Sodium AbnormaIities

by
GIen E. Hastings MD
ApriI 26, 2003

I HYPONATREMIA:
A Definitions & CIinicaI Manifestations
1,2
:
! Hyponatremia means that the serum sodium (S
Na
+
) is <136mEq/dL
1
.
! Symptomatic hyponatremia is hyponatremia accompanied by CNS changes that are not
attributable to another condition (such as diabetic hyperosmolar coma, liver failure, myxedema coma
or Addisonian crisis or drug effects) that may cause similar CNS symptoms. Symptomatic
hyponatremia is rare when S
Na
+
>125mEq/dL & unusual >120mEq/dL unless it is of rapid onset.
Symptomatic hyponatremia always calls for aggressive treatment with V saline, regardless of the
underlying cause. Symptoms indicate the need for treatment.
! Symptoms & Signs
1,2
include nausea & vomiting, muscular weakness, headache, lethargy,
reversible ataxia, delirium, seizures, coma, and terminally, increased intracerebral pressure,
respiratory depression, tentorial herniation and death.
B PreIiminary Diagnosis:
! The clinical evaluation of any patient
presenting with hyponatremia begins with
an assessment of mentaI status. f there
have been recent mental status changes
that are not explained by other causes &
are therefore attributed to the
hyponatremia, aggressive treatment of
the hyponatremic state becomes
mandatory.
! Keep in mind that mental status changes
are rare when S
Na
+
>125mEq/dL
2
unless
the Na
+
deficit occurs rapidly (such as
rapid infusion of a hypotonic V solution
during surgery). When S
Na
+
<125mEq/dL
& serum osmolality (S
Osmol
) <270mMol/L
& no other cause is apparent, the
changes may be 2
o
to hyponatremia.
! ExcIude Hyperosmotic HypergIycemic Coma (HHC): f S
Osmol
is>320mMol/L in children or
>340mMol/L in adults, mental status changes are more likely 2
o
to HHC than hyponatremia. When
the S
Osmol
is increased, look for hyperglycemia, or recent V infusion of hypertonic mannitol or dextran;
substances that can't freely cross cell membranes & therefore cause intracellular dehydration & CNS
symptoms as water moves to the extracellular space to dilute them. Uremia also increases S
Osmol
but
doesn't cause intracellular dehydration because urea crosses cell membranes freely.
! ExcIude toxins: f the S
Osmol
is normaI or only slightly increased & the osmolar gap (eg. Measured
S
Osmol
minus the calculated S
Osmol
) is >12mMol/L, or the anion gap (eg. Serum Na
+
- [Cl
-
+ HC0
3
]) >
10mEq/dL, an unidentified substance is displacing Na
+
ions. Pharmacologic properties of the
unidentified substance, rather than its osmotic effects may explain the mental status changes.
Calculated Serum Osmolality = (2 x plasma Na) + serum glucose/18 + BUN/2.8
Osmolar Gap = Measured Serum Osmolality Calculated Serum Osmolality
Anion Gap = Serum Na
+
(Cl
-
+HCO
3
-
)
n evaluating mental status change in ER patients, an eIevated osmoIar gap (as well as an elevated
anion gap) is a "wake-up call to look for one of the toxins listed in Table 1, & to use the conversion
factors shown in Table 1 for each of them, to account for the osmotic effect of each.
GLOSSARY:
Term Definition
ADH
BNP
CHF
CMP
COPD
CV
GFR
HV
Hyponatremia
NO
RAAS
SADH
S
Na+

