Is probably overdiagnosed. Con \201 rm if: Volume-deplete. \200 With volume resuscitation, u-Osm rapidly rises (with ADH suppression). CHAPTER 10 Fluids and electrolytes 784 Management of hyponatraemia In all cases \200 Identify those at most risk for neurologica l complications, and manage those most at risk with repeated review: \200 Acute hyponatraemia (<48 hours). \200 Thi azide-induced d Na + . \200 Premenopausal \231\200 (? estrogen, i responsiveness to ADH) . \200 Malnourished or alcoholic patients. \200 Even if well, i surveillance, as for sy mptomatic patients, with repeated Na + checks (see below). Assess the volume status correctly ( b pp. 12 and 114): the key to correct diagnosis and management. Stop contributing drugs 9 \202 uids ( (cid:2) 5% dextrose). \200 Correct d K + ( b p. 7 98) and d Mg 2+ ( b p. 808), if present. Is the patient symptomatic (encephalopathic) or is Na + <120mmol/L? \200 No: respond acco rding to volume status ( b see below). As a general rule, err on the side of cautious correction (if correction is needed at all). Yes: see b p. 786. Requires action \200\224 urgent if symptomatic. Managing asymptomatic hyponatraemia Hypovolaemic hyponatraemia \200 Resuscitate with 0.9% NaCL (154mmol/L NaCl) at 1 \200\223 3mL/kg/hr. Always correct d K + in concert by adding 20 \200\223 40mmol KCl to each 1L 0.9% NaCl. Euvolaemic hyponatraemia \200 Usually SIADH in hospitals and in the elderly (see b p. 785 ). Hypervolaemic hyponatraemia \200 Manage conservatively \202 uid restriction <1L/day ( 8 5 cups/day), and consider 20 \200\223 40mg furosemide od. MANAGEMENT OF HYPONATRAEMIA 785 Managing asymptomatic SIADH \200 Fluid restrict <800mL/day \200\224 but do not expect th is alone to work. \200 Salt and loop diuretic: PO NaCl as 600mg 4 \200\223 8 tablets dai ly (contains 10mmol/tab Na + , e.g. Slow Sodium ), furosemide 20 \200\223 40mg/daily (f ree water excretion in excess of urinary salt loss). (cid:2) Monitor closely (reserve as an inpatient tool). Demeclocycline 150 \200\223 300mg 6-hourly induces nephrogenic diabetes insipidus, reversing ADH effect. Use with caution in chronic hyponatraemia, as diuresis may be brisk. Gut side effects often limit longer-term use. Urea 30 \200\223 90g/day (not readily available in the UK). An alternative strategy would involve using vaptans : \200 Tolvaptan (oral) and conivapta n (parenteral use for <4 days) are \200\230 aquaretics \200\231 . Serious liver injury has limited use, and evolving data suggests a limited role for these agents. Oral competitive vasopressin (V 2 ) receptor antagonists, blocking the action of ADH on V 2 (and V 1 ) receptors, so preventing tubular water uptake. Cause increased excretion of free water (without electrolyte disturbance) by reducing AQP2 activity in the collecting duct, leaving cells insensitive to ADH and less permeable to water. Demonstrated in phase II and III trials to effectively reverse hyponatraemia in euvolaemic and hypervolaemic states. Expect i Na + 6 \200\223 7mmol/L on tolvapatan 15mg od. \200 (cid:2) Do not \202 uid-r estrict \200\224 allow patients access to free water, and monitor serum Na + regularly. Predominantly studied in chronic hyponatraemia with Na + >120mmol/L. Uncertain: indications for treatment (level of Na? Symptoms?), long-term survival advantage (may d hospital stay), duration of treatment. CHAPTER 10 Fluids and electrolytes 786 Hyponatraemia with encephalopathy X The brain and d Na + The skull limits the brain \200\231s capacity to increase in size: w ith d Na + , a falling osmolality l i intracellular water and symptomatic brain swelling. T he tight junctions between endothelial cells and astrocyte foot processes that constitute t he blood \200\223 brain barrier permit aquaporin-mediated water movement along osmotic gra dients. In response, the cerebral ECF is rapidly reduced (to allow more room) and intracell ular organic sol- utes (including the amino acid taurine) exported (lessens the osmolar gra dient that causes water in \202 ux) over 1 \200\223 2 days. If too rapid correction of chronic d Na + occurs, osmotic or central pontine myelinosis (CP M) may occur. As the brain cannot restore the solute contri- bution to intracellular tonici ty quickly, when the ECF osmolality is rapidly normalized, water leaves cells, causing cere bral dehydration and demyelina- tion (affecting the whole brain, not just the pons, as in t he original descrip- tion). Symptoms become apparent after around 24 hours. Manage in high dependency setting. \200 Na + by as little as 3 \200\223 7mmol/L will usu ally treat symptoms. \200 Repeat Na + every 2 hours initially, and then 4-hourly. IF acute, <48 hours \200\231 duration (often post-operative): \200\223 Aim for i Na + by 2mmol/L/h or until asymptomatic. \200\223 Never correct by >10 mmol/L/24 hours. IF chronic, >48 hours \200\231 duration: \200\223 Always consider CPM . \200\223 Aim for i Na + by 0.5mmol/L/h to i by 6mmol/L or until asymptomatic. \200\223 Aim for +8mmol/L in 24 hours, and do not correct by >10mmol/L/24 hours . Other measures: \200\223 Add in furosemide to prevent volume overload (as 20mg IVI 8-hourly). The diuresis caused will be hypotonic (i.e. water in excess of salt), adding to sodium correction. \200\223 In volume-overloaded patients intolerant of salt loads, 20% mannitol may be useful to allow use of 3% saline. \200\223 Do not correct by >10mmol/L/24 hours. Calculate Na + de \201 cit, and select appropriate mode of administration. Na + de \201 cit = total body water x [desired Na + \200\223 actual Na + ]. \200\223 TBW = 60% body weight in \231\202 and 50% body weight in \231\200 . \200\223 I f age >65, use 50% BW in \231\202 and 45% BW in \231\200 . \200\223 For example, aiming for a safe Na + of 125mmol/L in 53-year-old 70kg \231\202 with Na + 115, de \201 cit = 0. 6 x 70 x 10 = 420mmol Na + . \200 Generally, use 2.7% or 3% (hypertonic) saline, containi ng 462mmol and 513mmol NaCl, respectively, per 1L. Deliver via a central line. \200 Estimate effect of infusion by calculating change in Na + : HYPONATRAEMIA WITH ENCEPHALOPATHY 787 +Na Infusion fluid Na Na TBW + + = Change in Na for 1,000mL infusio nn + 1 For example, in the above patient, using 3% hypertonicsalline 1L over 24hours: \210\222 513 115 + 42 1 + = = Change in Na 9. 25 mmol/ ol/ LL L If a rapid increase were required (e.g. if \201 tting) and a target of >120mmol/L were de sired over 3 hours (see next paragraph), aim to infuse [5/9.25 x 1L] = 540mL of 3% saline a t 180mL/h. X An alternate strategy in \201 tting patients is to give a bolus of 100mL 2.7 % or 3% NaCl, and repeat after 10 minutes. Sodium \200\230 guesstimates \200\231 : for every 1L infused, a crude estimate of the sod ium change in plasma might be: \200 3% NaCl (Na + 513mmol/L) i 13mmol/L. \200 0.9% NaCl (Na + 154mmol/L) i 1.4mmol/L. \200 5% glucose (Na + 0) d 3.5mmol/L. Do not guess if you have time. CHAPTER 10 Fluids and electrolytes 788 Hypernatraemia Serum Na + >146mmol/L is usually due to a water de \201 cit and is associ- ated with severe underlying disease and signi \201 cant mortality ( 9 50%). With i Na + , ECF osmolality i , increasing osmotic drag on the intracellular compartment. This leads to cellular dehydration, most importantly in the brain: loss of volume creates vascular shear stress, resulting in bleeding and thrombosis. As in hyponatraemia ( b p. 780), compensation begins with cellular retention of salts and organic solutes in the brain, increas- ing cel lular tonicity and lessening water losses to the hyperosmolar ECF (occurs over days). Overz ealous correction leads to too rapid intracranial expansion of the brain, with potential te ntorial herniation. Causes include: Excess hypertonic \202 uids \200 IVI infusions ( 2 antibiotics), TPN, or enteral feeds. \200 Rarely, salt ingestion, or sea water near-drowning. Excess water loss \200 Renal: Diabetes insipidus (see Box 10.1), with/out altered thirst. \200 Diuretics. \200 Osmoti c diuresis (glucose in DKA, urea in recovering ATN). Gut: Diarrhea (and laxatives, such as lactulose). \200 Vomiting, NG losses, or \201 stulae. Skin: Sweating, burns. Decreased thirst In the unwell and elderly, esp. if on psychotropic drugs. Symptoms and signs Re \202 ect cerebral dehydration. Thirst, apathy, weakness, confusion l d con- sciousness, seizures, and coma. Cause often apparent clinically, with sepsis, pneum onia, and uncontrolled diabetes common. Investigations U&E, plasma osmolality, glucose. Urine Na + , osmolality. With osmotic diu- resis, u-Osm is always >300mOsmol/kg. HYPERNATRAEMIA 789 Box 10.1 Diabetes insipidus 2 Polydipsia and polyuria (>6L/day) in adults without diabetes is usually due to DI or psychogenic polydipsia. ADH (also called arginine vasopressin, AVP) binds the V 2 receptor on collecting duct cells , leading to surface expression of free water chan- nels, or aquaporins, through which wate r is rapidly taken up. DI can be cranial (i.e. impaired release of ADH): Trauma or post-operative. \200 Tumors or in \201 ltrative processes (sarcoid, TB). \200 Infective (meningitis, encephalitis). \200 Cerebral vasculitis (SLE, Wegener \200\231s) . More commonly, DI is nephrogenic (resistance to ADH). Causes include: \200 Congenital. \200 Drug-induced ( lithium , amphotericin, foscarnet, demeclocycline). \200 Hypokalaemi a or hypercalcaemia. \200 Tubulointerstitial disease (medullary cystic disease, b p. 599) . Lithium prevents translocation of aquaporins to the collecting duct api- cal membrane and is the most common cause of nephrogenic DI. Diagnosis rests on \201 nding i UO (>3L/day) with dilute urine (<300mOsmol/kg). Exclude o smotic diuretics, d K + , or i Ca 2+ . A \202 uid deprivation test 9 DDAVP (synthetic