Pocket Medicine





•  Disorders of serum sodium are generally due to Ds in total body water, not sodium

•  Hyper- or hypo-osmolality → rapid water shifts → Ds in brain cell volume → Δ MS, seizures

Key hormones

•  Antidiuretic hormone (ADH): primary hormone that regulates sodium concentration stimuli for secretion: hyperosmolality, ↓↓ effective arterial volume (EAV), angiotensin II action: insertion of aquaporin-2 channels in collecting ducts → passive water reabsorption urine osmolalityis an indirect functional assay of the ADH-renal axis Uosm range: 60 mOsm/L (no ADH) to 1200 mOsm/L (maximal ADH)

•  Aldosterone: primary hormone that regulates total body sodium (and ∴ volume) stimuli for secretion: hypovolemia (via renin and angiotensin II), hyperkalemia action: iso-osmotic reabsorption of sodium in exchange for potassium or H+



•  Excess of water relative to sodium; almost always due to ↑ ADH

•  ↑ ADH may be appropriate (eg, hypovolemia or hypervolemia with ↓ EAV)

•  ↑ ADH may be inappropriate (SIADH)

•  Rarely, ↓ ADH (appropriately suppressed), but kidneys unable to maintain nl [Na]serum

1° polydipsia: ingestion of massive quantities (usually >12 L/d) of free H2O overwhelms diluting ability of kidney (normal dietary solute load ~750 mOsm/d, minimum Uosm = 60 mOsm/L → excrete in ~12 L; if H2O ingestion exceeds this amount → H2O retention)

“tea & toast” and “beer potomania”: ↓↓ daily solute load, ↑ free H2O → insufficient solute to excrete H2O intake (eg, if only 250 mOsm/d, minimum Uosm = 60 mOsm/L → excrete in ~4 L; if H2O ingestion exceeds this amount → H2O retention)

Workup (NEJM 2000;342:1581; JASN 2012;23:1140)

•  History: (1) acute vs. chronic (>48 h); (2) sx severity; (3) risk for neuro complications (alcoholism, malnourished, cirrhosis, older females on thiazides, hypoxia, hypoK)

•  Measure plasma osmolality

Hypotonic hyponatremia most common scenario; true excess of free H2O relative to Na Hypertonic hyponatremia: excess of another effective osmole (eg, glc, mannitol) that draws H2O intravascularly; each 100 mg/dL ↑ glc >100 mg/dL → ↓ [Na] by 2.4 mEq/L Isotonic hyponatremia: rare lab artifact from hyperlipidemia or hyperproteinemia

•  For hypotonic hyponatremia, ✓ volume status (vital signs, orthostatics, JVP, skin turgor, mucous membranes, peripheral edema, BUN, Cr, uric acid)

•  Uosm diagnostically useful in limited circumstances, because almost always >300 exceptions: Uosm <100 in 1° polydipsia & ↓ solute intake moreover, Uosm >300 ≠ SIADH; must determine if ↑ ADH appropriate or inappropriate however, Uosm important when deciding on treatment (see below)

•  If euvolemic and ↑ Uosm, evaluate for glucocorticoid insufficiency and hypothyroidism

Figure 4-4 Approach to hyponatremia

Hypovolemic hypotonic hyponatremia (ie, ↓↓ total body Na, ↓ TBW)

•  Renal losses (UNa >20 mEq/L, FENa >1%): diuretics (esp. thiazides, as loop diuretics

↓ tonicity of medullary interstitium and impair urine concentrating ability), salt- wasting nephropathy, cerebral salt wasting, mineralocorticoid deficiency

•  Extrarenal losses (UNa <10 mEq/L, FENa <1%): GI losses (eg, diarrhea), third-spacing (eg, pancreatitis), inadequate intake, insensible losses

Euvolemic hypotonic hyponatremia (ie, ↑ TBW relative to total body Na)

•  SIADH (eu- or mild hypervolemia, inapprop ↑ UOsmnormal UNa, ↓ BUN & UA)

malignancy: lung, brain, GI, GU, lymphoma, leukemia, thymoma, mesothelioma

pulmonary: pneumonia, TB, aspergillosis, asthma, COPD, PTX,  pressure ventilation

intracranial: trauma, stroke, hemorrhage, infxn, hydrocephalus, Guillan-Barré syndrome

drugs: antipsychotics, antidepressants (esp. SSRIs), chemotherapy, AVP, MDMA

miscellaneous: pain, nausea, postoperative state

•  Endocrinopathies: ↑ ADH activity seen in glucocorticoid deficiency (co-secretion of ADH & CRH) and severe hypothyroidism/myxedema coma (↓ CO & ↓ GFR)

