Which fluid electrolyte imbalance may develop in a patient who consumes spironolactone?

A 23-year-old woman was admitted with a 3-day history of fever, cough productive of blood-tinged sputum, confusion, and orthostasis. Past medical history included type 1 diabetes mellitus (DM). A physical examination in the emergency department indicated postural hypotension, tachycardia, and Kussmaul respiration. The breath was noted to smell of “acetone.” Examination of the thorax indicated consolidation in the right lower lobe.

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APPROACH TO DIAGNOSIS

The diagnosis of the acid-base disorder should proceed in a stepwise fashion as emphasized in the text (see Chap. 51).

1. The normal anion gap (AG) is 8–12 (10 meq/L is a reasonable approximation for calculation purposes), but in this case, the AG is clearly elevated (20 meq/L). Therefore, the change in AG (ΔAG) = 10 meq/L.

2. Compare the ΔAG and the Δ[HCO3−]. In this case, the ΔAG is 10 and the Δ[HCO3−] (25–14) is 11. Therefore, the increment in the AG is approximately equal to the decrement in bicarbonate (ΔAG = Δ[HCO3−]).

3. Estimate the respiratory compensatory response. In this case, the predicted PaCO2 for the patient’s [HCO3−] of 14, should be ~29 mmHg. This value is obtained by adding 15 to the measured [HCO3−] (15 + 14 = 29) or by calculating the predicted PaCO2 from the Winter equation: 1.5 × [HCO3−] + 8 (±3). In either case, the predicted value for PaCO2 of 29 is significantly higher than the measured value of 24. Demonstrating that the prevailing PaCO2 is lower than predicted for compensation alone, and indicates the coexistence of a superimposed respiratory alkalosis.

4. In summary, this patient has a mixed acid-base disturbance of two components: (a) high AG acidosis secondary to ketoacidosis and (b) respiratory alkalosis (which was secondary to community-acquired pneumonia in this case). The latter resulted in an additional component of hyperventilation that exceeded the compensatory response driven by metabolic acidosis alone, explaining the normal pH, and emphasizes the concept that physiologic compensation does not return the pH to normal. The finding of respiratory alkalosis in the setting of a high-gap acidosis indicates another cause of the respiratory component. Respiratory alkalosis frequently accompanies community-acquired pneumonia.

Taken together, the clinical features of this case include hyperglycemia, hypovolemia, ketoacidosis, central nervous system (CNS) signs of confusion, and superimposed pneumonia. This clinical scenario is consistent with diabetic ketoacidosis (DKA) developing in a patient with known type 1 DM, when an infection is acquired. Infections are common precipitating factors in the development of ketoacidosis in patients with DM.

The diagnosis of DKA is usually not challenging, but should be considered in all patients with an elevated AG and metabolic acidosis with a history of DM. Hyperglycemia and ketonemia (positive acetoacetate at a dilution of 1:8 or greater) are sufficient criteria for diagnosis in patients with DM. The Δ[HCO3−] should approximate the increase in the plasma anion gap (ΔAG), but this equality can be modified by several factors. For example, the ΔAG will often decrease with IV hydration, as glomerular filtration increases and ketones are excreted into the urine. The decrement in plasma sodium is the result of hyperglycemia, which induces the movement of water into the extracellular compartment from the intracellular compartment of cells that require insulin for the transport of glucose. Additionally, a natriuresis occurs in response to an osmotic diuresis associated with hyperglycemia. Moreover, in patients with DKA, thirst is very common and water ingestion often continues. Organic acidoses, unlike mineral acidoses, do not cause a significant shift of potassium from the cell to the extracellular fluid (ECF). The plasma potassium concentration may be mildly elevated in DKA because of the combined effect of insulin deficiency and hyperosmolality, but may be excreted as a result of the ongoing osmotic diuresis. Therefore, in DKA a significant total body deficit of potassium is usually present. Clearly, hypokalemia at the time of presentation of a patient in DKA portends severe total body potassium depletion. Recognition of the total body deficit of potassium is critically important. The inclusion of potassium replacement in the therapeutic regimen at the appropriate time and with the appropriate indications (see below) may be lifesaving. Volume depletion is a very common finding in DKA and is a pivotal component in the pathogenesis of the disorder.

APPROACH TO MANAGEMENT

Patients with DKA often have a sustained and significant deficit of sodium, potassium, water, bicarbonate, and phosphate. The general approach to treatment requires attention to all of these abnormalities. Successful treatment of DKA involves a stepwise approach, as follows:

1. Replace ECF volume deficits. Since most patients present with actual or relative hypotension and, at times, impending shock, the initial fluid administered should be 0.9% NaCl and should be infused until the systolic blood pressure is >100 mmHg or until 2–3 L cumulatively have been administered. During the initial 2–3 h of infusion of replacement fluids, the decline in blood glucose can be accounted for by dilution and increased renal excretion. Glucose should be added to the infusion as D5 normal saline (NS) or D5 0.45% NS once the plasma glucose declines to ≤230 mg/dL.

2. Abate the production of ketoacids. Regular insulin is required during DKA as an initial bolus of 0.1 U/kg body weight (BW) IV, followed immediately by a continuous infusion of 0.1 U regular insulin/kg BW per h in NS. The effectiveness of IV insulin (not subcutaneous) can be tracked by observing the decline in plasma ketones, or more conveniently, the narrowing of the AG and its return to the normal value. This relationship holds because the increment in the AG above the normal value of 10 meq/L represents accumulated ketoacids in DKA. The subsequent disappearance of ketoacid anions with insulin and IV fluid therapy is reflected by the narrowing, and eventual correction of the AG. Typically, the plasma AG returns to normal within 8–12 h.

3. Replace potassium deficits. Although patients with DKA often have hyperkalemia due to insulin deficiency and hyperosmolality, they are usually severely K+ depleted. KCl (20 meq/L) should be added to each liter of IV fluids only when urine output has been established, and after insulin has been administered.

4. Correct the metabolic acidosis. The plasma bicarbonate concentration will usually not increase for several hours because of dilution from administered IV fluids. The plasma [HCO−] approaches 18 meq/L once ketoacidosis disappears. Sodium bicarbonate therapy is often not recommended or necessary and is contraindicated for children. Bicarbonate is administered to adults with DKA for extreme acidemia (pH <7.1); for elderly patients (>70 years.), a threshold pH of 7.20 is recommended. Sodium bicarbonate, if administered, should only be given in small amounts. A reasonable therapeutic goal is to increase the [HCO3−] to a value of 10 meq/L, or pH to 7.23; but certainly not to the normal values. Since ketoacids are metabolized in response to insulin therapy, bicarbonate will be added to the ECF as ketoacid metabolism is restored. Overshoot alkalosis may occur from the combination of exogenously administered sodium bicarbonate plus metabolic production of bicarbonate.

5. Phosphate. In the first 6–8 h of therapy, it may be necessary to infuse potassium with phosphate because of the unmasking of phosphate depletion in malnourished patients during combined insulin and glucose therapy. The latter therapy drives phosphate into the cell. Therefore, in patients with DKA, the plasma phosphate level should be followed closely but phosphate should never be replaced empirically. Phosphate should be administered to patients with a declining plasma phosphate, and should be discontinued once the serum phosphate returns to the low normal level. Therapy is advisable as potassium phosphate, at a rate of 6 mmol/h.