ana log of ADH) is diagnostic ( 2 seek expert advice). Treatment depends on cause. Cranial DI is treated with intranasal desmopressin 10 \200\223 20 micrograms bd. Drug effect lasts for 6 \200\223 12 hours. Nephrogenic DI , if congenital or lithium-induced, is treated with thi- azide diuretics (hy povolaemia l d Na + absorption proximally, 6 reduced water delivery to the collecting duct) and NSAIDs (such as indometacin which antagonizes the effect of ADH). (cid:2) Simultanous use of desmopressin and 5% glucose should be used with extreme caution (analogous to pourin g water into a closed box). CHAPTER 10 Fluids and electrolytes 790 Treatment of hypernatraemia 2 Treat the underlying cause. \200 Aim for Na + 145mmol/L. \200 Calculate water de \201 cit (and include ongoing losses in calculations): +Na Infusion fluid Na Na TBW \200 TBW = 60% body weight in \231\202 and 50% body weight in \231\200 . \200 If age >65, use 50% weight in \231\202 and 45% weight in \231\200 . For example, in a 53-year-old 70 kg \231\202 with Na + 170mmol/L, TBW = 42L. Using 5% glu cose (no Na + ), [0 \200\223 170]/43 = \200\223 3.95mmol/L. So, 1L 5% dex- trose will red uce Na + to 166mmol/L. Aiming to correct only 0.5mmol/L/h will require 1L/8h, or 125mL/h if no ongoing \202 uid losses . As a rule of thumb, allow for 1.5L insensible loss/day. \200 Reassess patient repeatedly. \200 If i Na + is acute (<24 hours), can be reversed q uickly. Usually occurs + + = Change in Na for 1,000mL infusio nn + 1 with infusion of hypertonic solutions, but also with rapid loss of hypotonic \202 uid (sw eating, burns). \200 Correct at 1mmol/L/h. \200 Measure Na + 2-hourly initially, then 4 -hourly. If chronic (>24 hours), correct more slowly to prevent rehydration injury to the brain: \200 Document neurological status. \200 Correct at no greater than 0.5mmol/L/h or no less than 10mmol/L/ day. Correct 50% of the water de \201 cit in \201 rst 12 \200\223 24 hours. \200 Correct r emaining water de \201 cit over next 24 \200\223 48 hours. \200 Measure Na + 2-hourly i nitially, then 4-hourly. Choice of \202 uid \200 Water PO, if orientated, or per NG if able. \200 5% glucose o r 0.45% (half-normal) saline IVI if cannot use the gut. May require insulin to control hyperglycaemia if using 5% glucose. OEDEMA AND ITS TREATMENT 791 Oedema and its treatment Oedema occurs with interstitial expansion of the ECF, becoming cli nically apparent if >2L \202 uid excess in this compartment. It is most obvious in the de pendent areas (ankles), but it may affect the face and eyelids, especially in the morning. Anasarca refers to severe oedema, progressing from the peripheries to the trunk. Oedema may occur with other extravascular signs of salt and water retention (pleural effusions, ascit es). Causes include: \200 Congestive heart failure. \200 Liver failure. \200 Nephroti c syndrome ( b p. 554). \200 Acute or chronic renal failure ( d GFR l d salt excretion). \200 Drug-induced (NSAIDs, calcium channel blockers). \200 Premenstrual or pregnant \231\200 (estrogen effect). \200 Venous insuf \201 ciency (localized oedema). Development of oedema For oedema to develop, salt and water retention must occur (to expand the ECF) and/or capillary permeability must increase (to allow \202 uid shifts into the interstitium). The \200\230 over \201 ll \200\231 hypothesis suggests that Na + retention is the primar y factor in the development of oedema: any state that leads to d EABV ( b p. 778) l s hyper aldosteronism, sympathetic overactivity, and non-osmotic ADH release. This then causes salt and water retention, an increase in ECF vol- ume, and oedema. The \200\230 under \201 ll \200\231 hypothesis explains oedema associated with d albumin as a fall in plasma oncotic pressure (provided largely by albumin) with unchanged hydrosta tic pressure, resulting in \202 uid movement into the extravascular space. This then lead s to s \202 uid retention. Oedema and hypoalbuminaemia in the nephrotic syndrome Experimental evidence suggests the \200\230 under \201 ll \200\231 hypothesis to be incor- rect with d s-albumin: the transc apillary oncotic gradient is maintained with hypoalbuminaemia, as interstitial colloid osmo tic pressure (COP) is reduced in tandem with falls in the plasma COP (the interstitial \202 uid not only maintains a COP countering plasma COP, but can be varied). Rather, in \202 ammatory cytokines impair capillary permeability, a falling EABV l salt retention, i u rinary albumin modi \201 es Na + handling directly in the nephron, and renal resistance to ANP develops. The net effect is one of salt retention, with equilibration of the expanded ECF into the interstitium. CHAPTER 10 Fluids and electrolytes 792 Diuretics All diuretics block the reuptake of Na + , and thus Cl \200\223 and water. All c ircu- late highly protein-bound and are thus not well \201 ltered