•  Psychogenic polydipsia (Uosm <100, ↓ uric acid): usually requires intake >12 L/d

•  Low solute (↓ UNa, ↓ Uosm) “tea & toast”; “beer potomania”

•  Reset osmostat: chronic malnutrition (↓ intracellular osmoles) or pregnancy (hormonal effects) → ADH physiology reset to regulate a lower [Na]serum

Hypervolemic hypotonic hyponatremia (ie, ↑ total body Na, ↑ ↑ TBW)

•  CHF (↓ CO → ↓ EAV; UNa <10 mEq/L, FENa <1%)

•  Cirrhosis (splanchnic arterial vasodilation + ascites → ↓ EAV; UNa <10 mEq/L, FENa <1%)

•  Nephrotic syndrome (hypoalbuminemia → edema → ↓ EAV; UNa <10 mEq/L, FENa <1%)

•  Advanced renal failure (diminished ability to excrete free H2O; UNa >20 mEq/L)

Treatment (Curr Opin Nephrol Hypertens 2010;19:493)

•  Approach: depends on volume statusacuity of hypoNa, and if symptomatic

Asx or chronic symptomatic: correct [Na]serum at rate of ≤0.5 mEq/L/h

Acute sx: initial rapid correction of Na (2 mEq/L/h for the first 2–3 h) until sx resolve

Rate of ↑ Na should not exceed 6 (chronic) to 8 (acute) mEq/L/d to avoid central pontine myelinolysis/osmotic demyelination syn. (CPM/ODS: paraplegia, dysarthria, dysphagia)

•  Frequent lab draws and IVF rate adjustments are cornerstones of treatment

•  Overly rapid correction: can lead to CPM/ODS. Should be emergently reversed w/ dDAVP ± D5W; partial neurologic recovery possible (CJASN 2008;3:331)

•  Effect of IV fluids (http://www.medcalc.com/sodium.html)

     however, above assumes entire infusate retained without any output of Na or H2O if Pt euvolemic, as in SIADH, infused Na will be excreted eg, 1 L NS (154 mEq of Na or 308 mOsm of solute in 1 L free H2O) given to Pt with SIADH with Uosm = 616 → 308 mOsm solute excreted in 0.5 L H2O → net gain 0.5 L H2O → ↓ [Na]serum ∴ normal saline can worsen hyponatremia 2° SIADH if Uosm > infusateosm

•  Hypovolemic hyponatremia: volume repletion with normal saline at a slow rate. Once volume replete → stimulus for ADH removed → kidneys excrete free H2O → serum Na will correct very rapidly (D5W ± ddAVP if overcorrection) (KI 2009;76:587).

•  SIADH (NEJM 2007;356:2064): free water restrict + treat underlying cause

hypertonic saline (± loop diuretic) if sx or Na fails to ↑ w/ free H2O restriction 1 L hypertonic saline (3% NaCl) will raise [Na]serum by ~10 mEq (see above) ~50 mL/h will ↑ [Na] by ~0.5 mEq/L/h; 100–200 mL/h will ↑ [Na] by ~1–2 mEq/L/h formula only provides estimate; ∴ recheck serum Na frequently (at least q2h)

salt tabs: particularly if chronic and no CHF

aquaresis: conivaptan (IV V1a & V2 vasopressin receptor antag) or tolvaptan (oral V2 antag; NEJM 2006;355:2099); used for symptomatic SIADH resistant to above Rx but rate of correction can be rapid (AJKD 2010;56:325)

demeclocycline: causes nephrogenic DI, ↓ Uosm

•  Hypervolemic hyponatremiafree water restrict

mobilize excess Na & H2O (use loop diuretics; avoid thiazides) & ↑ EAV (vasodilators to ↑ CO in CHF, colloid infusion in cirrhosis)

aquaresis: tolvaptan effective and safe, however no proven mortality benefit, hypoNa recurs after stopping drug, expensive and must monitor for overcorrection (JASN 2010;21:705; J Hepatol2012;56:571)


Pathophysiology (NEJM 2000;342:1493)

•  Deficit of water relative to sodium; by definition, all hypernatremic Pts are hypertonic

•  Usually loss of hypotonic fluid (ie “dehydration”); occasionally infusion of hypertonic fluid

•  And impaired access to free water (eg, intubation, Δ MS, elderly): hypernatremia is a powerful thirst stimulus, ∴ usually only develops in Pts w/o access to H2O