6. Always seek underlying factors, such as infection, myocardial infarction, pancreatitis, cessation of insulin therapy or other events, responsible for initiating DKA. The case presented here is illustrative of this common scenario.

7. Volume overexpansion with IV fluid administration, especially 0.9% NaCl, is common and contributes to the development of hyperchloremic acidosis during the later stages of treatment of DKA. Volume overexpansion should be avoided. Since isotonic saline solution represents a [Cl−] of 154 meq/L, it is prudent to change the IV infusion to 0.45% NaCl, once clinical evidence of volume resuscitation is achieved. All too commonly, patients with DKA receive a surfeit of IV 0.9% NaCl, instigating specific complications, such as volume overexpansion and hyperchloremia.

A 22-year-old woman is referred for evaluation of weakness for 5 months. The patient denies vomiting or ingestion of diuretics, but notes “salt craving” as manifest by eating highly salty food snacks several times daily. On physical examination, the BP is 100/60, and with standing the examining physician notes significant orthostasis. There is no elevation of the jugular venous pressure (JVP) or peripheral edema and the examination of the heart reveals normal heart sounds and no murmurs, rubs, or gallops.

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Clearly response D is incorrect since the arterial pH is high, not low. Taken together, the laboratory values clearly suggest a metabolic alkalosis (low [tCO2], elevated arterial pH, and an increased PCO2). However, how does one determine if the increase in the PCO2 to a value of 50 mmHg is the expected compensatory response or, in other words, is there a concomitant respiratory acidosis (response B)? The easiest approximation of the expected PCO2 can be obtained by simply adding the number 15, to the measured tCO2 concentration; or, as in this case 38 + 15 = 53 (mmHg). This approach can be used in the range of serum [tCO2] values from 10 to 40 meq/L and is reasonably accurate within a range of ±3. Also, it is important to note that values of PCO2 >50 mmHg in compensation for metabolic alkalosis are unusual as the hypercapnic response becomes limited by the associated hypoxia, and the age of the patient, as well as whether there is lung disease present. Therefore, response B is not correct and by elimination the most accurate response is response C (pure metabolic alkalosis). Now, how does one place the obvious hypokalemia into perspective; what is the cause in this case? Examination of the urine electrolytes reveals that the urine [K+] of 42 meq/L is inappropriately high (>10 meq/L) for the prevailing hypokalemia and indicates an inappropriately high excretion of K+ by the kidney. If desired, the transtubular potassium gradient (TTKG) can be calculated from the data available. The value for TTKG is calculated and is 11, indicating, therefore, that there is inappropriate secretion of K+ by the distal convoluted tubule 2 (DCT2) and principal cells of the cortical collecting duct (CCD), in this patient. The ECF volume contraction, and relative hypotension with orthostasis, and an elevated TTKG, suggests renal loss of K, moreover, since the urine [Cl−] is also elevated, there is an inappropriately high level of Cl− excretion. The differential diagnosis in this situation might include: surreptitious diuretic abuse, Bartter or Gitelman’s syndrome (since the urine [Cl−] is high, not low, surreptitious vomiting seems highly unlikely). Therefore, to be sure, you consider additional laboratory data. A screen of the urine for diuretics was obtained and was negative. However, and most importantly, a spot urine for [Ca+2] and [Cr] indicated significant hypocalciuria (Ca/Cr = 32 which is <44 mg/g). Furthermore, the additional features of hypermagnesuria and hypomagnesemia when taken together indicate that the correct diagnosis is Gitelman’s syndrome in this case. Gitelman’s syndrome is caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC) in renal distal convoluted cells. If appropriate, genetic confirmation of this diagnosis can be pursued.

A 63-year-old man was admitted to the intensive care unit (ICU) with a severe aspiration pneumonia. Past medical history included schizophrenia, for which he required institutional care; treatment had included neuroleptics and intermittent lithium, the latter restarted 6 months before admission. The patient was treated with antibiotics and intubated for several days, with the development of polyuria (3–5 L/d), hypernatremia, and acute renal insufficiency; the peak plasma Na+ concentration was 156 meq/L, and peak creatinine was 2.6 mg/dL. Urine osmolality was measured once and reported as 157 mOsm/kg, with a coincident plasma osmolality of 318 mOsm/kg. Lithium was stopped on admission to the ICU.

On physical examination, the patient was alert, extubated, and thirsty. Weight was 97.5 kg. Urine output for the previous 24 h had been 3.4 L, with an IV intake of 2 L/d of D5W.

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After 3 days of intravenous hydration, a water deprivation test was performed. A single dose of 2 μg IV desmopressin (DDAVP) was given at 9 h (+9):

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APPROACH TO DIAGNOSIS

Why did the patient develop hypernatremia, polyuria, and acute renal insufficiency? What does the water deprivation test demonstrate? What is the underlying pathophysiology of this patient’s hypernatremic syndrome?

This patient became polyuric after admission to the ICU with severe pneumonia, developing significant hypernatremia and acute renal insufficiency. Polyuria can result from either an osmotic diuresis or a water diuresis. An osmotic diuresis can be caused by excessive excretion of Na+-Cl−, mannitol, glucose, and/or urea, with a daily solute excretion of >750–1000 mOsm/d (>15 mOsm/kg body water per d). In this case, however, the patient was excreting large volumes of very hypotonic urine, with a urine osmolality that was substantially lower than that of plasma; this, by definition, was a water diuresis, resulting in inappropriate excretion of free water and hypernatremia. The appropriate response to hypernatremia and a plasma osmolality >295 mOsm/kg is an increase in circulating arginine vasopressin (AVP) and the excretion of low volumes (<500 mL/d) of maximally concentrated urine, i.e., urine with osmolality >800 mOsm/kg; this patient’s response to hypernatremia was clearly inappropriate, due to either a loss of circulating AVP (central diabetes insipidus [CDI]) or renal resistance to AVP (nephrogenic diabetes insipidus [NDI]). Ongoing loss of free water was sufficiently severe in this patient that absolute hypovolemia ensued, despite the fact that ~2/3 of the excreted water was derived from the intracellular fluid compartment rather than the ECF compartment. Hypovolemia led to an acute decrease in glomerular filtration rate (GFR), i.e., acute renal insufficiency, with gradual improvement following hydration (see below).

Following the correction of hypernatremia and acute renal insufficiency with appropriate hydration (see below), the patient was subjected to a water deprivation test followed by administration of DDAVP. This test helps determine whether an inappropriate water diuresis is caused by CDI or NDI. The patient was water restricted beginning in the early morning, with careful monitoring of vital signs and urine output; overnight water deprivation of patients with diabetes insipidus is unsafe and clinically inappropriate, given the potential for severe hypernatremia. The plasma Na+ concentration—more accurate and more immediately available than plasma osmolality—was monitored hourly during water deprivation. A baseline AVP sample was drawn at the beginning of the test, with a second sample drawn once the plasma Na+ reached 148–150 meq/L. At this point, a single 2-μg dose of the V2 AVP receptor agonist DDAVP was administered. An alternative approach would have been to measure AVP and administer DDAVP when the patient was initially hypernatremic; however, it would have been less safe to administer DDAVP in the setting of renal impairment as clearance of DDAVP is affected by renal function.