S
Osmol

SSRs
U
Osmol

TBW
TB
Na+

U
Na+

V
2
Antidiuretic Hormone (also: Arginine Vasopressin)
(Brain) or B-Type Naturetic Peptide
Congestive Heart Failure
Central Pontine Myelinolysis,
Chronic Obstructive Pulmonary Disease
Cardiovascular
Glomerular Filtration Rate
Human mmunodeficiency Virus
Serum sodium < 136mg/dL
Nitric Oxide
Renin/Angiotensin/Aldosterone System
Syndrome of nappropriate ADH Secretion
Serum Sodium
Serum Osmolality
Selective Serotonin Reuptake nhibitor
Urine Osmolality
Total Body Water
Total Body Sodium
Urine Sodium Concentration
Vasopressin Type-2 Receptor
Hyponatremia & Hypernatremia Page 2 of 14
! n "True, Hypotonic (DiIutionaI)
Hyponatremia, both serum Na
+
& S
Osmol
are
decreased, but TB
Na+
is decreased in
relationship to TBW. TBW on the other hand
might be increased, decreased or normal & may
be caused either by increased water intake or to
increased Na
+
loss.
! Once the clinician decides that the patient's immediate problem is mentaI status change 2
o
to
diIutionaI hyponatremia, it implies that permanent neurological damage may ensue unless the
hyponatremia is corrected & that osmotic demyelinization (another kind of neurological damage that
will be described later) may occur if corrections are made too rapidly. At this point in the clinical
process, the clinician collects baseline blood & urine laboratory samples for analysis & proceeds with
treatment, without worrying (for the time being) with determining the cause of the hyponatremia. This
outline also will now turn to treatment & return to pathophysiology & causal diagnosis later.
C The Duration of Symptomatic Hyponatremia is critically important for 2 reasons:
! The likelihood of hyponatremia causing neurological damage secondary to cerebral edema is
greatest when a large change in serum sodium concentration occurs rapidly. The neuronal cytosol
can't become hypotonic as quickly as can the extracellular fluids. t takes about 13 hours for the
intracellular osmolality to equilibrate
2
. So in
the meantime the brain inspissates water &
swells within the confines of the skull. This
upon occasion causes pressure induced
ischemic damage. Symptomatic acute
hyponatremia that has occurred within
hours must be corrected rapidIy. Although controversy exists about the most appropriate correction
rate, limiting the increase in S
Na
+
to 1-2mEq/L/hour or less seems prudent, except in the most dire of
circumstances
1
. Table 2 lists those most at risk for cerebral edema.
! After 13 hours of systemic hyponatremia the brain's adjustment of its internal osmolality will approach
that of the extracellular milieu. f after that time hypertonic saline is infused to rapidly, the increasing
extracellular sodium will draw water out of the brain substance, dehydrating it & sometimes causing a
form of CNS demyelination called "central pontine myelinolysis. Chronic hyponatremia (even when
symptomatic) must always be corrected more sIowIy if central pontine myelinolysis is to be avoided.
! To review: Symptoms (not the laboratory findings) indicate the need for aggressive V treatment.
Their duration (more accurately the probable duration) & severity tells you how fast.
A Rates of Correction in Different Circumstances with SaIine SoIutions of Different Strengths:
! Status EpiIepticus: 1
st
, stop the convulsion with 2-4mg of lorazepam V if needed, then correct Na
+
:
! Seizure, Coma, Obtundation or Other Life Threatening Event: Seizure activity can be controlled
by increasing S
Na
+
by 3 to 5 mEq/dL. n life threatening circumstances initial rates of infusion are
calculated to raise S
Na
+
by 1-2mEq/hour
1
. Should seizures recur or should coma not quickly respond,
short cautious increases up to 4mEq/hour may be acceptable. After termination of seizure activity or
arousal from a comatose state begins, the hourly infusion rate is readjusted to increase S
Na
+
by no
more than 8mEq/dL over the 1
st
24 hours & no more than 16mEq/dL over the 1
st
48 hours.
! Serum Sodium should be monitored hourIy during the early hours of therapy & the infusion rate
must be adjusted to maintain the desired rate of change.
1 CaIcuIation of the Rate of Administration of InitiaI BoIus in Life Threatening Emergencies*:
The initial V flow rate for emergencies is calculated to raise S
Na
+
by 1-2mEq/dL/hour
1
. So, (the
patient's weight in Kg x 0.6 [men] or 0.5 [women] + 1liter insensible loss) x the desired # of mEq
correction (1-2mEq/hour until seizures or coma abate) x 1000cc, divided by the number of
mEq/liter of Na
+
in the infusate (513 for 3% saline) less the patient's Na
+
mEq/dL times the
number of hours of infusion, yields the initial infusion rate in cc/hour.
(0.6 x Weight in Kg + 1) x 1mEq x 1000cc = Initial Rate of 3% Saline in mL/hour.
(513mEq-patient's Na
+
) x # hours of infusion
TabIe 1: Ineffective OsmoIites
1,2
Substance Conversion Factors mg/dL to mmoI/L
Urea
Lactate
Ethanol
Ethylene glycol
Methanol
sopropanol
2.8
9.0
4.6
6.2
3.2
6.1
TabIe 2: Patients at High Risk for CerebraI Edema
2
:
Menstruating women given hypotonic fluids perioperatively
Elderly women taking thiazide diuretics
Children (especially during treatment for DKA)
Polydipsic psychiatric patients
Hypoxemic patients
Hyponatremia & Hypernatremia Page 3 of 14
ExampIe: A 70Kg man is to be treated with 3% saline for seizures related to serum Na
+
of
118mEq/dL. Calculate the 1
st
hour's rate of administration:
(0.6 x Wt in Kg + 1) x 1mEq x 1000cc = 43 x 1 x 1000 = 108.9cc/hour untiI seizures stop.
(513 118) x 1 395
* Most authors
1,2,3,4
calculate an estimate of the total body Na
+
deficit & then, as a second step, derive a
correction rate which is determined by the concentration of the infusate to be used (or vice versa). We only
need to know the desired rate of administration, not the total body Na
+
or the #mEq correction/L. So we
simplified the math & combined both calculations into a single formula.
2 Adjustment of the Rate of Administration Once the Emergency is ControIIed:
When the seizure or coma abates, the rate is sIowed.
The goaI of treatment is to correct the hyponatremia enough to eliminate symptoms without
correcting it so vigorously as to evoke osmotic demyelinization (eg. central pontine myelinolysis).
f we are to accomplish this goal it is important that the correction rate not exceeded 8mEq during
either of the first 2 days of treatment. To accomplish this we must recalculate the 1
st
24 hour's
rate of administration taking into account the # mEq of Na
+
already infused. n the previous
example, we corrected the S
Na
+
by 2mEq of Na
+
over the first 2 hours, the rate of infusion for the
next 22 hours is calculated as below:
([0.6 x Wt in Kg]+1L/d insensible H
2
O loss) x (8mEq # mEq already corrected) x 1000cc =
(513mEq #mEq original Na
+
) x # hours remaining out of 24
([0.6 x 70]+1) x (8 -2) x 1000 = ([42]+1) x (6) x 1000 = 43 x6x 1000 =258000 =29.7cc/hour
(513 118) x 22 395 x 22 8690 8690
The adjusted correction rate would thus be 29.7cc/hour over the remainder of the 1
st
24 hours.
! Chronic Hyponatremia with Non-Life-Threatening CNS Symptoms:
Slow infusion rates not to lower the S
Na
+
by 1mEq/dL in any one hour, or 8mEq/dL/day in either of the
1
st
2 days are recommended. Calculations are as follows:
1 CaIcuIation of Infusion Rates with Different SaIine Concentrations:
Since the goal is to correct the S
Na
+
deficit at a rate not to exceed 8 mEq per 24 hours for the first
48 hours, first calculate the upper limit infusion rate over the 1
st
24-hour period. Three percent
saline contains 513 mEq/liter so, if you wanted to correct a man's sodium deficit by 8mEq per
24hour period, the formula would be:
([0.6
*
x Wt in Kg] +1L) x 8 mEq Na
+
x 1000cc = Maximum rate mL 3% saline/hour.
(513mEq Patient's Na
+
) x 24 hours
Five percent saline contains 855mEq/liter. n circumstances of fluid overload one might use 5%
saline. The calculation for the hourly infusion rate over the first 24 hours would be:
([0.6
*
x Wt in Kg] +1L) x 8mEq x 1000cc = Maximum Hourly rate mL 5% saline.
(855mEq Patient's Na
+
) x 24 hours
f 1 Normal saline is used, 154mEq/liter is used in the divisor:
([0.6
*
x Wt in Kg] + 1L) x 8 mEq x 1000cc = Maximum rate 1N saline/hour
(154mEq Patient's Na
+
) x 24hrs
* If the patient is female the ratio of body water to body weight is 0.5 instead of 0.6 as in men.
Remember, this is the maximum flow rate/ 24 hours to avoid demyelination. Less is better!
2 BaseIine Laboratory Tests:
As you are initiating treatment don't forget to obtain baseIine Iab tests that you will need for
diagnostic purposes: t is critically important to send both urine & serum specimens to the
laboratory, before treatment, for urine & serum osmoIaIity, Na
+
, K
+
& CI
-
, as well as serum uric
acid, BUN & creatinine. The urine SpG can be used as a crude proxy for urine osmolality
pending return of the measured values.
3 Monitor Serum Sodium HourIy during the early hours of therapy & adjust the infusion rate
adjusted to maintain the desired rate of change.