by the glomerulus. This complex is taken up from the peritubular \202 uid by proximal tubular cells and the diur etic released prior to excretion to act in the urinary space (except for spironolactone and other mineralocorticoid receptor antagonists). For use in hypertension, see b p. 498. Commonly used diuretics include Loop diuretics \200 Site of action: blocks Na + uptake at the Na + K + 2Cl \200\223 (NKCC) co-transporter in the thick ascending limb of the loop of Henle. Speci \201 c side effects: i u-Ca 2+ , ototoxicity. \200 Examples: furosemide, bumetanid e, torasemide. Thiazide diuretics \200 Site of action: blocks Na + uptake at the Na + Cl \200\223 co-tr ansporter in the distal tubule. Speci \201 c side effects: i u-Ca 2+ (may cause hypercalcaemia). \200 Examples: bendro \202 umethiazide, hydrochlorothiazide, metolazone, indapamide. Amiloride/triamterene Site of action: blocks Na + uptake at the apical Na + channel (ENaC) in the collecting duct. Mineralocorticoid receptor antagonists \200 Site of action: blocks Na + uptake by downreg ulating apical Na + channel (ENaC) expression in the collecting duct. Spironolactone enters cells from the circulation, rather than the urinary space, and binds the intracellular min eralocorticoid receptor (MR). Speci \201 c side effects: i K + , anti-androgenic effects (not eplerenone). \200 Exampl es: spironolactone, eplerenone. \200 General side effects include: d K + ( not with spiro nolactone), d Na + , d Mg 2+ , i uric acid, skin rashes, interstitial nephritis, dyslipidaemia ( X insulin resista nce, impotence). Using diuretics in oedematous states (cid:2) Always institute appropriate salt restriction when using diuretics, and consider \202 uid restriction to <1,000mL/day. \200 Assess vo lume status daily. \200 Measure weight daily to assess response. \200 Strict input/outp ut charts may be helpful. \200 Measure serum electrolytes regularly. \200 Monitoring u- Na + excretion may be helpful in diuretic resistance. DIURETICS 793 (cid:2) Do not forget bed rest as a useful tool in mobilizing oedema and encourag- ing diur esis . Nephrotic syndrome Often requires high doses of loop diuretics (furosemide 160 \200\223 24 0mg daily), as i urinary albumin binds free diuretic. Consider add-on thiazide diuret- ics (e.g. metolazone 2.5 \200\223 5mg/day PO), but beware rapid-onset d Na + , and titrate dos e against daily weight loss. X Furosemide and albumin infusions are frequently used in an attempt to improve drug delive ry \200\224 probably without real bene \201 t. May be of use if s-Alb <20g/dL. Administer as 100mL 20% human albumin solution, with 40 \200\223 160mg furosemide IVI, over 2 \200 \223 4 hours. Renal failure Loop diuretic if GFR <50mL/min. May require 240mg PO daily in 2 \200\223 3 d ivided doses. Best response with IVI loop diuretic (furosemide 200mg) or as continuous infu sion (furosemide 10 \200\223 50mg/h to a maximum of 500mg/ day to prevent ototoxicity). Bu metanide is better absorbed and should be considered in diuretic resistance (up to 8mg/day) . If poor response, consider add-on thiazide, as described in \200\230Nephrotic syndrome \200\231. Congestive cardiac failure Loop diuretics better than thiazides, e.g. furosemide 40mg od. E vidence from RALES and EPHESUS trials has con \201 rmed a role for mineralocorticoid recep tor blockade, so this class often used as \201 rst line. Hyperkalaemia is a real concern, as such patients are often on ACE inhibitors or B -blockers ( b p. 797). Cirrhosis Spironolactone (50 \200\223 200mg od) prevents s hyperaldosteronism, with add-on thiazide ( not loop \200\224 too marked a diuresis may precipitate ARF) if required. Resi stant ascites is best treated with paracentesis under albumin cover. As it is dif \201 cul t to resorb more than 1L of ascites over a day, a diu- resis that sees daily weight loss of >0.5kg (where 1kg is a surrogate for 1L negative balance through diuresis, and not related to paracentesis) should cause concern over precipitating pre-renal failure. CHAPTER 10 Fluids and electrolytes 794 Potassium K + is the second most abundant cation in the body ( 7 3.5mol). Dietary K + amoun ts to 80 \200\223 150mmol/day. Only around 65mmol is present in the ECF, with the great ma jority (98%) found within cells in muscle (and, to a lesser extent, liver, red cells, and b one). Once absorbed, K + is rapidly buff- ered by removal from the ECF into the intracellul ar compartment: insulin and B -adrenergic catecholamines stimulate membrane Na + /K + -ATPa se to pump K + into cells (in a 3:2 ratio). This electrochemical gradient (the cell membran e potential) is critical to nerve conduction, muscle contraction, and normal cell function. Total body K + balance is regulated by renal excretion: K + is freely \201 l- tered at th e glomerulus ( 7 700mmol/day) and is reabsorbed by the PCT (75%), the loop of Henle (15%), and the A -intercalated cells of the collect- ing duct. K + secretion is responsible for mo st urinary potassium loss and is tightly controlled by aldosterone in the DCT and the princ ipal cells of the collecting duct. The collecting duct ROMK channel is the major chan- nel through which K + is secreted, whereas maxi-K + tends to respond to increased \202 ow in the distal nephron and secrete K + . In health, around 1 \200\223 1.5mmol/kg/day is excreted in urine, with a small fraction ( 7 10mmol) in feces. 