The patient’s water deprivation test was consistent with NDI, with an AVP level within the normal range in the setting of hypernatremia (i.e., no evidence of CDI) and an inappropriately low urine osmolality that failed to increase by >50% or >150 mOsm/kg after both water deprivation and the administration of DDAVP. This defect would be considered compatible with “complete” NDI; patients with “partial NDI” can achieve urine osmolalities of 500–600 mOsm/kg after DDAVP treatment, but will not maximally concentrate their urine to 800 mOsm/kg or higher.

NDI has a number of genetic and acquired causes, which all share interference with some aspect of the renal concentrating mechanism. For example, loss-of-function mutations in the V2 AVP receptor cause X-linked NDI. This patient suffered from NDI due to lithium therapy, perhaps the most common cause of NDI in adult medicine. Lithium causes NDI by several mechanisms, including direct inhibition of renal glycogen synthase kinase-3 (GSK3), a kinase thought to be the pharmacological target of lithium in psychiatric disease; renal GSK3 is required for the response of principal cells to AVP. Lithium also induces the expression of cyclooxygenase 2 (COX-2) in the renal medulla; COX-2-derived prostaglandins inhibit AVP-stimulated salt transport by the thick ascending limb and AVP-stimulated water transport by the collecting duct, thereby exacerbating lithium-associated polyuria. The entry of lithium through the amiloride-sensitive epithelial Na+ channel (ENaC) (Fig. S1-1) is required for the effect of the drug on principal cells, such that combined therapy within lithium and amiloride can mitigate lithium-associated NDI. However, lithium causes chronic tubulointerstitial scarring and chronic kidney disease after prolonged therapy, such that patients may have a persistent NDI long after stopping the drug, with a reduced therapeutic benefit from amiloride. Notably, this particular patient had been treated intermittently for several years with lithium, with the development of chronic kidney disease (baseline creatinine of 1.3–1.4) and NDI that persisted after stopping the drug.

FIGURE S1-1

Water, sodium, potassium, ammonia, and proton transport in principal cells (PC) and adjacent type A intercalated cells (A-IC). Water is absorbed down the osmotic gradient by principal cells, through the apical aquaporin-2 (AQP-2) and basolateral squaporin-3, and aquaporin-4 channels. The absorption of Na+ via the amiloride-sensitive epithelial sodium channel (ENaC) generates a lumen-negative potential difference, which drives K+ excretion through the apical secretory K+ channel, renal outer medullary K+ channel (ROMK), and/or the flow-dependent BK channel. Transepithelial ammonia (NH3) transport and proton transport occur in adjacent type A IC via apical and basolateral ammonia channels and apical H+-ATPase pumps, respectively; NH4+ is ultimately excreted in the urine, in the defense of systemic pH. Electrogenic proton secretion by type A IC is also affected by the lumen-negative potential difference generated by the adjacent principal cells, such that reduction of this lumen-negative electrical gradient can reduce H+ excretion. Type A IC also reabsorb filtered K+ in potassium-deficient states via apical H+/K+-ATPase.

APPROACH TO MANAGEMENT

How should this patient be treated? What are the major pitfalls of therapy?

This patient developed severe hypernatremia due to a water diuresis from lithium-associated NDI. Treatment of hypernatremia must include both replacement of the existing free water deficit and daily replacement of ongoing free water loss. The first step is to estimate total-body water (TBW), typically estimated as 50% of the BW in women and 60% in men. The free water deficit is then calculated as [(Na+ − 140)/140] × TBW. In this particular patient, the free water deficit was 4.2 L at a weight of 97.5 kg and plasma Na+ concentration of 150 meq/L. This free water deficit should be replaced slowly >48–72 h, to avoid increasing the plasma Na+ concentration by >10 meq/L/24 h. A common mistake is to replace this deficit while neglecting to replace ongoing losses of free water, such that plasma Na+ concentration either fails to correct or, in fact, increases.

Ongoing losses of free water can be estimated using the equation for electrolyte-free water clearance:

For this particular patient, the CeH2O was 2.5 L/d when initially evaluated, i.e., with urine Na+ and K+ concentrations of 34 and 5.2 meq/L, plasma Na+ concentration of 150 meq/L, and a urinary volume of 3.4 L. Therefore, the patient was given 2.5 L of D5W over the first 24 h to replace ongoing free water losses, along with 2.1 L of D5W to replace half his free water deficit. Daily random urine electrolytes and urinary volume measurement can be utilized to monitor CeH2O and adjust daily fluid administration in this manner, while following plasma Na+ concentration. Physicians often calculate the free water deficit to guide therapy of hypernatremia, providing half the deficit in the first 24 h. This approach can be adequate in patients who do not have significant ongoing losses of free water, e.g., with hypernatremia due to decreased free water intake. This case illustrates how free water requirements can be grossly underestimated in hypernatremic patients if ongoing, daily free water losses are not taken into account.

A 78-year-old man was admitted with pneumonia and hyponatremia. Plasma Na+ concentration was initially 129 meq/L, decreasing within 3 days to 118–120 meq/L despite fluid restriction to 1 L/d. A chest CT revealed a right 2.8 × 1.6 cm infrahilar mass and postobstructive pneumonia. The patient was an active smoker. Past medical history was notable for laryngeal carcinoma treated 15 years prior with radiation therapy, renal cell carcinoma, peripheral vascular disease, and hypothyroidism. On review of systems, he denied headache, nausea, and vomiting. He had chronic hip pain, managed with acetaminophen with codeine. Other medications included cilostasol, amoxicillin/clavulanate, digoxin, diltiazem, and thyroxine. He was euvolemic on examination, with no lymphadenopathy and a normal chest examination.

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The patient was treated with furosemide, 20 mg PO bid, and salt tablets. The plasma Na+ concentration increased to 129 meq/L with this therapy; however, the patient developed orthostatic hypotension and dizziness. He was started on demeclocycline, 600 mg PO in the morning and 300 mg in the evening, just before discharge from hospital. Plasma Na+ concentration increased to 140 meq/L with a blood urea nitrogen (BUN) of 23 and creatinine of 1.4, at which point demeclocycline was reduced to 300 mg PO bid. Bronchoscopic biopsy eventually showed small-cell lung cancer (SCLC); the patient declined chemotherapy and was admitted to hospice.

APPROACH TO DIAGNOSIS AND MANAGEMENT

What factors contributed to this patient’s hyponatremia? What are the therapeutic options?

This patient developed hyponatremia in the context of a central lung mass and postobstructive pneumonia. He was clinically euvolemic, with a generous urine Na+ concentration and low plasma uric acid concentration. He was euthyroid, with no evidence of pituitary dysfunction or of secondary adrenal insufficiency. The clinical presentation is consistent with the syndrome of inappropriate antidiuresis (SIAD). Although pneumonia was a potential contributor to the SIAD, it was notable that the plasma Na+ concentration decreased despite a clinical response to antibiotics. It was suspected that this patient had SIAD due to SCLC, with a central lung mass on chest CT and a significant smoking history. There was a history of laryngeal cancer and renal cancer, but with no evidence of recurrent disease; these malignancies were not considered contributory to his SIAD. Biopsy of the lung mass ultimately confirmed the diagnosis of SCLC, which is responsible for ~75% of malignancy-associated SIAD; ~10% of patients with this neuroendocrine tumor will have a plasma Na+ concentration of <130 meq/L at presentation. The patient had no other “nonosmotic” stimuli for an increase in AVP, with no medications associated with SIAD, and minimal pain or nausea.