Hyponatremia & Hypernatremia Page 4 of 14
4 RepIace Other EIectroIytes: f the patient is hypokaIemic, potassium must be replaced at the
same time as hyponatremia is corrected because concomitant hypokalemia also decreases
osmolality & predisposes to central pontine myelinolysis. K
+
ion concentrations in the infusate
must be accounted for, so a different flow-rate formula must be used. n the case of 3% saline
plus a total of 80mEq of KCl over the 24-hour period, the calculation would be:
(0.6 x Wt in Kg+1L) x 8 mEq Na
+
x 1000cc = mL 3% saline + KCl/hour.
([513mEq Na
+
+ 80mEq K
+
] [Patient's Na
+
+ K
+
]) x 24hrs
f magnesium is low along with hypokalemia, it too must be replaced in order for K
+
replacement
to succeed.
! Chronic Asymptomatic Hyponatremia:
1 Do NOT treat with V fluids! There is no benefit & a large downside risk of iatrogenic injury. V
saline is administered ONLY for control of symptoms; not to control the laboratory findings. t is
not too uncommon for elderly alcoholics with beer potomania to arrive asymptomatic with S
Na
+
of
#104. The most common mistake in managing hyponatremia occurs when the physician
becomes alarmed by a chronic asymptomatic laboratory abnormality found at baseline.
2 Management of Chronic Asymptomatic Hyponatremia:
FIuid Restriction is effective & cheap but it causes constipation in adults, may produce
suboptimal outcomes in children with meningitis & in the elderly, & compliance is poor.
SuppIementaI Sodium (23gm/day) pIus furosemide, started at 40mg/day & titrated to optimal
dosage along with table salt & fluids ad lib, is probably the most realistic treatment. K
+
depletion
must be prevented or treated if it occurs. f furosemide more than 180mg/day of furosemide is
required, an equivalent dose of bumetanide might better be substituted to avoid ototoxicity.
Urea (30-60g/day) has been given to increase the filtered solute load, thereby causing an osmotic
diuresis that permits more liberal fluid intake. Urea is unpalatable; G symptoms limit its use.
DemecIocycIine inhibits the renal response to ADH & allows unlimited fluid intake. Used
therapeutically, it is expensive, nephrotoxic, neurotoxic, photosensitizing, & it causes polyuria.
Lithium also inhibits tubular response to ADH & allows unrestricted water intake, but lithium is
neurotoxic unreliable owing to its narrow therapeutic range.
A Vasopressin Type-2 Receptor BIocker is under investigation but is not available at present.
B Avoidance of Osmotic DemyeIinization (CentraI Pontine MyeIinoIysis):
One of the difficult features about central pontine myelinolysis (CPM) is that it doesn't cause symptoms or
signs until it's too late to do anything about it (eg. 2 or 3 days after
treatment, the patient develops an unstable gait followed by
ascending paralysis). The only way to treat it is to avoid it in the first
place by correcting hyponatremia at a slow controlled rate, as has
been described in previous sections. The reason the 8mEq/24 hours
rate of correction was selected as the upper rate limit is that there
have been isolated reports of the CPM having occurred in patients with S
Na
+
corrected at 9-10mEq Na
+
/24
hours. Central pontine myelinolysis is not a benign condition. 6% of a series of 44 alcoholics who were
available for followup after an episode of CMP had died, 32% were totally dependent 32% had permanent
neurological impairment, & 30% had recovered completely. Those at high risk are shown in Table 3.
C PathophysioIogy:
! Osmolality is normally maintained between 280 & 290 mmol/dL in the intracellular compartment.
When osmotic pressure in the extracellular compartment abruptly decreases below these levels,
water moves into the cells causing intracellular (eg. cerebral) edema. When the extracellular osmotic
pressure increases, water moves out causing cellular dehydration, which if severe may cause
osmotic demyelination (i.e. central pontine myelinolysis). Sodium ions accounts for about 95% of the
countervailing extracellular osmotic force. That is why Na
+
abnormalities are prone to induce cellular
edema or dehydration edema. Under normal circumstances the effective extracellular osmolality may
be estimated using the formula:
S
Osmol
= (2 x plasma Na) + serum glucose/18 + BUN/2.8
When CNS changes are related to dilutional hyponatremia (the most common cause), both the
calculated & the serum osmolalities measured directly by the laboratory should be lower than
280mmol/dL & their values should be within 10mmol/dL of one & other.
TabIe 3: Osmotic DemyeIination Risk
2

Alcoholics
Malnourished patients
Hypokalemic patients
Burn victims
Elderly women on thiazides
Hyponatremia & Hypernatremia Page 5 of 14
D. Diagnosis:
! Hyponatremic States with NormaI or High S
OsmoI
"the Red Herrings":
f S
Osmol
is normal or high when S
Na
+
is decreased, it means that S
Na
+
is being displaced by
another osmotically-active substance (eg. glucose, mannitol, etc. See Table 1). f the molecules
displacing Na
+
can't move freely back & forth across the cell membrane, the substance is termed
"osmotically active & will draw water out of the intracellular compartment & brain causing
dehydration, not edema. Cerebral edema may occur during treatment. A clinical example is the
catastrophic onset of cerebral edema during treatment of DKA in children. Treatment is sIow
elimination of the "effective osmoIite (eg. treat DKA & hyperglycemia slowly).
Other substances, termed "ineffective osmoIites (eg. urea) travel freely across the cell membrane
& therefore don't produce an osmotic gradient across the cell membrane, nor do they cause
intracellular edema or dehydration. Yet they do replace extracellular Na
+
, thereby causing
hyponatremia. Some of these substances cause CNS changes related to pharmacological
properties, unrelated to but sometimes confused with symptoms caused by the accompanying
hyponatremia. Such substances include: methanoI, ethanoI, isopropanoI & ethyIene gIycoI.
Their presence may be suspected when you find an increased osmoIar gap (eg. calculated S
Osmol