2 Obligate urinary K + loss (10 \200\223 15mmol/day) will a lways occur, no matter how low the serum K + Aldosterone secretion is increased directly by hyperkalaemia (and hypo- volaemia) and suppr essed by hypokalaemia, controlling K + in the normal range (3.5 \200\223 5.0mmol/L). Aldos terone l Na + absorption through ENaC, the epithelial sodium channel. As luminal electroneg ativity increases with Na + absorption, Cl \200\223 uptake is enhanced along paracellular pathways, with secretion of K + and H + back into the lumen. Other factors are important in urinary K + excretion: \200 Flow in the distal tubule activates stretch-sensitive K + ch annels l i urinary K + loss. i tubular sodium delivery l i luminal sodium-activating ENaC directly. \200 ADH or vasopr essin may stimulate (some) sodium reabsorption, so i K + loss. \200 Alkalosis. WNK proteins (with no lysine (K)) are key modulators of K + excretion and potentially of \202 uid and sodium balance as well \200\224 their role in K + con- trol continues to be c lari \201 ed. POTASSIUM 795 CHAPTER 10 Fluids and electrolytes 796 Hyperkalaemia See b p. 130 for further discussion. True hyperkalaemia is either due to increased release from cells or decreased excretion by the kidney. Since the release of important trials using spironolactone or eplerenone (in ad dition to ACE inhibitors) in the treatment of heart failure, dangerous hyperkalaemia has be come more common in those with better renal function. Pseudohypokalaemia 2 i K + is often spurious: always recheck result. Traumatic venepuncture l cellular K + leakage and false hyperkalaemia. This l 1 \200\223 2mmol/L rise in the app arent K + . Fine-bore needles, tourniquets, and \201 st clenching can all induce mechanic al release of K + from cells, as can cold temperature. More common with i WCC (>100) or i p latelet count (>400 x 10 9 ). Common causes include \200 CKD per se. \200 K + -rich diets (bananas, other fruits) wit h CKD. \200 Drug-induced (esp. combinations of the following): ACE inhibitors/ARB. \200 K + -sparing diuretics (spironolactone, eplerenone, amiloride). \200 NSAIDs. \200 Heparin and LMW heparins (inhibit normal aldosterone release). \200 Ciclosporin. \200 High-dose trimethoprim. \200 Digoxin toxicity (but not therapeutic l evels of digoxin). \200 B -blockers. Hypoaldosteronism (including type 4 RTA, b p. 825). \200 Addison \200\231s. \200 Increa sed release from cells: Acidosis (lactic). \200 Insulin de \201 ciency (DKA). \200 Rhabdomyolysis, strenuous e xercise, or tumor lysis. \200 Massive haemolysis. \200 Succinylcholine use. HYPERKALAEMIA 797 Hyperkalaemia with aldosterone antagonism RALES and EPHESUS, two major trials demonstrating a 15 \200\223 30% reduc- tion in mortality due to CCF in patients treated with agents tha t block the action of aldosterone (spironolactone, eplerenone), launched an era of aldoster one antagonism in heart failure and beyond. Widespread use (occasionally inappropriate) has followed \200\224 clinical trials have been designed to exclude those with signi \201 ca nt renal disease (those most at risk of hyperkalaemia). In 2004, Juurlink et al. described the effects of instituting these trials in less well-de \201 ned populations with heart failure in Ontario and demon- strated a 6-fold i in hyperk alaemic deaths. Since ACE inhibitors/ARB are also indicated to treat CCF, serious hyperkala emia may occur. If using such combination therapy: \200 Calculate GFR ( b pp. 30 \200\223 37) \200\224caution if abnormal. \200 Stop NSAIDs. \200 Advise about dietary K + restri ction ( b p. 259). \200 If d GFR <60mL/min, add in loop diuretic to waste K + . \200 If acidotic (s-HCO 3 \200\223 <21mmol/L), add NaHCO 3 500 \200\223 600mg bd. \200 Do not increase spironolactone above 25mg/day if + ACE inhibitor. \200 Check K + regularly. If K + >5.5mmol/L, discontinue either ACE-I/ARB or spironolactone/eplerenone. (cid:2) Hyperkalaemia arises when dehydration, concurrent illness, or dete- riorating renal or cardiac function supervenes in patients on combina- tion therapy. Always check K + . Th ose with K + >5.0 are at risk. Rare causes of hyperkalaemia include \200 Hyperkalaemic periodic paralysis: mutations in skeletal Na + channel SCN4A coded on 17q23 lead to episodic paralysis, i K + , and d Na + in response to varied t riggers, as Na + and water