The patient had no symptoms attributable to hyponatremia but was judged at risk for worsening hyponatremia from severe SIAD. Persistent, chronic hyponatremia (duration >48 h) results in an efflux of organic osmolytes (creatine, betaine, glutamate, myoinositol, and taurine) from brain cells; this response reduces intracellular osmolality and the osmotic gradient favoring water entry. This cellular response does not fully protect patients from symptoms, which can include vomiting, nausea, confusion, and seizures, usually at plasma Na+ concentration <125 meq/L. Even patients who are judged “asymptomatic” can manifest subtle gait and cognitive defects that reverse with correction of hyponatremia. Chronic hyponatremia also increases the risk of bony fractures due to an increased risk of falls and to a hyponatremia-associated reduction in bone density. Therefore, every attempt should be made to correct plasma Na+ concentration safely in patients with chronic hyponatremia. This is particularly true in malignancy-associated SIAD, where it can take weeks to months for a tissue diagnosis and the subsequent reduction in AVP following initiation of chemotherapy, radiotherapy, and/or surgery.

What are the therapeutic options in SIAD? Water deprivation, a cornerstone of therapy for SIAD, had little effect on the plasma Na+ concentration in this patient. The urine:plasma electrolyte ratio (urinary [Na+]+[K+]/plasma [Na+]) can be utilized to estimate electrolyte-free water excretion and the required degree of water restriction; patients with a ratio of >1 should be more aggressively restricted (<500 mL/d), those with a ratio of ~1 should be restricted to 500–700 mL/d, and those with a ratio <1 should be restricted to <1 L/d. This patient had a urine:plasma electrolyte ratio of 1, and predictably did not respond to a moderate water restriction of ~ 1 L/d. A more aggressive water restriction would have theoretically been successful; however, this can be very difficult for patients with SIAD to tolerate, given that their thirst is also inappropriately stimulated.

Combined therapy with furosemide and salt tablets can often increase the plasma Na+ concentration in SIAD; furosemide reduces maximal urinary concentrating ability by inhibiting the countercurrent mechanism, whereas the salt tablets mitigate diuretic-associated NaCl loss and amplify the ability to excrete free water by increasing urinary solute excretion. This regimen is not always successful and requires careful titration of salt tablets to avoid volume depletion; indeed, in this particular patient, the plasma Na+ concentration remained <130 meq/L and the patient became orthostatic. The principal cell toxin, demeclocycline, is an alternative oral agent in SIAD. Treatment with demeclocycline was very successful in this patient, with an increase in plasma Na+ concentration to 140 meq/L. However, demeclocycline can be natriuretic, leading to a prerenal decrease in GFR. Demeclocycline has also been implicated in nephrotoxic injury, particularly in patients with cirrhosis and chronic liver disease, in whom the drug accumulates. Notably, this particular patient developed a significant but stable decrease in GFR while on demeclocycline, necessitating a reduction in the administered dose.

A major recent advance in the management of hyponatremia was the clinical development of AVP antagonists (vaptans). These agents inhibit the effect of AVP on renal V2 receptors, resulting in the excretion of electrolyte-free water and correction of hyponatremia. The specific indications for these agents are not as yet clear, despite U.S. Food and Drug Administration (FDA) approval for the management of both euvolemic and hypervolemic hyponatremia. It is, however, anticipated that the vaptans will have an increasing role in the management of SIAD and other causes of hyponatremia. Indeed, were this particular patient to have continued with active therapy for his cancer, substitution of demeclocycline with oral tolvaptan (a V2-specific oral vaptan) would have been the next appropriate step, given the development of renal insufficiency with demeclocycline. As with other measures to correct hyponatremia (hypertonic saline, demeclocycline, etc.), the vaptans have the potential to “overcorrect” plasma Na+ concentration (a rise of >8–10 meq/L per 24 h or 18 meq/L per 18 h), thus increasing the risk for osmotic demyelination (see Case 5). Therefore, the plasma Na+ concentration should be monitored closely during the initiation of therapy with these agents. In addition, long-term use of tolvaptan has been associated with abnormalities in liver function tests; hence, use of this agent should be restricted for only 1–2 months, with careful monitoring of liver function.

A 76-year-old woman presented with a several-month history of diarrhea, with marked worsening >2–3 weeks before admission (up to 12 stools a day). Review of systems was negative for fever, orthostatic dizziness, nausea and vomiting, or headache. Past medical history included hypertension, kidney stones, and hypercholesterolemia; medications included atenolol, spironolactone, and lovastatin. She also reliably consumed >2 L of liquid/d in management of the nephrolithiasis.

The patient received a liter of saline over the first 5 h of her hospital admission. On examination at hour 6, the heart rate was 72 sitting and 90 standing, blood pressure 105/50 mmHg lying and standing. The patient’s JVP was indistinct and there was no peripheral edema. On abdominal examination, the patient had a slight increase in bowel sounds, but a nontender abdomen and no organomegaly.

The plasma Na+ concentration on admission was 113 meq/L, with a creatinine of 2.35 (see Table S1-1). At hospital hour 7, the plasma Na+ concentration was 120 meq/L, potassium 5.4 meq/L, chloride 90 meq/L, bicarbonate 22 meq/L, BUN 32 mg/dL, creatinine 2.02 mg/dL, glucose 89 mg/dL, total protein 5.0, and albumin 1.9. The hematocrit was 33.9, white count 7.6, platelets 405. An AM cortisol was 19.5, with TSH 1.7. The patient was treated with 1 μg of intravenous desmopressin acetate (DDAVP), along with 75 mL/h of intravenous half-NS. After the plasma Na+ concentration dropped to 116 meq/L, intravenous fluid was switched to NS at the same infusion rate. Subsequent results are shown in Table S1-1.

TABLE S1-1Serial Laboratory Data for Case 5

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TABLE S1-1 Serial Laboratory Data for Case 5

APPROACH TO DIAGNOSIS

This patient presented with hypovolemic hyponatremia and a “prerenal” reduction in GFR, with an increase in serum creatinine. She had experienced diarrhea for some time, and manifested an orthostatic tachycardia after a liter of NS. As expected for hypovolemic hyponatremia, the urine Na+ concentration was <20 meq/L in the absence of congestive heart failure or other causes of “hypervolemic” hyponatremia; and she responded to saline hydration with an increase in plasma Na+ concentration and a decrease in creatinine.

The initial hypovolemia increased the sensitivity of this patient’s AVP response to osmolality, both decreasing the osmotic threshold for AVP release and increasing the slope of the osmolality response curve. AVP has a half-life of only 10–20 min; therefore, the acute increase in intravascular volume after a liter of intravenous saline led to a rapid reduction in circulating AVP. The ensuing water diuresis is the primary explanation for the rapid increase in plasma Na+ concentration in the first 7 h of her hospitalization.

