborts acute attacks

of hypokalemic periodic paralysis within 15 to 20 minutes. Another 60 meq can be given if no improvement is noted. However, the presence of hypokalemia must be confirmed prior to therapy, since potassium can worsen episodes due to the normokalemic or hyperkalemic forms of periodic paralysis. Prevention of hypokalemic episodes consists of

the restoration of euthyroidism in thyrotoxic patients and the administration of a B blocker in either familial or thyrotoxic periodic paralysis. B blockers can minimize the number and severity of attacks. A nonselective B blocker (such as propranolol) should be given; B1-selective agents are less likely to inhibit the B2 receptor-mediated hypokalemic effect of epinephrine.

Other modalities that may be effective for prevention include: K+ supplementation, K+-sparing diuretics, a low-carbohydrate diet, and the carbonic anhydrase inhibitor . (Acetazolamide) Marked Increase in Blood Cell Production

An acute increase in hematopoietic cell production is associated with potassium uptake by the new cells and possible hypokalemia. This most often occurs after the administration of vitamin B12 or folic acid to treat a megaloblastic anemia or of granulocyte-macrophage colonystimulating factor (GM-CSF) to treat neutropenia . Metabolically active cells can also take up potassium after blood has been drawn. This has been described in patients with acute myeloid

leukemia. In this setting, the measured plasma potassium concentration may be below 1 meq/L (without symptoms) if the blood is allowed to stand at room temperature. This can be prevented by rapid separation of the plasma from the cells or storage of the blood at 4C Hypothermia Accidental or induced hypothermia can

drive potassium into the cells and lower the plasma potassium concentration to below 3.0 to 3.5 meq/L. Hypomagnesemia Hypomagnesemia is present in up to 40 percent of patients with hypokalemia. In many cases, as with diuretic therapy, vomiting, or diarrhea, there are concurrent potassium and magnesium losses.

In addition, hypomagnesemia of any cause can lead to increased urinary potassium losses via an uncertain mechanism. Hypomagnesemia Documenting the presence of hypomagnesemia is particularly important because the hypokalemia often cannot be corrected until the magnesium deficit is repaired. The concurrent presence of hypocalcemia (due

both to decreased release of parathyroid hormone and resistance to its calcemic effect) is often a clue to underlying magnesium depletion. Polyuria Normal subjects can, in the presence of the potassium depletion, lower the urine potassium concentration to a minimum of 5 to 10 meq/L. If, however, the urine output is over 5 to 10 L/day, then obligatory potassium losses can

exceed 50 to 100 meq per day. This problem is most likely to occur in primary (often psychogenic) polydipsia. : :-1: : --- : : - --- : : -2 : : -3 -4 -5 : :EKG

T U : ST : QU : : PR - QRS -6 - : : -7 - - -8 : DI-9

GTT-10: Diagnosis of Hypokalemia Hypokalemia is a common clinical problem, the cause of which can usually be determined from the history (as with diuretic use, vomiting, or diarrhea). Measurement of the blood pressure and urinary potassium excretion and assessment of acid-base balance are often helpful.

URINARY RESPONSE A normal subject can, in the presence of potassium depletion, lower urinary potassium excretion below 25 to 30 meq per day. Random measurement of the urine potassium concentration can also be used, but may be less accurate than a 24-hour collection. It is likely that extrarenal losses are present if the urine potassium concentration is less than 15

meq/L (unless the patient is markedly polyuric). Higher values, however, do not necessarily indicated potassium wasting if the urine volume is reduced. DIAGNOSIS Metabolic acidosis with a low rate of potassium excretion is, in an asymptomatic patient, suggestive of lower gastrointestinal losses due to laxative abuse or a villous adenoma

Metabolic acidosis with potassium wasting is most often due to diabetic ketoacidosis or to type 1 (distal) or type 2 (proximal) renal tubular acidosis. Metabolic alkalosis with a low rate of potassium excretion is due to surreptitious vomiting (often in bulimia in an attempt to lose weight) or diuretic use (in which the urinary collection is obtained after the diuretic

effect has worn off). Metabolic alkalosis with potassium wasting and a normal blood pressure is most often due to surreptitious vomiting or diuretic use or to Bartter's syndrome. In this setting, measurement of the urine chloride concentration is often helpful, being low in vomiting.

Metabolic alkalosis with potassium wasting and hypertension is suggestive of : surreptitious diuretic therapy in a patient with underlying hypertension, renovascular disease, or one of the causes of primary mineralocorticoid excess. : :

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Causes of Hyperkalemia The plasma potassium concentration is determined by the relationship between potassium intake, the distribution of potassium between the cells and the extracellular fluid, and urinary potassium excretion. In normal subjects, dietary potassium is largely excreted in the urine.

The degree of potassium secretion is primarily stimulated by three factors: an increase in the plasma potassium concentration; a rise in the plasma aldosterone concentration; enhanced delivery of sodium and water to the distal secretory site. Ingestion of a K load leads initially to the

uptake of most of the excess K by the cells, a process that is facilitated by insulin and the B2adrenergic receptors, both of which increase the activity of the Na-K-ATPase pump in the cell membrane. This is then followed by the excretion of the excess K in the urine within six to eight hours . POTASSIUM ADAPTATION Hyperkalemia is a rare occurrence in normal subjects, because the cellular and urinary

adaptations prevent significant potassium accumulation in the extracellular fluid. This phenomenon, called potassium adaptation, is mostly due to more rapid potassium excretion in the urine. INCREASED POTASSIUM RELEASE FROM CELLS Pseudohyperkalemia Refers to those conditions in which the