are pumped into cells in exchange for K + . Type 1 pseudohypoaldosteronsim: presents in infancy as salt wasting, d Na + , and collapse. Either due to resistance to the actions of aldosterone (defect in type 1 mineralocorticoid receptor, with i K + ) or defects in ENaC ( b p. 931). Gordon \200\231s syndrome (type 2 pseudohypoaldosteronism or familial hyperkalaemic hyperte nsion): the clinical inverse of Gitelman \200\231s syndrome ( b p. 800). Presents as i BP, d renin and aldosterone, i K + , and acidosis and normal renal function. Mutations in genes encoding WNK-1 and \200\223 4 (negative regulators of NCCT, b p. 930) are responsible and lead to reduced functioning thiazide-sensitive Na-Cl co-transporter in the distal tubule. CHAPTER 10 Fluids and electrolytes 798 Hypokalaemia One of the most common electrolyte abnormalities seen, esp. in patients on diu retics. Although K + of 3 \200\223 3.5mmol/L is generally well tolerated, hypokalaemia of <2.5mmol/L can be life-threatening (esp. in the presence of digitalis or if the drop is rap id). Causes \200 Inadequate intake <25mmol/day (either dietary or IV). \200 Increased gut lo sses: Vomiting or NG losses ( i Na + loss in vomitus l s hyperaldosteronism and i NaHCO 3 delivered to the distal nephron). Diarrhea or laxative abuse. \200 VIPoma, Zollinger \200\223 Ellison syndrome. \200 Ile ostomy or enteric \201 stula, colonic villous adenoma. Redistribution into cells: B -agonism (any cause of i sympathetic drive, e.g. delirium tremens). \200 B -agonist dru gs (bronchodilators, decongestants, tocolytics). \200 Insulin, theophylline, or caffeine (activate Na + /K + -ATPase pump). (cid:2) Refeeding in malnourished (and total body K + deplete) patients. Alkalosis. \200 Vigorous exercise p hyperaldosteronism: adrenal adenoma (Conn \200\231s syndrome), bilateral adrenal hyperplasia \200\224 plasma aldosterone:renin ratio. Renin-secreting tumors ( i BP in the young). \200 Cushing \200\231s disease. \200 s hyp eraldosteronism ( b p. 478): Liver failure, heart failure, nephrotic syndrome. Renal losses: Diuretics (esp. thiazides, loops), including abuse of diuretics. \200 Acquired renal tubu lar disease ( b p. 76) or RTA ( b p. 824). \200 Bartter \200\231s, Liddle \200\231s, and Gitelman \200\231s syndromes ( b p. 800). Other drugs: Amphotericin and aminoglycosides (tubular toxicity). \200 Glucocorticoids (esp. at high d ose) or mineralocorticids. \200 Carbenoxolone and liquorice (have a mineralocorticoid eff ect). Hypomagnesaemia. \200 Familial hypokalaemic periodic paralysis. \200 Thyrotoxic periodi c paralysis. \200 Correction of vitamin B12 de \201 ciency. Symptoms and signs See previous list of causes for speci \201 c associations \200\224 usu ally picked up on U&E. 2 Take a full drug history, particularly for diuretics. Exclude diar rhea. \200 Fatigue, constipation, proximal muscle weakness, and d tone (progressing to ascending paralysis as K + d ). Cardiac arrhythmias, esp. if underlying heart disease. Chronically, i BP, glucose intolerance, and d urinary concentrating ability. HYPOKALAEMIA 799 Investigations \200 U&E, Mg 2+ . Venous pH, and calculate the anion gap. Either perform 24-hour urinary K + or do spot u-K + and u-Cr. Calculate the urinary K/ Cr ratio (KCR). Also, CK (may have spontaneous rhabdomyolysis). Digoxin level if on drug. If 24-hour u-K + <15mmol/L, losses are EXTRARENAL. \200 Or, depending on the KCR, focus a ttention as shown in Table 10.2. Table 10.2 Investigations of hypokalaemia KCR (mmol/mmol) <1 Extrarenal KCR >1, BP d or normal Tubular/renal KCR >1, BP i Mineralocorticoid axis (cid:2) Check the ECG: small T waves, U wave (after T), PR interval i , ST segments d . d i n extracellular K + hyperpolarizes cell membranes l a cell less sensitive to stimuli. Treatment (cid:2) Is the patient on digoxin? Will potentiate digoxin \200\231s arrhythmogen ic- ity. Note that diuretic-induced hypokalaemia is exacerbated if dietary Na + intake is h igh. Always aim to treat the underlying cause over time. Mild (>2.5mmol/L): Oral slow-release potassium chloride 50 \200\223 150mmol/day in divided doses (treatment limited by GI intolerability). Check K + regularly. \200 Rule of thumb is to treat until alkalosis resolves. \200 i di etary K + and ? switch to/add in K + -sparing diuretic. \200 Common options include Sando -K (12mmol/tab), or Slow-K (8mmol/tab). If acidotic, rather use KHCO 3 . (cid:2) Severe or symptomatic hypokalaemia (K <2.5mmol/L, arrhythmias, liver failure, or ex treme weakness): \200 Cardiac monitor. \200 Check Mg 2+ , and correct if need be ( b p. 808). \200 Avoid glucose-containing solutions or sodium bicarbonate. \200 IVI 0.9% sal ine 1L with 20 \200\223 40mmol KCl at no more than 10 \200\223 20mmol KCl/h through peripheral cannula. If d K + with hyperchloraemic acidosis (RTA, b p. 824, or gut losses), avoid 0.9% saline, and