APPROACH TO MANAGEMENT

The key concern in this case was the evident chronicity of the patient’s hyponatremia, with several weeks of diarrhea followed by 2–3 days of acute exacerbation. This patient was judged to have “chronic” hyponatremia, i.e., with a suspected duration of >48 h; as such, she would be predisposed to osmotic demyelination were she to undergo too rapid a correction in her plasma Na+ concentration, i.e., by >8–10 meq/L in 24 h or 18 meq/L in 48 h. At presentation, she had no symptoms that one would typically attribute to acute hyponatremia, and the plasma Na+ concentration had already increased by a sufficient amount to protect from cerebral edema; however, she had corrected by 1 meq/L per h within the first 7 h of admission, consistent with impending overcorrection. To reduce or halt the increase in plasma Na+ concentration, the patient received a microgram of intravenous DDAVP along with intravenous free water. Given the hypovolemia and resolving acute renal insufficiency, a decision was made to administer half-NS as a source of free water, rather than D5W; this was switched to NS when plasma Na+ concentration acutely dropped to 117 meq/L (see Table S1-1).

Overcorrection of chronic hyponatremia is a major risk factor for the development of osmotic demyelination syndrome (ODS). Animal studies show a neurological and survival benefit in ODS of “re-lowering” plasma Na+ concentration with DDAVP and free water administration; this approach is demonstrably safe in patients with hyponatremia, with no evident risk of seizure or other sequelae. This combination can be used to prevent an overcorrection or to re-lower plasma Na+ concentration in patients who have already overcorrected. DDAVP is required since in most of these patients endogenous AVP levels have plummeted, resulting in a free water diuresis; the administration of free water alone has minimal effect in this setting, given the relative absence of circulating AVP. An alternative approach in patients who present with severe hyponatremia is to treat prospectively with twice daily DDAVP to prevent changes in AVP bioactivity, coadministering hypertonic saline to increase slowly the plasma Na+ concentration in a more controlled fashion.

This patient’s plasma Na+ concentration remained depressed for several days after DDAVP administration. It is conceivable that residual hypovolemic hyponatremia attenuated the recovery of the plasma Na+ concentration. Alternatively, attenuated recovery was due to persistent effects of the single dose of DDAVP. Of note, although the plasma half-life of DDAVP is only 1–2 h, pharmacodynamic studies indicate a much more prolonged effect on urine output and/or urine osmolality. One final consideration is the effect of the patient’s initial renal dysfunction on the pharmacokinetics and pharmacodynamics of the administered DDAVP, which is renally excreted; DDAVP should be administered with caution for the re-induction of hyponatremia in patients with chronic kidney disease or acute renal dysfunction.

A 44-year-old woman was referred from a local hospital after presenting with flaccid paralysis. Severe hypokalemia was documented (2.0 meq/L) and an infusion containing KCl was initiated.

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APPROACH TO DIAGNOSIS

The diagnosis in this case is classic hypokalemic distal renal tubular acidosis (dRTA) from Sjögren’s syndrome. This patient presented with a non-AG metabolic acidosis (AG = 10 meq/L) associated with severe hypokalemia. The urine AG was positive indicating an abnormally low excretion of ammonium in the face of systemic acidosis. The urine pH was inappropriately alkaline, yet there was no evidence of hypercalciuria, nephrocalcinosis, or bone disease. With more careful questioning and a thorough review of systems, it was evident that the patient exhibited all of the typical features of the sicca syndrome (xerostomia and keratoconjunctivitis sicca, but without synovitis, arthritis, or rash, or evidence of another collagen vascular disease). The patient was subsequently shown to have hyperglobulinemia, and the positive anti-Ro/SS-A, and anti-La/SS-B, confirmed the diagnosis of Sjögren’s syndrome.

These findings, taken together, indicate that the cause of this patient’s hypokalemia and nongap metabolic acidosis was a renal tubular disease. The hypokalemia and abnormally low excretion of ammonium, as estimated by the positive urine AG, in the absence of glycosuria, phosphaturia, or aminoaciduria (Fanconi syndrome), defines the entity, classic dRTA, also known as Type 1 RTA.

Classic dRTA occurs frequently in patients with Sjögren’s syndrome and is a result of an immunologic assault on the collecting duct, causing failure of the H+-ATPase to be inserted into the apical membrane of Type A intercalated cells (A-IC). Sjögren’s syndrome is one of the best documented acquired causes of classic dRTA. The loss of H+-ATPase function also occurs with certain inherited forms of classic dRTA, in which there may be inherited abnormalities of the genes that encode for one of the subunits of the H+-ATPase. There was no family history in the present case and other family members were not affected. A number of autoantibodies have been associated with Sjögren’s syndrome; it is likely that these autoantibodies prevent the normal trafficking of the H+-ATPase to the apical membrane of the Type A IC of the collecting tubule. As a result, the H+-ATPase remains in intracellular compartments and is inactive. While proximal RTA has also been reported in patients with Sjögren’s syndrome, it is much less frequent and there were no features of proximal tubule dysfunction (Fanconi syndrome) in this patient. The hypokalemia associated frequently with classic dRTA is due to secondary hyperaldosteronism from volume depletion.

APPROACH TO MANAGEMENT

The long-term renal prognosis for patients with classic dRTA due to Sjögren’s syndrome has not been established. Nevertheless, the metabolic acidosis and the hypokalemia respond to alkali replacement with either sodium citrate solution (Shohl’s solution) or sodium bicarbonate tablets (1–2, 650 mg. tablets daily or bid) . The long-term goal is to correct the serum bicarbonate to the normal value of 25 meq/L. Obviously, potassium deficits must be replaced initially, but chronic potassium replacement is often not required in dRTA patients because sodium bicarbonate (or citrate) therapy corrects the secondary hyperaldosteronism associated with volume depletion. A consequence of the interstitial infiltrate seen in patients with Sjögren’s syndrome and classic dRTA is progression of chronic kidney disease. Cytotoxic therapy plus glucocorticoids has been the mainstay of therapy in Sjögren’s syndrome for many years, and the B-lymphocyte infiltration in salivary gland tissue subsides and urinary acidification improves after treatment with rituximab, suggesting resolution or improvement in the interstitial nephritis.

A 32-year-old man was admitted to hospital with weakness and hypokalemia. The patient had been very healthy until 2 months previously when he developed intermittent leg weakness. His review of systems was otherwise negative. He denied drug or laxative abuse, and was on no medications. Past medical history was unremarkable, with no history of neuromuscular disease. Family history was notable for a sister with thyroid disease. Physical examination was notable only for reduced deep tendon reflexes.

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APPROACH TO DIAGNOSIS

This patient developed hypokalemia due to a redistribution of potassium between the intracellular and extracellular compartments; this pathophysiology was readily apparent following calculation of the TTKG. The TTKG is calculated as (POsm × UPotassium)/(PPotassium × UOsm). The expected values for the TTKG are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia. Alternatively, a urinary K+-to-creatinine ratio of >13 mmol/g creatinine (>1.5 mmol/mmol creatinine) is compatible with excessive renal K+ excretion. In this case, the calculated TTKG was 2.5, consistent with appropriate renal conservation of K+ and a nonrenal cause for hypokalemia. In the absence of significant gastrointestinal loss of K+, the patient was diagnosed with a “redistributive” subtype of hypokalemia.