•  ✓ Uosm, UNa, volume status (vital signs, orthostatics, JVP, skin turgor, BUN, Cr)

Figure 4-5 Approach to hypernatremia

Extrarenal H2 O loss (Uosm >700–800)

•  GI H2O loss: vomiting, NGT drainage, osmotic diarrhea, fistula

•  Insensible loss: fever, exercise, ventilation

Renal H2O loss (Uosm <700–800)

•  Diuresis: osmotic (glc, mannitol, urea), loop diuretics

•  Diabetes insipidus (J Clin Endocrinol Metab 2012;97:3426)

ADH deficiency (central) or resistance (nephrogenic)

Central: hypothalamic or posterior pituitary disease (congenital, trauma/surgery, tumors, infiltrative/IgG4); also idiopathic, hypoxic encephalopathy, anorexia, EtOH

Nephrogenic (Annals 2006;144:186)

  congenital (ADH receptor V2 mutation, aquaporin-2 mutation; Pediatr Nephrol 2012;27:2183)

drugs: lithium, amphotericin, demeclocycline, foscarnet, cidofovir   metabolic: hypercalcemiasevere hypokalemia, protein malnutrition, congenital   tubulointerstitial: postobstructionrecovery phase of ATN, PKD, sickle cell,   Sjögren’s, amyloid, pregnancy (placental vasopressinase)

DI usually presents as severe polyuria and mild hypernatremia

Other (Uosm >700–800)

•  Na overload: hypertonic saline (eg, resuscitation w/ NaHCO3), mineralocorticoid excess

•  Seizures≠ exercise: ↑ intracellular osmoles → H2O shifts → transient ↑ [Na]serum


•  Restore access to H2O or supply daily requirement of H2O (≥1 L/d)

•  Replace free H2O deficit (also replace concurrent volume deficit if appropriate):

      eg, 1 L D5W given to 70-kg man w/ [Na] = 160 mEq/L will ↓ [Na]serum by 3.7 mEq

•  Rate of Ø of Na should not exceed 0.5 mEq/L/h to avoid cerebral edema shortcut: in 70-kg man, 125 mL/h of free H2O will ↓ [Na] by ~0.5 mEq/L/h

•  1/2 NS (77 mEq/L) or 1/4 NS (38 mEq/L) provides both volume & free H2O (500 or 750 mL of free H2O per L, respectively); can give free H2O via NGT/OGT

•  Formulas provide only estimates; ∴ recheck serum Na frequently

•  DI and osmotic diuresis: see “Polyuria” section below

•  Na overload: D5W + diuretic


Definition and pathophysiology

•  Polyuria defined as >3 L UOP per day

•  Due to an osmotic or a water diuresis; almost always due to osmotic diuresis in inpatients


•  Perform a timed urine collection (6 h sufficient) and measure Uosm

•  24-h osmole excretion rate = 24-h UOP (actual or estimate) × Uosm

>1000 mOsm/d → osmotic diuresis

<800 mOsm/d → water diuresis

Osmotic diuresis

•  Etiologies

Glucose (uncontrolled diabetes mellitus)


Urea: recovering ARF, ↑ protein feeds, hypercatabolism (burns, steroids), GI bleed

NaCl administration

Propylene glycol

Water diuresis

•  Etiologies: diabetes insipidus (DI) (Naserum >140) or 1° polydipsia (Naserum <140) see “Hypernatremia” above for list of causes of central and nephrogenic DI

•  Workup of DI: Uosm <300 (complete) or 300–600 (partial)

water deprivation test (start in a.m., ✓ Naserum, Posm, Uosm, UOP q1–2h)

Deprive until Posm >295, then ✓ Uosm. If Uosm <300, then administer vasopressin (5 U SC) or dDAVP (10 µg intranasal), then check Uosm in 1–2 h: Uosm ↑ by >50% = central DI Uosm unchanged = nephrogenic DI

✓ ADH level before and after water deprivation to evaluate proper response

Figure 4-6 Approach to polyuria


•  1º polydipsia: treat psychiatric illness, check meds, restrict access to free H2O

•  Osmotic diuresis: address underlying cause, replace free H2O deficit (see “Hypernatremia” for formula to calculate) and ongoing losses

•  DI:

central DI: desmopressin (dDAVP)

nephrogenic DI: treat underlying cause if possible; Na restriction + thiazide (mild volume depletion → ↓ delivery of filtrate to dysfxnal diluting segment of kidney), consider amiloride for lithium-induced DI (Kid Int 2009;76:44)

pregnancy-induced DI: due to vasopressinase from placenta, ∴ Rx w/ dDAVP