minus the measured S
Osmol
.>10mOmol/L). n the emergency room an elevated osmolar gap may be
your first clue to test for one or more of the "unmeasured osmoIites in Table 1. More than one
such substance may be present at the same time (eg. skid row alcoholics don't start drinking the
"canned heat" until the booze runs out). The laboratory values may be reported in mg/dL. Table 1
lists conversion factors that convert lab values expressed in mg/dL to mOsmol/L. n these cases
CNS effects are unlikely to be related to the hyponatremia; more likely due to pharmacologic or
metabolic perturbations caused by the drug(s) or substance(s). The treatment will be different from
that of hypotonic hyponatremia. Example: Henry's S
Na
+
is 116 but his blood ethanol is 246mg/dL,
glucose 124, & BUN 8. His breath smells sweet. s ethanol the only unidentified substance on
board? The Calculated S
Osmol
= (2 x plasma Na) + serum glucose/18 + BUN/2.8 +ethanol/4.6 =
(2 x 116) + 124/18 +8/2.8 + 246/4.6 = 236 + 6.9 + 2.9 + 53.5 = 295.3mMol/L. The laboratory reports
the S
Osmol
at 320mMol/L. Henry either has lactic acidosis, ketonemia or a concomitant toxic ingestion
! "True", Hypotonic (DiIutionaI) Hyponatremia indicates a deficit of total body Na
+
(TB
Na+
) in
relation to total body water (TBW). The 2 laboratory values shared in common by every condition
causing this aberration are: (1) S
Na
+
< 135mEq/dL (usually <125mEq/dL unless of rapid onset) & (2)
S
Osmol
< 280mMol/dL. The TBW itself may be increased, decreased or normal. The hyponatremia
may be related either to increased water intake or to increased Na
+
loss. The hyponatremia in most
such states results from excessive ADH stimulation engendered by decreased circulatory volume.
The increased ADH restores the volume with Na
+
deficient H
2
O. n other cases it results from
diminished delivery of H
2
O to the distal nephron because of decreased GFR, an increase in proximal
tubular reabsorption or a sodium uptake block in the loop of Henle or in the distal segments of the
nephron:
1 DiIutionaI Hyponatremia Caused by Decreases in TotaI Body Sodium (Dehydration):
ntravenous corrections of dilutional hyponatremia with dehydration are made with 1 normal
saline with simultaneous replacement of other electrolyte deficiencies
1,2
. Causes include:
a GI & Third Space Losses of Sodium:
n general, G losses & sequestration (eg. "third-spacing) stimulate avid renal conservation of
Na
+
& Cl
-
, that reduce urinary Na
+
(U
Na+
) & Cl
-
urinary Na
+
(U
Cl
-
) <10mMol/L. The exception is
that after protracted vomiting with massive Cl
-
loss, the resultant metabolic alkalosis
engenders bicarbonaturia. Bicarbonate, being non-reabsorbable, draws Na
+
with it into the
urine & raises U
Na+
>20mEq/L. Urine Cl
-
(U
Cl
-
) remains depressed <10mEq/L however. That
is why U
Cl
-
is commonly said to be the most reliable indicator of hypovolemia. U
CI
-
<10mEq/L
distinguishes GI from renaI fIuid Ioss
2
.






Hyponatremia & Hypernatremia Page 6 of 14
b Renal Losses of Sodium: feature urinary Na
+
wasting (U
Na+
> 20mEq/L)
Thiazide Diuretics are the most common cause of renal Na
+
wasting. They work exclusively
in the distal renal tubule interfering with retention of Na
+
, K
+
, Cl
-
, & H
2
O thereby producing
hyponatremia in predisposed patients (usually underweight women), hypokalemia, &
hypochloremic metabolic alkalosis. The mechanism of production of hyponatremia involves
activation of ADH receptors as well as ADH stimulation
2
.
MineraIocorticoid Insufficiency is likely when serum K
+
is elevated, creatinine is normal,
U
Na+
> 20mEq/L & HCO
3
-
is elevated 2
o
to mild metabolic alkalosis.
SaIt-Losing Nephropathies occur with polycystic kidneys & medullary cystic disease,
chronic pyelonephritis, analgesic & obstructive nephropathies.
Osmotic Diuresis as occurs with diabetic, starvation & alcoholic ketoacidosis produces
obligatory Na
+
loss, volume contraction & with continued fluid intake, hyponatremia.
CerebraI SaIt Wasting is a rare complication of subarachnoid hemorrhage that leads to
hyponatremia & volume contraction, perhaps in part through the stimulated release of Brain-
type natruretic peptide.
2 n DiIutionaI Hyponatremia with Increased TotaI Body Water (Edematous States) TB
Na+
is
increased but TBW is increased even more as fluid moves from the vascular compartment into
the interstitium, impelled by increased intravascular hydrostatic pressure & diminished oncotic
pressures imposed by the increased circulating fluid volume stimulated by ADH.
Emergency V treatment of edema-associated dilutional hyponatremia is made with 3% or 5%
saline simultaneously with V furosemide, thereby avoiding infusion of a large fluid volume while
stimulating water diuresis. Thiazides should be avoided in this situation because they act on the
distal tubule & thereby prevent the secretion of dilute urine
2
.
Diagnosis of the specific cause is based on the clinical presentation. As shown in the list of
diagnostic possibilities in the Diagnostic Flow Chart, the most common causes are liver, kidney or
heart failure.
a mpaired cardiac output, common to all forms of Congestive Heart FaiIure: increases
preload pressures & decreases tissue perfusion. These effects are interpreted by a variety of
bodily signaling mechanisms, to indicate hypovolemia. They activate the sympathetic
nervous system & the RAAS, stimulate secretion of ADH, epinephrine, angiotensin ,
aldosterone & the counter-regulatory hormones atrial & B-type natruretic peptides, the net
effect of which is to inhibit excretion of Na
+
& water, measures that might have been of short
term benefit, had the problem been hypovolemia, but are universally misdirected in CHF. Na
+

& H
2
O are always increased if there is a prominent ADH effect or large diuretic doses are
required for symptom control.
b n advanced Hepatic Cirrhosis with PortaI Hypertension, increased portal pressures
impede venous return from the splanchnic vasculature at the same time that insufficiently
metabolized amines induce nitric oxide (NO) that dilates it & increases its permeability. The
net result of which is to reduce effective tissue perfusion even as the cardiac increases. The
various bodily sensors again read this diminution of tissue perfusion & increased venous
pressure as hypovolemia & again activates the sympathetic nervous system, the RAAS &
ADH but not the natruretic peptides. The clinical outcome in advanced cases is ascites,
peripheral edema, increased TB
Na+
& TBW & dilutional hyponatremia. n those cases the
RAAS is frequently so hyperstimulated that spironolactone (a competitive inhibitor of the
aldosterone receptor) becomes an indispensable part of the diuretic regimen. When that is
the case, a spot urine specimen demonstrates a U
Na+
< 10mEq/L & a U
K+
> 20mEq/L. After
spironolactone's begins to increase the U
Na
+
& decrease the U
K+
, furosemide may be safely
started without fear of "bottoming out the S
Na
+
.
c n both acute & chronic Kidney FaiIure both sodium & water excretion is impaired, owing at
least in part to the decreased volume of fluid filtered each day. Edema occurs when dietary
intake of sodium exceeds the excretory capacity & hyponatremia occurs when dietary water
exceeds the impaired excretory capacity. n the Nephrotic Syndrome volume contraction
stimulates ADH production, increasing TBW & causing hyponatremia.