More than 98% of total body potassium is intracellular; regulated buffering of extracellular K+ by this large intracellular pool plays a crucial role in the maintenance of a stable plasma K+ concentration. Clinically, changes in the exchange and distribution of intra- and extracellular K+ can cause significant hypo- or hyperkalemia. Insulin, β2-adrenergic activity, thyroid hormone, and alkalosis promote cellular uptake of K+ by multiple inter-related mechanisms, leading to hypokalemia. In particular, alterations in the activity of the endogenous sympathetic nervous system can cause hypokalemia in several settings, including alcohol withdrawal, hyperthyroidism, acute myocardial infarction, and severe head injury.

Weakness is common in severe hypokalemia; hypokalemia causes hyperpolarization of muscle, thereby impairing the capacity to depolarize and contract. In this particular patient, Grave’s disease caused hyperthyroidism and hypokalemic paralysis (thyrotoxic periodic paralysis [TPP]). TPP develops more frequently in patients of Asian or Hispanic origin. This predisposition has been linked in some patients to coding mutations in Kir2.6, a muscle-specific, thyroid hormone-induced K+ channel. These coding mutations cause loss-of-function in the Kir2.6 protein, leading to a “dominant negative” effect on muscle Kir channels following induction by thyroid hormone. The hypokalemia in TPP is also attributed to both direct and indirect activation of the Na+/K+-ATPase by thyroid hormone, resulting in increased uptake of K+ by muscle and other tissues. Thyroid hormone induces expression of multiple subunits of the Na+/K+-ATPase in skeletal muscle, increasing the capacity for uptake of K+; hyperthyroid increases in β-adrenergic activity are also thought to play an important role in TPP.

Clinically, patients with TPP present with weakness of the extremities and limb girdle, with paralytic episodes that occur most frequently between 1 and 6 A.M. Precipitants of weakness include high carbohydrate loads and strenuous exercise. Signs and symptoms of hyperthyroidism are not always present, often leading to delays in diagnosis. Hypokalemia is often profound and usually accompanied by redistributive hypophosphatemia, as in this case. A TTKG of <2–3 separates patients with TPP from those with hypokalemia due to renal potassium wasting, who will have TTKG values that are >4. This distinction is of considerable importance for therapy; patients with large potassium deficits require aggressive repletion with K+-Cl−, which has a significant risk of rebound hyperkalemia in TPP and related disorders.

APPROACH TO MANAGEMENT

Ultimately, definitive therapy for TPP requires treatment of the associated hyperthyroidism. In the short-term, however, potassium replacement is necessary to hasten muscle recovery and prevent cardiac arrhythmias. The average recovery time of an acute attack is reduced by ~50% in patients treated with intravenous K+-Cl− at a rate of 10 meq/h; however, this incurs a significant risk of rebound hyperkalemia, with up to 70% developing a plasma K+ concentration of >5.0 meq/L. This potential for rebound hyperkalemia is a general problem in the management of all causes of “redistributive hypokalemia”; hence the need to distinguish these patients accurately and rapidly from those with a large K+ deficit due to renal or extra-renal loss of K+. An attractive alternative to K+-Cl− replacement in TPP is treatment with high-dose propranolol (3 mg/kg), which rapidly reverses the associated hypokalemia, hypophosphatemia, and paralysis. Notably, rebound hyperkalemia is not associated with this treatment.

A 66-year-old man was admitted to hospital with a plasma K+ concentration of 1.7 meq/L and profound weakness. The patient had noted progressive weakness over several days, to the point that he was unable to rise from bed. Past medical history was notable for SCLC with metastases to brain, liver, and adrenals. The patient had been treated with one cycle of cisplatin/etoposide 1 year before this admission, complicated by acute kidney injury (peak creatinine of 5, with residual chronic kidney disease), and three subsequent cycles of cyclophosphamide/doxorubicin/vincristine, in addition to 15 treatments with whole-brain radiation.

On physical examination the patient was jaundiced. BP was 130/70, increasing to 160/98 after a liter of saline, with a JVP at 8 cm. There was generalized muscle weakness.

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The patient’s hospital course was complicated by acute respiratory failure attributed to pulmonary embolism; he expired 2 weeks after admission.

APPROACH TO DIAGNOSIS

Why was this patient hypokalemic? Why was he weak? Why did he have an alkalosis?

This patient suffered from metastatic SCLC, persistent despite several rounds of chemotherapy and radiotherapy. He presented with profound hypokalemia, alkalosis, hypertension, severe weakness, jaundice, and worsening liver function tests.

With respect to the hypokalemia, there was no evident cause of nonrenal potassium loss, e.g., diarrhea. The urinary TTKG was 11.7, at a plasma K+ concentration of 1.7 meq/L; this TTKG value is consistent with inappropriate renal K+ secretion, despite severe hypokalemia. The TTKG is calculated as (POsm × UPotassium)/(PPotassium × UOsm). The expected values for the TTKG are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia (see also Case 2 and Case 6). Alternatively, a urinary K+-to-creatinine ratio of >13 mmol/g creatinine (>1.5 mmol/mmol creatinine) is compatible with excessive renal K+ excretion.

The patient had several explanations for excessive renal loss of potassium. First, he had a history of cisplatin-associated acute kidney injury, with residual chronic kidney disease. Cisplatin can cause persistent renal tubular defects, with prominent hypokalemia and hypomagnesemia; however, this patient had not previously required potassium or magnesium repletion, suggesting that cisplatin-associated renal tubular defects did not play a major role in this presentation with severe hypokalemia. Second, he was hypomagnesemic on presentation, suggesting total body magnesium depletion. Magnesium depletion has inhibitory effects on muscle Na+, K+-ATPase activity, reducing influx into muscle cells and causing a secondary increase in K+ excretion. Magnesium depletion also increases K+ secretion by the distal nephron; this is attributed to a reduction in the magnesium-dependent, intracellular block of K+ efflux through the secretory K+ channel of principal cells (renal outer medullary K+ channel [ROMK]—see Fig. S1-1). Clinically, hypomagnesemic patients are refractory to K+ replacement in the absence of Mg2+ repletion. Again, however, this patient had not previously developed significant hypokalemia, despite periodic hypomagnesemia, such that other factors must have caused the severe hypokalemia.

The associated hypertension in this case suggested an increase in mineralocorticoid activity, causing increased activity of ENaCs in principal cells, NaCl retention, hypertension, and hypokalemia. The increase an ENaC-mediated Na+ transport in principal cells would have led to an increase in the lumen-negative potential difference in the connecting tubule (CNT) and CCD, driving an increase in K+ secretion through apical K+ channels (see Fig. S1-1). This explanation is compatible with the very high TTKG, i.e., an increase in K+ excretion that is inappropriate for the plasma K+ concentration.

What caused an increase in mineralocorticoid activity in this patient? The patient had bilateral adrenal metastases, indicating that primary hyperaldosteronism was unlikely. The clinical presentation (hypokalemia, hypertension, and alkalosis) and the history of SCLC) suggested Cushing’s syndrome, with a massive increase in circulating glucocorticoids, in response to ectopic adrenocorticotropic hormone (ACTH) secretion by his SCLC tumor. Confirmation of this diagnosis was provided by a very high plasma cortisol level, high ACTH level, and increased urinary cortisol (see the laboratory data above).