rather use KCl as listed here. 2 Danger of rapid onset hyperkalaemia . Recheck K + . \200 In volume-restricted patients or those with profound and ongoing hypokalaemia, KCl can be given into a central vein as 20 \200\223 40mmol/100mL 0.9 % saline (NOT glucose, risk of hypokalaemia) at not >40mmol/h using a volumetric pump. Must be in high dependency surroundings. CHAPTER 10 Fluids and electrolytes 800 Bartter \200\231s, Gitelman \200\231s and Liddle \200\231s syndromes Bartter \200\231s syndrome Autosomal recessive tubular hypomagnesaemia and a hypokalaemic m eta- bolic alkalosis with hypocalciuria. Type 5 Bartter \200\231s is inherited in an auto- somal dominant fashion. At least six subtypes now detected, all sharing impaired Na + reabsorp- tion in the thick a scending limb of the loop of Henle. Mutations in a num- ber of channels on both the apical and basolateral membranes (including NKCC2, CLC-Ka and CLC-Kb, CaR, and ROMK) are responsib le for salt wasting and mild volume depletion. It is, in effect, what is seen with loop diu retic use . Subsequent s hyperaldosteronism (and juxtaglomeru- lar apparatus hyperplasia) l eads to a hypokalaemic metabolic alkalosis. i luminal Na + impairs Ca 2+ absorption, leadin g to normal to i u-Ca 2+ . Diagnosis In children (or adolescents) with failure to thrive, polydipsia, polyuria, and cr amps. Sensorineural deafness in type 4 Bartter \200\231s. Lower BP than gen- eral populatio n, d K + , mild metabolic alkalosis, i u-Na + , i u-K + , i u-Ca 2+ , i u-prostaglandin E2 (reduced NaCl entry into macula densa, leading to increased COX-2 expression), i renin, i a ldosterone. Treatment Aim to normalize K + . Start with amiloride 5 \200\223 40mg day (large doses may be needed!). Add on oral potassium supplementation as potassium chloride 25 \200\223 100m mol/day (for drugs, see b p. 799). (cid:2) Recheck K + after 5 \200\223 7 days to ensure t hat the dosing is appropriate. NSAIDs (indometacin) if i u-PGE2. ACE-I may help normalize K + . Often dif \201 cult to treat and demanding of patient (child!) compliance. Gitelman \200\231s syndrome Autosomal recessive inheritance, characterized by hypomagnesaem ia, hypokalaemia with hypocalciuria, and metabolic alkalosis. Heterogeneous loss-of-function mutations largely affecting the SLC12A3 gene encoding the th iazide-sensitive Na-Cl co-transporter in the DCT, with impaired Na + reabsorption. i Na + l oss leads to s hyperaldoster- onism and a hypokalaemic metabolic alkalosis. It is, in effec t, what is seen with thiazide diuretic use . Increased urinary Mg 2+ loss, with signi \201 - cant hypomagnesaemia, is thought to occur as a result of a reduction in TRPM6 (an epithe lial magnesium channel) density in the DCT. BARTTER \200\231S, GITELMAN \200\231S AND LIDDLE \200\231S SYNDROMES 801 Diagnosis In young adults, with often asymptomatic d K + (2.0 \200\223 3.0mmol/L). May be weakness and myalgia, and symptoms of d urinary concentrating ability (nocturia, in particular, polyuria, and polydipsia). Investigations Include d Mg 2+ . Mild metabolic alkalosis. i renin, i aldosterone. Urinary u-PGE2 is not raised (unlike Bartter \200\231s). Genetic testing is available though not wi dely so. Treatment Generally good prognosis. Amiloride 5 \200\223 40mg od 9 K + supplementation ( b p. 799). No role for NSAIDs. Liddle \200\231s syndrome Autosomal dominant inheritance. Caused by gain-of-function mutations in ENaC (epithelial so dium channel expressed on the apical surface of collecting duct cells), resulting in a fail ure to endocytose ENaC from the surface membrane of collecting duct cells. Constitutive ove rexpression leads to i Na + reabsorption which leads to d BP 9 oedema. Enhanced Na + uptake renders the lumen more electronegative, opening the tran- sepithelial ROMK K + channel, le ading to K + wasting and a hypokalaemic metabolic alkalosis. Aldosterone is appropriately s uppressed. Diagnosis In young hypertensives (often with severe i BP and a +ve family history), with d K + (may be mild) and mild metabolic alkalosis. d renin, d aldoster- one (see Table 10.3). Treatment Low-salt diet (<100mmol/day) 9 amiloride 5 \200\223 10mg od (or triamterene \200\224 directly inhibits ENaC). Table 10.3 Differentiating inherited channelopathies Bartter \200\231s Gitelman \200\231s Liddle \200\231s N/ d i BP N K + d d d Mg 2+ N or d d N i u-PGE2 N N i i d Aldosterone Age Infancy Early adulthood Childhood CHAPTER 10 Fluids and electrolytes 802 Calcium, magnesium, and phosphorus Calcium 99% of total body Ca 2+ ( 7 1kg) is stored in bo ne. Extracellular Ca 2+ accounts for a small fraction: of this; 7 40% is bound to albumin, with 50% available as physiologically active, free (or ionized) Ca 2+ . The remainder is co m- plexed with anions, such as bicarbonate or phosphate. Free intracellular Ca 2+ is found at 10 4 higher a concentration