Hyponatremia & Hypernatremia Page 7 of 14
! Hyponatremia with NormaI TB
Na+
(EuvoIemic) is common among hospitalized patients because
many of its causes are either iatrogenic or related to a comorbid condition. The most common
pathogenetic antecedent is the syndrome of inappropriate ADH secretion (SADH), the diagnostic
criteria for which are shown in Table 4. ts causes are described last. The laboratory test that stands
as the haIImark of excessive ADH is decreased serum uric acid resulting in part from impaired
renal urate reabsorption secondary to increases in the fluid volume filtered, & in part suppression of
urate uptake, mediated by V
2
receptors on the proximal renal tubule. Other causes include:
1 Drug ReIated Hyponatremia: All categories of
antidepressant drugs are associated with SADH but
the odds ratio is 13.3 to one that the drug is an SSR
rather than a tricyclic or atypical antidepressant, in
elderly patients on thiazide diuretics. Risk factors
other than age & concomitant hyponatremia-
producing-drugs include female sex & previous
episodes of hyponatremia. The pathogenesis is
believed to be multifactorial.
Carbamazepine-induced hyponatremia has been
ascribed to SADH, but in hyponatremia produced by
its analog oxcarbazepine, ADH is not increased & the
mechanism is presumed to involve ADH receptor sensitization. Vincristine, vinblastine & the first-
generation sulfonylurea chlorpropamide also cause hyponatremia that has been attributed to
stimulation of ADH release. Chlorpropamide also sensitizes renal tubule cell ADH receptors.
Desmopressin & lycine vasopressin are analogues of ADH & thereby promote water retention by
similar mechanisms. Bromocriptine stimulates ADH release.
2 Perioperative Hyponatremia usually occurs because of ADH stimulated by the infusion of large
amounts of hypotonic V fluids or prolonged irrigation of the bladder or uterus with hypotonic
solutions. t may rarely occur as a late complication of general anesthesia.
3 Psychosis ReIated Hyponatremia is
most common among acutely psychotic
schizophrenic patients. ts cause is
multifactorial & its relationship to
psychogenic polydipsia is unclear.
4 GIucocorticoid Deficiency impairs
water excretion by altering renal
hemodynamics & increasing renal
tubular permeability as well as through
ADH over-excretion.
5 Myxedema suppresses both cardiac
output & GFR, thus stimulating ADH by
both CV & renal mechanisms.
6 SIADH, the Syndrome of nappropriate
ADH Secretion includes conditions in
which the disease produces ADH
exogenously & those in which ADH is
increased because of "inappropriate
stimulation. Common causes of SADH are shown in Table 5.
D References:
1 Adrogue HJ, Madias NE. Hyponatremia N Engl J Med 2000;342:1581-9.
2 Kumar S, Berl T. Electrolyte quintet: Sodium. Lancet 1998;352:220-8.
3 Singer GG, Brenner BM. Ch. 249: Fluid & Electrolyte Disturbances, in Harrison's Principles of
Internal Medicine. 1998;14th Ed. New York, McGraw Hill, pp 265-77.
4 Schrier RW. Treatment of hyponatremia. N Engl J Med 1985; 312;1121-3.
5 Moses AM, Streeten DH. Ch. 330: Disorders of the neurohypophysis, in Harrison's Principles of
Internal Medicine. 1998;14th Ed. New York, McGraw Hill, pp 2003-11.

TabIe 4: Diagnostic Criteria for SIADH
2
Primary:
! S
Osmol
< 270mosMol/dL.
! U
Osmol
> 100mosMol/L.
! Clinical Euvolemia.
! ncreased U
Na+
with normal H
2
O & Na
+
intake
! No adrenal, thyroid pituitary or renal disease
Secondary:
! Abnormal H
2
O Excretion: (Urine excretion
< 90% of load of 20cc H
2
O/kg within 4 hours
& U
Osmol
> 100mosMol/L.
! Plasma ADH level is inappropriate to S
Osmol
.
! Serum Na
+
corrects with fluid restriction but
not with volume expansion.
TabIe 5: Causes of SIADH
1,2,3
:
Cancers (Ectopic ADP):
Small Cell Lung Cancer
Thymomas
Hodgkin's & Non-
Hodgkin's Lymphoma
Olfactory Neuroblastoma
Pancreatic Cancer
Duodenal Cancer
Lung Disease & Infections:
Tuberculosis
Pneumonia, Viral or Bacterial
Empyema or Abscess
COPD
HV with P. carinii, CNS
infections or Malignancies
CNS Diseases:
Skull Fracture
Subdural Hematoma
Subarachnoid Hemorrhage
Cerebrovascular Thrombosis
Meningitis
Cerebral Atrophy
Acute Encephalitis
Guillain-Barr Syndrome
Drugs:
SSRs & tricyclic drugs
Opiates
General Anesthesia
Carbamazepine
Vincristine, Vinblastine or
Cyclophosphamide
Chlorpropamide
Lypressin or Desmopressin
Endocrine:
Hypothyroidism
Glucocorticoid nsufficiency
MisceIIaneous:
Positive Pressure Ventilation
Acute ntermittent Porphyria
Lupus Erythematosus
Hyponatremia & Hypernatremia Page 8 of 14
FIGURE I: DIAGNOSTIC FLOW CHART FOR HYPONATREMIA
1,2,3





































Hyponatremia
Dehydrated
Hypotonic (SOsmol <280mMol/dL) Non-hypotonic (SOsmol >280mMol/dL)
Exogenous OsmoIite
(SOsmol 280-290mMol/dL)
Urea
Lactate
Ethanol
Methanol
sopropanol
Ethylene glycol
Pseudohyponatremia
(SOsmol 280-290mMol/dL)
Hyperlipidemia
Paraproteinemia
Edematous
(UNa+<20mEq/L)
CHF
Cirrhosis
Nephrotic syndrome
Toxemia of Pregnancy
(UNa+>20mEq/L)
Acute or Chronic
Renal Failure
EuvoIemic
ExtrarenaI Na
+
Loss
(UNa+ usually <10mEq/L)
(UCl
-
always<10, UOsmol>200)
Diarrhea
Vomiting
Blood Loss
Excessive Diaphoresis
"Third Spacing:
Bowel Obstruction
Peritonitis
Pancreatitis
Muscle Trauma
Burns
Osmotic
(SOsmol>290mMol/dL)
Hyperglycemia
Mannitol
RenaI Na
+
Loss
(UNa+> 20mEq/L)
Diuretics
Osmotics
Ketonuria
Bicarbonaturia
Mineralocorticoid
nsufficiency ($ K
+
)
Na
+
Wasting
Nephropathy
Extended vomiting
With 2
o
RTA.
Thiazide Diuretics (SK+ $, UNa+>20mEq/L)
Endocrine Causes (UNa+>20mEq/L)
Glucocorticoid nsufficiency
Hypothyroidism
Causes of SIADH (UOsmol >100mMol/L after H2O loading, UNa+>20mEq/L, $ Serum Uric Acid)
Drugs
Desmopressin
Oxytocin
NSADs
SSRs
Phenothiazines
Opiates
Nicotine
Chlorpropamide
Clofibrate
Carbamazepine
Cyclophosphamide
Vincristine
Cancer
Lung
Mediastinal
Extrathoracic
tumors