Why would an increase in circulating cortisol cause an apparent increase in mineralocorticoid activity? Cortisol and aldosterone have equal affinity for the mineralocorticoid receptor (MLR); thus, cortisol has “mineralocorticoid-like” activity; however, cells in the aldosterone-sensitive distal nephron (the DCT, CNT, and collecting duct are protected from circulating cortisol by the enzyme 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2), which converts cortisol to cortisone (Fig. S1-2); cortisone has minimal affinity for the mineralocorticoid receptor (MLR). Activation of the MLR causes activation of the basolateral Na+/K+-ATPase, activation of the thiazide-sensitive Na+-Cl− cotransporter in the DCT, and activation of apical ENaCs in principal cells of the CNT and collecting duct (see Fig. S1-2). Recessive loss-of-function mutations in the 11βHSD-2 gene lead to cortisol-dependent activation of the MLR and the “syndrome of apparent mineralocorticoid excess” (SAME), comprising hypertension, hypokalemia, hypercalciuria, and metabolic alkalosis, with suppressed plasma renin activity (PRA) and suppressed aldosterone. A similar syndrome is caused by biochemical inhibition of 11βHSD-2 by glycyrrhetinic/glycyrrhizinic acid (found in licorice, for example), and/or carbenoxolone.

FIGURE S1-2

11β-hydroxysteroid dehydrogenase-2 (11βHSD-2) and syndromes of apparent mineralocorticoid excess. The enzyme 11βHSD-2 protects cells in the aldosterone-sensitive distal nephron (the distal convoluted tubule [DNT], connecting tubule [CNT], and collecting duct) from the illicit activation of mineralocorticoid receptors (MLRs) by cortisol. Binding of aldosterone to the MLR leads to activation of the thiazide-sensitive Na+-Cl− cotransporter in DCT cells and the amiloride-sensitive epithelial sodium channel (ENaC) in principal cells (CNT and collecting duct). Aldosterone also activates basolateral Na+/K+-ATPase and, to a lesser extent, the apical secretory K+ channel ROMK. Cortisol has equivalent affinity for the MLR to that of aldosterone; metabolism of cortisol to cortisone, which has no affinity for the MLR, prevents these cells from activation by circulating cortisol. Genetic deficiency of 11βHSD-2 or inhibition of its activity causes the syndromes of apparent mineralocorticoid excess (see also Case 8).

In Cushing’s syndrome caused by increases in pituitary ACTH, the incidence of hypokalemia is only 10%, whereas it is ~70% in patients with ectopic secretion of ACTH, despite a similar incidence of hypertension. The activity of renal 11βHSD-2 is reduced in patients with ectopic ACTH compared with Cushing’s syndrome, resulting in a syndrome of apparent mineralocorticoid excess; the prevailing theory is that the much greater cortisol production in ectopic ACTH syndromes overwhelms the renal 11βHSD-2 enzyme, resulting in activation of renal MLRs by unmetabolized cortisol (see also Fig. S1-2).

Why was the patient so weak? The patient was profoundly weak due to the combined effect of hypokalemia and increased cortisol. Hypokalemia causes hyperpolarization of muscle, thereby impairing the capacity to depolarize and contract. Weakness and even ascending paralysis can frequently complicate severe hypokalemia. Hypokalemia also causes a myopathy and predisposes to rhabdomyolysis; notably, however, the patient had a normal creatine phosphokinase (CPK) level. Cushing’s syndrome is often accompanied by a proximal myopathy, due to the protein-wasting effects of cortisol excess.

The patient presented with a mixed acid-base disorder, with a significant metabolic alkalosis and a bicarbonate concentration of 44 meq/L. A venous blood gas was drawn soon after his presentation; venous and arterial blood gases demonstrate a high level of agreement in hemodynamically stable patients, allowing for the interpretation of acid-base disorders with venous blood gas results. In response to his metabolic alkalosis, the pCO2 should have increased by 0.75 mmHg for each 1 meq/L increase in bicarbonate; the expected pCO2 should have been ~55 mmHg. Given the pCO2 of 62 mmHg, he had an additional respiratory acidosis, likely caused by respiratory muscle weakness from his acute hypokalemia and subacute hypercortisolism.

The patient’s albumin-adjusted AG was 21 + (4 − 2.8) × 2.5 = 24; this suggests a third acid-base disorder, AG acidosis. Notably, the measured AG can increase in alkalosis, due to both increases in plasma protein concentrations (in hypovolemic alkalosis) and to the alkalemia-associated increase in net negative charge of plasma proteins, both causing an increase in “unmeasured anions”; however, this patient was neither volume-depleted nor particularly alkalemic, suggesting that these effects played a minimal role in his increased AG. Alkalosis also stimulates an increase in lactic acid production, due to activation of phosphofructokinase and accelerated glycolysis; unfortunately, however, a lactic acid level was not measured in this patient. It should be noted in this regard that alkalosis typically increases lactic acid levels by a mere 1.5–3 meq/L, and that the patient was not significantly alkalemic. Regardless of the underlying pathophysiology, the increased AG was likely related to the metabolic alkalosis, given that the AG had decreased to 18 by hospital day 2, coincident with a reduction in plasma bicarbonate.

Why did the patient have a metabolic alkalosis? The activation of MLRs in the distal nephron increases distal nephron acidification and net acid secretion. In consequence, mineralocorticoid excess causes a saline-resistant metabolic alkalosis, which is exacerbated significantly by the development of hypokalemia. Hypokalemia plays a key role in the generation of most forms of metabolic alkalosis, stimulating proximal tubular ammonium production, proximal tubular bicarbonate reabsorption, and distal tubular H+, K+-ATPase activity.

APPROACH TO MANAGEMENT

The first priority in the management of this patient was to increase his plasma K+ and magnesium concentrations rapidly; hypomagnesemic patients are refractory to K+ replacement alone, hence the need to correct hypomagnesemia immediately. This was accomplished via the administration of both oral and intravenous K+-Cl−, giving a total of 240 meq over the first 18 h; 5 g of intravenous magnesium sulfate was also administered. Multiple 100 mL “minibags” of saline containing 20 meq each were infused, with cardiac monitoring and frequent measurement of plasma electrolytes. Of note, intravenous K+-Cl− should always be given in saline solutions, since dextrose-containing solutions can increase insulin levels and exacerbate hypokalemia.

This case illustrates the difficulty in predicting the whole body deficit of K+ in hypokalemic patients. In the absence of abnormal K+ redistribution, the total deficit correlates with plasma K+ concentration, which drops by ~0.27 mM for every 100-mmol reduction in total body stores; this would suggest a deficit of ~650 meq of K+ in this patient, at the admission plasma K+ concentration of 1.7 meq/L. Notably, however, alkalemia induces a modest intracellular shift of circulating K+ such that this patient’s initial plasma K+ concentration was not an ideal indicator of the total potassium deficit. Regardless of the underlying pathophysiology in this case, close monitoring of plasma K+ concentration is always essential during the correction of severe hypokalemia in order to gauge the adequacy of repletion and to avoid overcorrection.

Subsequent management of this patient’s Cushing’s syndrome and ectopic ACTH secretion was complicated by the respiratory issues. The prognosis in patients with ectopic ACTH secretion depends on the tumor histology and the presence or the absence of distant metastases. This patient had an exceptionally poor prognosis, with widely metastatic SCLC that had failed treatment; other patients with ectopic ACTH secretion caused by more benign, isolated tumors, most commonly bronchial carcinoid tumors, have a much better prognosis. In the absence of successful surgical resection of the causative tumor, management of this syndrome can include surgical adrenalectomy or medical therapy to block adrenal steroid production.