than in the extracellular space, a gradient maintained by an energy-dependent membrane Ca 2+ ATPase. Intracellular Ca 2+ is key to many signaling pathw ays within cells \200\224 Ca 2+ is also important in skeletal health, membrane function, n euromuscular integrity, and coagulation. The serum normal range is 2.1 \200\223 2.5mmol/L ( 7 1.2mmol/L ionized), with Ca 2+ availa ble from both the gut and bone stores. Gut Ca 2+ absorption occurs via transcellular (uptak e via TRPV6, the apical Ca 2+ channel with subsequent energy-dependent basolateral ef \202 ux) and paracellular path- ways. Uptake is under the control of (active) 1,25(OH) 2 vitami n D 3 . The ionized fraction is freely \201 ltered across the glomerulus and mainly reabsorbed in the PCT and loop of Henle. Most Ca 2+ is resorbed paracel- lularly along a concentration g radient, but TRPV5 regulates (the \201 nal 10% of total) distal calcium uptake in a PTH- and vitamin D-dependent manner. Urinary Na + is able to strongly in \202 uence urinary Ca 2+ excretion: in the thick ascending loop of Henle, i Na + delivery forces i Na + uptake, a t the expense of Ca 2+ resorption l hypercalciuria. This is a key factor in stone formation ( b p. 716). Falling Ca 2+ activates parathyroid calcium-sensing receptors (CaRs), leading to parathyroi d hormone (PTH) release. PTH increases renal tubu- lar Ca 2+ reabsorption and hydroxylation of vitamin D 3 to the active metab- olite, increasing intestinal uptake. PTH also enhances bone osteoclastic activity. There is also evidence that PTH receptors are present on cells not directly involved in calcium homeostasis (such as endothelial cells and cardiomyocytes ), suggesting that PTH may have effects beyond its role in calcium/phosphate regulation. Magnesium Magnesium (Mg 2+ ) is the fourth most common cation in the body and is found larg ely in the intracellular compartment or stored in bone. Only 1% of the 25g total body Mg 2+ is in the ECF, with the majority found in bone or muscle. It is a key component of ATP-req uiring reactions and is necessary for the synthesis of protein and maintaining membrane fun ction, nerve conduction, and muscle contraction. Mg 2+ , like Ca 2+ , also regulates PTH secretion \200\224 d Mg 2+ leads to PTH release and vise versa. Profound d Mg 2+ l symptomatic d Ca 2+ . The normal range is 0.75 \200\223 0.95mmol/L in plasma. The kidney dominates the control o f Mg 2+ homeostasis. Mg 2+ is absorbed from the gut and freely \201 ltered across the glo merulus. In health, 70% is then reabsorbed in the thick ascending loop of Henle (TALH) \200\224 the strongly negative paracellular CALCIUM, MAGNESIUM, AND PHOSPHORUS 803 protein paracellin-1 allows ef \201 cient absorption of the cations Mg 2+ and Ca 2+ under control of both PTH and the calcium-sensing receptor. Fine control is achieved in the DCT w here the transmembrane (transcel- lular) protein TRPM6 allows further uptake. Loss of funct ion of either paracellin-1 or TRPM6 leads to urinary Mg 2+ wasting and d Mg 2+ . Phosphorus Phosphorus occurs largely as the inorganic fraction phosphate in the cir- culati on. Organic phosphorus exists as protein-bound phospholipids and is not measured in clinica l practice. Phosphate is essential to almost all biochemical systems. Absorbed by the type II sodium/phosphate co-transporter (NaPi) from the intestine, again in a vitamin D 3 -dependent manner, 80% is found in bone. The normal range for plasma phospha te is 0.8 \200\223 1.4mmol/L (higher in children). Freely \201 ltered in the kidney, it is largely reabsorbed in the PCT (depending on oral intake) by the type II NaPi. Tubular reabsorption of phosphate is controlled by PTH (which inhibits reabsorption) and al so by \201 broblast growth factor 23 (produced by osteo- cytes which leads to lower level s of serum phosphate by reducing tubular reabsorption and by inhibition of 1 A -hydroxylati on of vitamin D). CHAPTER 10 Fluids and electrolytes 804 Hypocalcaemia Total serum Ca 2+ is low with d albumin, though the free fraction may be norm al. Always correct for albumin: Corrected Ca 2+ = measured Ca 2+ + [40 \200\223 serum Alb] \227 0.02 Causes of hypocalcaemia \200 Vitamin D de \201 ciency: Malnutrition (osteomalacia). \200 Malabsorption (gastrectomy, short bowel, coeliac diseas e, chronic pancreatitis). CKD (loss of 1 A -hydroxylase). \200 Vitamin D-dependent rickets (anticonvulsants, nephro tic or Fanconi syndrome). \200 Hypoparathyroidism: Post-parathyroidectomy \200\224 \200\231 hungry bone syndrome \200\231 ( b p. 254). (cid:2) Inadvertent after thyroidectomy! \200 Inherited, pseudohypoparathyroidism. Hyperphosphataemia ( i phosphate increases bone Ca 2+ deposition): Tumor lysis ( b p. 160). \200 Rhabdomyolysis ( b p. 152). \200 Administered or ingested . Acute pancreatitis. \200 d Mg 2+ . \200 Acute alkalosis (reduction in ionized calcium).