MisceIIaneous
Postoperative state
Severe nausea
Severe pain
HV infection
Lung Disease
nfections
ARDS
Positive-pressure
ventilation
CNS Diseases
Acute Psychosis
Mass Lesions
Stroke
Hemorrhage
Trauma
nflammatory &
Demyelinating
Diseases.
Decreased SoIute Intake
(UOsmol<80mEq/L after Na
+
loading)
Beer Potomania
Tea & Toast Diet
Excessive H
2
O Intake
(UOsmol <80mMol/dL before, & >500mMol/dL after H2O deprivation)
Primary Polydipsia
Na
+
free rrigant solutions used in hysteroscopy & TURP
Near Drowning.
Dilute nfant Formulas
Multiple Tap Water Enemas
Hyponatremia & Hypernatremia Page 10 of 14
II HYPERNATREMIA:
A Definitions & CIinicaI Manifestations
1,2
:
! Hypernatremia means that serum sodium (S
Na
+
) >145mEq/dL
1
.
! PhysioIogy: The body has 2 lines of defense that prevent hypernatremia: the kidneys & thirst. Both
have to be impaired for hypernatremia to occur. Vasopressin release (stimulating renal conservation
of water) begins at a serum osmolality (S
Osmol
) of 280mOsmol/L. Thirst is stimulated at 290mOmol/L.
! Symptomatic hypernatremia is hypernatremia accompanied by CNS changes that are not
attributable to another condition (such as diabetic hyperosmolar coma, liver failure, myxedema coma,
Addisonian crisis or drug effects that may cause similar CNS symptoms).
! The Symptoms & Signs
1,2
that result from the hypernatremia depends on the speed of onset. Rapid
V sodium loading may produce hyperpnea, restlessness, a characteristic high-pitched cry in infants,
seizures or coma & occasionally vascular rupture, CNS bleeding, & permanent neurological damage
or death. When, as is more common, the changes occur more slowly, the brain substance has time
to adjust its internal osmolality & symptoms are milder: With increasing chronicity, intense thirst is
replaced by muscular weakness, headache, lethargy, delirium, coma, & death.
! VuInerabIe PopuIations include the very young, the very old, & hospitalized patients. Sustained
hypernatremia can only occur when thirst or mobility are impaired, so those with altered mental
status, ventilator patients, infants, nursing home patients are most subject to hypernatremia
secondary to water deprivation. Hospitalized patients are vulnerable to inadvertent V sodium loading
B PathophysioIogy:
! Sodium is confined to & is the dominant osmolite in the extracellular compartment, so when
excessive, it always draws water from the intracellular compartment & dehydrates the brain.
! The changes in neuronal cell membrane potentials that follow acute sodium loading may produce
seizures, coma, or other manifestations of disorderly activation or suppression of neuronal structures.
! mmediately after acute sodium Ioading the brain begins acclimating by inspissating solute that
increases the intracellular osmolality to a level that matches the extracellular milieu. At that point
shrinkage reverses & within 13 hours the brain volume begins to normalize.
! The price paid for the return of normal brain volume is that now the intracellular compartment is
hyperosmolar & is kept so by trapped intracellular solutes that move through the cell membrane very
slowly. f, after acclimatization occurs normal hydration is too rapidly restored, the now hypertonic
cells will inspissate water & swell, causing mental status changes, seizures, coma or death.
! The clinical manifestations of hypernatremia of graduaI onset are much more subtle. Elderly adults
have few or no symptoms unless serum sodium is above 160mEq/dL. Thereafter, generalized
weakness coupled with mental status changes & lethargy are followed by somnolence, coma &
sometimes by seizures & death.
C CIinicaI Assessment: There are 3 important questions in the assessment of hypernatremic patients:
a Symptoms determine the urgency & route (V, oral, or NG tube) of treatment.
b Duration of the hypernatremia determines the rate of correction.
c Fluid VoIume Status is determined by the cause & determines the optimal infusate.
! Symptoms of CNS involvement, lethargy, stupor, coma or seizure require immediate treatment with
hypotonic saline or D5W. Advanced hypovolemic hypernatremia with hemodynamic compromise
requires fluid resuscitation with normal saline followed by correction of hypernatremia with hypotonic
saline or D5W. Oral or nasogastric rehydration may be attempted in alert, relatively asymptomatic
patients with an intact & functional G tract.
! Duration: The serum Na
+
correction rate may be as rapid as 1mEq/hour without risking cerebral
edema, in patients with acute hypernatremia that has occurred within the previous 12 hours. The
brains of those with symptomatic hypernatremia of remote onset that has occurred more slowly over
several days will have acclimated to the hyperosmolar state, so the hypernatremia must be corrected
more slowly. Rates not to exceed 0.5mEq/hour of sodium are recommended.