A stuporous 22-year-old man was admitted with a history of behaving strangely. His friends indicated he experienced recent emotional problems stemming from a failed relationship and had threatened suicide. There was a history of alcohol abuse but his friends were unaware of recent alcohol consumption. The patient was obtunded on admission, with no evident focal neurological deficits. The remainder of the physical examination was unremarkable.

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Urinalysis revealed crystalluria, with a mixture of “envelope” and “needle”-shaped crystals.

APPROACH TO DIAGNOSIS

This patient presented with CNS manifestations and a history of suspicious behavior, suggesting ingestion of a toxin. The AG was strikingly elevated at 35 meq/L. The ΔAG of 25 significantly exceeded the ΔHCO3− of 15. The fact that the Δ values were significantly disparate indicates that the most likely acid-base diagnosis in this patient is a mixed high AG metabolic acidosis and a metabolic alkalosis. The metabolic alkalosis in this case may have been the result of vomiting. Nevertheless, the presence of an elevated osmolar gap is an extremely important finding and immediately raises the possibility of toxic alcohol ingestion. The osmolar gap of 33 (difference in measured and calculated osmolality or 325 – 292) in the face of a high AG metabolic acidosis is diagnostic of an osmotically active metabolite in plasma; a difference of >10 mOsm/kg indicates a significant concentration of an unmeasured osmolyte. Examples of toxic osmolytes include toxic alcohols, such as ethylene glycol, diethylene glycol, methanol, and propylene glycol.

Several caveats apply to the interpretation of the osmolar and AGs in the differential diagnosis of toxic alcohol ingestions. First, unmeasured, neutral osmolytes can also accumulate in lactic acidosis and alcoholic ketoacidosis, i.e., an elevated osmolar gap is not specific to AG acidoses associated with toxic alcohol ingestions. Second, patients can present having extensively metabolized the ingested toxin, with an insignificant osmolar gap but a large AG, i.e., the absence of an elevated osmolar gap does not rule out toxic alcohol ingestion. Third, the converse can also be seen in patients who present earlier after ingestion of the toxin, i.e., a large osmolar gap with minimal elevation of the AG. Finally, clinicians should be aware of the effect of coingested ethanol, which can also elevate the osmolar gap and can reduce metabolism of the toxic alcohols via competitive inhibition of alcohol dehydrogenase (see below), thus attenuating the expected increase in the AG. Ethylene glycol is commonly available as antifreeze or solvents and may be ingested accidently or in a suicide attempt. The metabolism of ethylene glycol by alcohol dehydrogenase generates acids such as glycoaldehyde, glycolic acid, and oxalic acid. The initial effects of intoxication are on the CNS, and in the earliest stages mimic inebriation, but may quickly progress to full-blown coma. Delay in treatment is one of the most common causes of mortality with toxic alcohol poisoning. The kidney shows evidence of acute tubular injury with widespread deposition of calcium oxalate crystals within tubular epithelial cells. Cerebral edema is common, as is crystal deposition in the brain; the latter is irreversible.

The co-occurrent crystalluria is typical of ethylene glycol intoxication; both needle-shaped monohydrate and envelope-shaped dihydrate calcium oxalate crystals can be seen in the urine as the process evolves. Circulating oxalate can also complex with plasma calcium, reducing the ionized calcium as in this case.

Although ethylene glycol intoxication should be verified eventually by measuring ethylene glycol levels, therapy must be initiated immediately in this life-threatening situation. While therapy can be initiated with confidence in cases of known or witnessed ingestions, such histories are rarely available. Therapy should thus be initiated in patients with severe metabolic acidosis and elevated anion and osmolar gaps. Other diagnostic features, e.g., hypocalcemia or acute renal failure with crystalluria, can provide important confirmation for urgent, empiric therapy.

APPROACH TO MANAGEMENT

Since all the osmotically active toxic alcohols, ethylene glycol, diethylene glycol, methanol, and propylene glycol, are metabolized by alcohol dehydrogenase to generate toxic products, competitive inhibition of this key enzyme is common to the treatment of all four intoxications. The most potent inhibitor of alcohol dehydrogenase, and the drug of choice this circumstance, is fomepizole (4-methyl pyrazole). Fomepizole should be administered intravenously as a loading dose (15 mg/kg) followed by doses of 10 mg/kg every 12 h, for 4 doses, and then 15 mg/kg every 12 h thereafter until ethylene glycol levels have been reduced to <20 mg/dL and the patient is asymptomatic with a normal pH. Additional very important components of the treatment of toxic alcohol ingestion include fluid resuscitation, thiamine, pyridoxine, folate, sodium bicarbonate, and hemodialysis. Hemodialysis is used to remove both the parent compound and toxic metabolites, but also removes administered fomepizole, necessitating adjustment of dosage frequency. Gastric aspiration, induced emesis, or the use of activated charcoal is only effective if initiated within 30–60 min after ingestion of the toxin. When fomepizole is not available, ethanol, which has more than tenfold affinity for alcohol dehydrogenase compared to other alcohols, may be substituted and is quite effective. Ethanol must be administered IV to achieve a blood level of 22 meq/L (100 mg/dL). A disadvantage of ethanol is the obtundation that follows its administration, which is additive to the CNS effects of ethylene glycol. Furthermore, if hemodialysis is utilized, the infusion rate of ethanol must be increased because it is rapidly dialyzed. In general, hemodialysis is indicated for all patients with ethylene glycol intoxication when the arterial pH is <7.3 or the osmolar gap exceeds 20 mOsm/kg H2O. Isopropanol is also a toxic alcohol and is the primary component of “rubbing alcohol,” windshield deicer fluid, and some antifreezes. It is also metabolized by alcohol dehydrogenase. However, it is important to recognize that isopropanol intoxication is an exception to the treatment paradigm outlined above because, although ingestion of isopropyl alcohol also causes an increase in the osmolar gap, in the absence of lactic acidosis from shock, it does not increase the AG because isopropanol is metabolized primarily to acetone. Therefore, isopropanol ingestion is typically not life threatening as fatality is very rare. One caution in isopropal alcohol ingestion is that it should not be overtreated, and the indications for and specific type of therapy understood. The hallmark of isopropanol intoxication is marked ketonemia and ketonuria without metabolic acidosis. Fomepizole is not indicated. Isotonic fluids should be administered to induce a significant increase in urine output. Nevertheless, massive isopropyl alcohol ingestion may cause coma when isopropyl alcohol levels >500 mg/dL (80 mmol/L). In such severe cases, the clinician should consider tracheal intubation to protect the airways. Hemodialysis may be recommended for patients who are persistently unstable hemodynamically. However, dialysis is very rarely required, even when measured serum levels are >500 mg/dL, as long as the patient maintains a stable BP and tissue perfusion.

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Which patient is considered to be at an increased risk of a fluid and electrolyte imbalance?

Which electrolyte influences excitability of nerve and muscle?

Which acute condition will place the patient at high risk of hyperkalemia?

Which electrolyte is necessary for the production of adenosine tri phosphate?