elevation in the measured plasma potassium concentration is due to potassium movement out of the cells during of after the blood specimen has been drawn. Pseudohyperkalemia The major cause of this problem is mechanical trauma during venipuncture, resulting in the release of potassium from red cells . It can also occur in hereditary spherocytosis and in

familial pseudohyperkalemia in which there is increased temperature-dependent leakage of potassium out of red blood cells after the specimen is collected. Pseudohyperkalemia Potassium also moves out of white cells and platelets after clotting has occurred. Thus, the serum potassium concentration normally exceeds the true value in the plasma

by 0.1 to as much as 0.5 meq/L. Although this difference in normals is not clinically important, the measured serum potassium concentration may be as high as 9 meq/L in patients with marked leukocytosis or thrombocytosis. Metabolic Acidosis The buffering of excess hydrogen ions in the cells can lead to potassium movement into the

extracellular fluid; this transcellular shift is obligated in part by the need to maintain electroneutrality. Insulin deficiency, Hyperglycemia, and Hyperosmolality The combination of insulin deficiency and the hyperosmolality induced by hyperglycemia frequently leads to hyperkalemia in uncontrolled

diabetes mellitus, even though the patient may be markedly potassium depleted due primarily to potassium losses in the urine. An elevation in plasma osmolality results in osmotic water movement from the cells into the extracellular fluid. This is accompanied by potassium movement out of the cells. Increased Tissue Catabolism Any cause of increase tissue breakdown result

in the release of potassium into the extracellular fluid. Clinical examples include trauma, the administration of cytotoxic or radiation therapy to patients with lymphoma or leukemia. Beta-adrenergic Blockade Nonselective B-adrenergic blockers interfere with the B2-adrenergic facilitation of K uptake by the cells.

This effect is associated with only a minor elevation in the plasma potassium concentration in normal subjects (less than 0.5 meq/L), since the excess potassium can be easily excreted in the Exercise K is normally released from muscle cells during exercise. This response may be mediated by two factors: A delay between potassium exit during

depolarization and subsequent reuptake by the Na-K-ATPase pump. With severe exercise, an increased number of open K channels in the cell membrane. These channels are inhibited by ATP, an effect that is removed by the exercise-induced decline in ATP levels which. The release of potassium during exercise may have a physiologically important role.

The local increase in the plasma potassium concentration has a vasodilator effect, thereby increasing blood flow and energy delivery to the exercising muscle. The degree of elevation in the systemic plasma potassium concentration is less pronounced and is related to the degree of exercise: 0.3 to 0.4 meq/L with slow walking;

0.7 to 1.2 meq/L with moderate exertion (including prolonged aerobic exercise with marathon running); and as much as 2 meq/L following exercise to exhaustion. The rise in the plasma K concentration is reversed after several minutes of rest, and is typically associated with a mild rebound hypokalemia (averaging 0.4 to 0.5 meq/L below the baseline

level) that may be arrhythmogenic in susceptible subjects. The degree of K release is attenuated by prior physical conditioning , but may be exacerbated by the administration of nonselective B-blockers and, for uncertain reasons, in patients with CHF. REDUCED URINARY POTASSIUM EXCRETION

Impaired urinary potassium excretion generally requires an abnormality in one or both of the two major factors required for adequate renal potassium handling: aldosterone and distal sodium and water delivery. Hypoaldosteronism Any cause of decreased aldosterone release or effect, such as that induced by hyporeninemic

hypoaldosteronism or certain drugs, can diminish the efficiency of K secretion. Rise in the plasma K concentration directly stimulates K secretion, partially overcoming the relative absence of aldosterone. The net effect is that the rise in the plasma K concentration is generally small in patients with normal renal function. Renal Failure

The ability to maintain K excretion at near normal levels is generally maintained in patients with renal disease as long as both aldosterone secretion and distal flow are maintained. Hyperkalemia generally develops in the patient who is oliguric or who has an additional problem such as a high K diet, increased tissue breakdown, hypoaldosteronism, or fasting in dialysis patients (which may both lower insulin

levels and cause resistance to B-adrenergic ). Effective Circulating Volume Depletion Decreased distal flow due to marked effective volume depletion (as in heart failure, cirrhosis, or a salt-wasting nephropathy) can also lead to hyperkalemia. Transtubular Potassium

Concentration Gradient The differential diagnosis of persistent hyperkalemia consists of those disorders in which urinary potassium excretion is impaired. The three most common causes of this problem are advanced renal failure, marked effective volume depletion (as with severe heart failure), and one of the causes of hypoaldosteronism.

TTKG is dependent upon two assumptions: 1: that the urine osmolality at the end of the cortical collecting tubule is similar to that of the plasma, since equilibration with the isosmotic interstitium will occur in the presence of antidiuretic hormone; 2: little or no potassium secretion or reabsorption takes place in the medullary collecting tubule.

Thus, the TTKG between the tubular fluid at the end of the cortical collecting tubule and the plasma can be estimated from: TTKG = [Urine K (Urine osmolality / Plasma osmolality)] Plasma K The TTKG in normal subjects on a regular diet is 8 to 9, and rises to above 11 with a potassium load, indicating increased

potassium secretion . Thus, a value below 7 and particularly below 5 in a hyperkalemic patient is highly suggestive of hypoaldosteronism . for example, the urine potassium concentration is 30 meq/L, the plasma potassium concentration is 6.5 meq/L, and the urine and plasma osmolality are 560

mosmol/kg and 280 mosmol/kg, respectively, then: TTKG = [30 (560/280)] 6.5 = 2.3 : : : --- : : : - :

: : EKG T Tall - : PR : QRS : : - - P - QRS T : ) (

: : : - + : : : B : : :

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