Hyponatremia & Hypernatremia Page 11 of 14
! FIuid VoIume Status is determined by the cause of the hypernatremia & indicates the optimal
infusate, or sequence of infusates.
1 Dehydration is the result of simultaneous loss of Na
+
& water. These losses are caused by G
dysfunction (eg. vomiting, diarrhea, nasogastric suction, enterocutaneous fistulae, or cathartic
abuse), renal losses (eg. intrinsic renal disease, loop & osmotic diuretics, post-obstruction &
polyuria following acute tubular necrosis), & cutaneous losses from burns or excessive sweating.
n situations requiring V therapy the appropriate infusate is 0.45% saline. The onIy role for 0.9%
saline is for fluid resuscitation of patients with hemodynamic shock. f resuscitation efforts are
successful, the hyponatremic state is then corrected with 0.45% saline. 0.9% saline is never the
appropriate infusate for correcting hypernatremia.
2 HypervoIemia (usually without edema) occurs acutely after inadvertent sodium overloading &
chronically from hyperaldosteronism or Cushing's disease. Hypervolemic hypernatremia is
treated with loop diuretics & D5W.
3 EuvoIemic Hypernatremia results from pure water deficit without significant sodium loss. Such
patients are not usually hypovolemic. The most usual causes include unreplaced insensible
losses from the skin & respiratory tract, hypodipsia, & the various types of diabetes insipidus.
Treatment of neurologically symptomatic Euvolemic hypernatremia is with D5W.
D Management:
! The goaI of management is restoration of serum Na
+
%145mEq/dL.
! The route of rehydration is determined by the presenting symptoms. Neurological symptoms call for
initial emergent treatment with V fluids. Oral replenishment should be used whenever possible (eg.
an alert oriented patient with an intact G tract).
! The rate of correction is calculated so as to avoid inducing cerebral edema. A safe correction rate
after acute sodium Ioading is 1mEq Na
+
/hour. A safe correction rate for patients with chronic
hypernatremia is 0.5mEq Na
+
/hour. The appropriate infusion rate for each type of infusate may be
calculated using the formula below:
! CaIcuIation of Infusion Rates: The desired rate of infusion of any given solution can be determined
by multiplying the patient's TBW* plus daily insensible water loss (WL, about 1 liter) by the number of
mEq of sodium correction desired times 1000cc (the number of cc's in one liter). The result is divided
by the number of mEq of Na in each liter minus the patient's initial Na level in mEq times the number
of hours over which the infusion is to occur:
(TBW+IWL) x # mEq desired x 1000cc =Initial Rate of infusate in mL/hour.
(mEq/L infusate - patient's Na
+
) x # hours of infusion
*TBW is estimated as 0.6 x weight in Kg for adult men, 0.5 for adult women & elderly men & 0.45 in elderly women.
1 Emergency Treatment of Patients with ChronicaIIy Acquired NeuroIogicaI Symptoms:
An 84yo 50Kg woman, admitted comatose from a nursing home after a decreasing level of
consciousness over the past week, with S
Na+
of 165mEq/dL, treated with 0.45% saline, BP:
109/72, Pulse: 84, would initially be given:
([0.45 x 50]+1) x 0.5 x 1000cc = 23.5 x 500 = 11750 = 133cc/hour.
(77 - 165) x 1 88 88
2 Emergency Treatment of Patients with AcuteIy Acquired NeuroIogicaI Symptoms:
A 38yo mentally retarded African American woman with type 2 insulin requiring diabetes mellitus
was referred from a nearby ER after her mental status deteriorated when she was given 2
ampules of Na
+
bicarbonate & a small dose of subcutaneous insulin for "diabetic ketoacidosis
when her blood sugar was found to be 550mg/dL & her urine positive for ketones. She arrived
comatose 2 hours after mental status deterioration had started, with BP 175/95, pulse 96
respirations sonorous at 16/minute, weight 96kg, blood glucose 642mg/dL, serum Na
162mEq/dL, BUN was 48, creatine 1.4, K, Cl, bicarbonate, serum ketones & ABGs were all within
normal limits. Serum osmolality was calculated:
Calculated Serum Osmolality = (2 x plasma Na) + serum glucose/18 + BUN/2.8
Calculated Serum Osmolality = (2 x 162) + 642/18 + 48/2.8 = 376mMol/dL
Measured serum osmolality was 370. The diagnosis of hyperosmolar hypernatremic coma was
made. nsulin by V infusion was titrated to reduce blood sugars by 50mg/dL/hour & it was
Hyponatremia & Hypernatremia Page 12 of 14
decided to treat initially with D5W targeted to reduce S
Osmol
by 1mOsmol/hour. The calculation is
as follows:
(TBW+IWL) x # mEq desired x 1000cc =Initial Rate of infusate in mL/hour.
(mEq/L infusate - patient's Na
+
) x # hours of infusion
([0.5 x 96]+1) x 1 x 1000 = 49000 = 302.5cc/hour, initial infusion rate.
(0 162) x 1 162
D5W was started at 300cc/hour. Serum electrolytes & glucose were followed hourly. Six hours
later the S
Na+
was 157mEq/dL, glucose was 302mg/dL, BUN was 36 & the patient began to
awaken. At this point the infusate was changed to 0.45% saline at a rate calculated to correct the
S
Na+
by no more than 12mEq during the first 24 hours of treatment. Since we had already
corrected by 5mEq/dL over the 1
st
6 hours, our calculation of desired rate of infusion of 0.45%
saline for the remaining 18 hours was:
(TBW+IWL) x # mEq desired x 1000cc =Initial Rate of infusate in mL/hour.
(mEq/L infusate - patient's Na
+
) x # hours of infusion
([0.5 x 96]+1) x 7 x 1000 = 343000 = 224.2cc/hour of 0.45% saline for the next 18 hours.
(77 162) x 18 1530
After the 1
st
24 hours of treatment the rate of infusion was readjusted to correct the S
Na+
by not
more than 12mEq/24 hours. Within 48 hours oral feedings were resumed & 4 days later she was
discharged neurologically intact.
! Management of Asymptomatic or MinimaIIy Symptomatic Hypernatremia is usually straight
forward: simply provide adequate hydration to mobility impaired persons & treat an obvious
underlying cause. Less often further diagnostic & therapeutic steps are required. The diagnostic
steps are discussed next:
E Diagnosis:
! Hypernatremia with HypovoIemia with or without Dehydration is almost always related to G or
renal losses, or to weeping of tissue fluid from extensive burns. Which one usually clinically obvious.
Profuse diaphoresis may occasionally reduce volume sufficiently to produce postural symptoms but
hemodynamic collapse is rare. n the unusual event of diagnostic uncertainty, burns, G & cutaneous
losses engender renal sodium conservation with a spot U
Na+
< 20mEq/L. Renal losses of Na
+
& water
drive U
Na+
above 20mEq/L. Both are managed with 0.45% saline. 1Normal saline isn't indicated for
correction of the hypernatremic state though it may be used for volume resuscitation of those who
present in hemodynamic shock. See Figure 2 for the diagnostic flow chart for hypernatremia.
! Hypernatremia with HypervoIemia occurs for one of 2 reasons: inadvertent sodium loading
endocrine dysfunction. By far the most frequently encountered of which is primary
hyperaldosteronism (Conn's syndrome) which is found in about 1% of hypertensive patients. The
most common initial clinical manifestation of increased intravascular volume in Conn's syndrome
Cushing's disease, & other causes of hypervolemic hypernatremia is hypertension not edema.
Conn's & Cushing's syndromes should be excluded in hypertensive patients with hypokalemia,
elevated bicarbonate & mild metabolic alkalosis, before they are started on thiazide diuretics.
Excessive sodium loading most tragically results from a therapeutic misadventure such as inadvertent
infant feedings of hypertonic formula, saline induced late abortions, or V bicarbonate injected during
CPR & the cause is clinically obvious. t may also occur from salt tablets or as a dialysis accident.
U
Na+
should be elevated in hypervolemic hypernatremia caused by any of these conditions. Figure 2
contains a more complete list of diagnostic considerations.
! EuvoIemic Hypernatremia is caused by the loss of pure water not accompanied by sodium loss. t
most common cause is unreplaced insensible fluid losses from the skin & respiratory tract in
immobilized institutionalized patients. Such patients are usually not hypotensive because water loss
without loss of solute decreases total body water, not just the circulatory volume. U
Osmol
is markedly
elevated. The diagnosis is usually obvious once it is considered.



Hyponatremia & Hypernatremia Page 13 of 14
FIGURE II: DIAGNOSTIC FLOW CHART FOR HYPERNATREMIA

































Not so clinically transparent is the differentiation of the renaI causes of euvolemic hypernatremia.
There are 3 possibilities: (1) Central diabetes insipidus (CD), (2) Acquired nephrogenic diabetes
insipidus (AND) & (3) Congenital nephrogenic diabetes insipidus (CND). Central & nephrogenic
diabetes insipidus are differentiated by the water deprivation test, which measures serum AVP &
U
Osmol
after water depravation sufficient to decrease body weight by 1/3 (or until 3 consecutive U
Osmol

fall within 10% of the same value), & again, 60 minutes after giving 5U of aqueous vasopressin M.
Expected results are shown in Table 6*.
* The remaining sections of this outline summarize information from reference # 2.
SERUM Na (S
Na+
) >145mEq/dL
LOSS of Na
+
& H
2
O
(Hypovolemia)
PURE H
2
O LOSS
(Euvolemia)
SODIUM GAIN
(Hypervolemic)
(U >20)
RENAL CAUSES:
(U
Na+
>20mMol/L)
Diuretics:
Loop Diuretics
Osmotic Diuretics
Diseases:
Post Obstruction
ntrinsic renal disease
Post ATN polyuria
EXTRARENAL CAUSES:
(U
Na+
<20mMol/L)
GI Causes:
Vomiting
Diarrhea
Nasogastric Suction
Enterocutaneous fistulae
Cathartic Abuse
Cutaneous Causes:
Excessive Diaphoresis
Burns
RENAL CAUSES:
DIABETES INSIPIDUS (DI):
CentraI (CDI):
diopathic (50%)
Post-traumatic
Metastatic (Breast) or 1
o
Tumor,
Cyst or Aneurism
TBC, Histoplasmosis or Sarcoid
Meningitis, Encephalitis, or
Guillain-Barr Syndrome
Ethanol nduced (temporary)
Congenital (rare):
Autosomal Dominant
Recessive (Wolfram syndrome)
Nephrogenic (NDI):
CongenitaI NDI:
Autosomal Recessive
Sex Linked Dominant
Acquired NDI:
Renal Diseases
Hypokalemia, Hypercalcemia
Drugs:
Lithium
Demeclocycline
Amphotericin
Foscarnet
Methoxyflurane
V
2
Receptor Antagonists
PRERENAL CAUSES:
INSENSIBLE H
2
O LOSSES:
Respiratory Tract
Skin & Mucous Membranes
PRIMARY HYPODYPSIA:
SODIUM LOADING:
Bicarb injected during CPR
Hypertonic V saline
Hypertonic nfant or Tube
Feeding Formula
ngestion of Salt Tablets
Hypertonic Renal Dialysate
Sea Water Drowning
Hypertonic Saline Enemas
NaCl Rich Emetics
ENDOCRINE CAUSES:
(S
K+
low, U
K+
high)
1
o
Hyperaldosteronism
Cushing's syndrome
Hyponatremia & Hypernatremia Page 14 of 14
CompuIsive water drinkers
(CWAD) have polyuria & polydipsia
that requires differentiation from
diabetes insipidus that can usually
be made on clinical grounds.
CWD's onset is vague, urine output
varies, nocturia is unusual & S
Osmol

< 270mOsmol/L. CD's onset is
usually abrupt, urine output is
constant, usually with nocturia. CD
patients usually prefer cold water & S
Osmol
>295mOsmol/L.
CentraI Diabetes Insipidus (CDI) is idiopathic in 50% of cases & related either to trauma, a space
occupying lesion or an infection in the remainder, except for 2 rare inherited forms. one autosomal
dominant & the other recessive. A list of likely causes is shown in Figure 2.
Short-term treatment of CD during acute episodes of severe dehydration may be with aqueous
vasopressin 5-10U/4-6hours, with caution regarding fluid overload & coronary or peripheral artery
vasospasm. IntranasaI desmopressin has no vasoconstrictive effects, is long acting, & safe in
pregnancy. Given every 12-24 hour intranasally it is the drug of choice for chronic, long-term
management. Drugs that release ADH, carbamazepine 400-600mg/day, clofibrate 500mg qid, or
chlorpropamide 250-500/day can be used to supplement therapy, or may in some cases be combined
with restriction of dietary solutes or with diuretic therapy. Ethanol & phenytoin also stimulate ADH
release.
Nephrogenic Diabetes Insipidus (NDI)
Acquired NDI is more common & less severe than the congenital form. Concentrating
mechanisms are incompletely impaired so urine volume is < 3L/day.
Any kind of chronic renaI faiIure may lead to ND, especially those (like sickle-cell disease,
anaIgesic nephropathy or the tubulointerstitial diseases) that interfere with the intermedullary
structures or their blood supply.
HypokaIemia & hypercaIcemia cause (usually) reversible concentration defects by interfering
with cyclic AMP, thereby reducing the response to ADP.
50% of patients taking Iithium will develop ND that may not be reversible, probably thru down
regulation of the ADH receptor. DemecIocycIine decreases ADH effect by interfering with
adenylate cyclase degradation. Amphotericin & foscarnet cause ND through renal toxicity.
CongenitaI NDI is diagnosed in severely dehydrated infants with hypernatremia, concentrated
urine fever & vomiting. Hydronephrosis, growth & mental retardation are often present. Acute
treatment requires rehydration with hypotonic (eg.2.5% rather than isotonic 5%) glucose because
the baby's ability to excrete solute hinges on the availability of hypotonic liquid. Administration of
thiazides & amiloride decrease urine volume by causing extracellular volume contraction, which
reduces urine flow sufficiently to increase proximal tubular reabsorption of sodium & water.
NSADS increase urinary osmolality from about 50 to about 200mOsmol/L. This reduces urine
output from 10-12L to 4-5L/day. Neither hormonal nor other forms of pharmacotherapy work.
F BibIiography:
1 Adrogue HJ, Madias NE. Hypernatremia N Engl J Med 2000;342:1493-9.
2 Kumar S, Berl T. Electrolyte quintet: Sodium. Lancet 1998;352:220-8.
3 Singer GG, Brenner BM. Ch. 249: Fluid & Electrolyte Disturbances, in Harrison's Principles of
Internal Medicine. 1998;14th Ed. New York, McGraw Hill, pp 265-77.

TabIe 6: Water Deprivation Test: Post-Dehydration VaIues by Diagnosis
Exogenous AVP
Diagnosis U
OsmoI

S
AVP
Before S
AVP
After
Normal >800 >2 No increase (&)
Complete CD <300 Undetectable &&&
Partial CD 300-800 <1.5 >10% &
ND <300-500 >5 No &
1
o
Polydipsia >500 <5 No &