In chronic heart failure (CHF), neurohumoral systems, which help to maintain circulatory homeostasis, are maladaptive and responsible for disease progression and congestion in the long term.
These neurologic symptoms are manifestations of brain edema resulting from fluid shifts from the hypotonic extracellular fluid into the more hypertonic brain. In acute symptomatic hyponatremia, the risk of complications from cerebral edema is much greater than the potential risk of treatment complications; therefore, immediate treatment is required to reduce the risk of neurologic complications.
There is a note of caution in hyponatremia treatment, cause too rapid correction can lead to more harm than benefit.
Many clinicians have advocated the use of slower methods to correct hyponatremia in such patients, because symptoms are mild and presumably relatively stable and not life threatening. However, a retrospective study of 53 postmenopausal women with chronic symptomatic hyponatremia has raised questions about this assumption…Ayus JC, Arieff AI. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA 1999;281:2299 –2304.
The decrease in effective arterial filling in heart failure contributes to the breakdown of baroreceptor-mediated suppression of AVP release. Since defective baroreceptor stimulation of AVP release overrides its inhibition by a hypo-osmolar state, patients with severe heart failure may have elevated levels of circulating AVP.
Hyponatremia improved, but heart failure mortality didn’t differ.
Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure–related morbidity.
Electrolyte dysbalance in chf – prognosis & management
IN CHF: PROGNOSIS &
Dr. Arindam Pande, MD, DM
Associate Consultant, Cardiology
Apollo Gleneagles Hospital, Kolkata
PATHOPHYSIOLOGY OF CHF
Chronic activation of
Renin-angiotensin-aldosterone system (RAAS)
Sympathetic nervous system
Antidiuretic hormone arginine vasopressin (AVP)
PATHOPHYSIOLOGY OF CHF
Chronic activation leads to
Excessive ventricular preload & afterload
Adverse ventricular remodelling
Pulmonary and systemic congestion
Electrolyte abnormalities, such as
The heart disease is the primum movens, but the
kidney is the end organ responsible for increased
tubular reabsorption of sodium and water.
Over time, a
rate, due to CHF
chronic kidney injury
due to comorbidities,
Sodium - dominant cation of extracellular fluid
Principal determinant of extracellular osmolality.
The low intracellular sodium concentration, approximately 10 mEq/L, is
maintained by Na+ K+-ATPase, which exchanges Na+ for K+
Sodium is necessary for the maintenance of intravascular volume.
Sodium excretion occurs in stool and sweat, but the kidney regulates
sodium balance and is the principal site of sodium excretion.
Plasma VOLUME- not osmolality determines the excretion of sodium
by the kidney
In hyponatremia or hypernatremia, the underlying pathophysiology
determines urinary Na+, not the serum sodium concentration
When extracellular sodium ↑’s→ plasma tonicity ↑→water efflux from
cells →cellular dehydration (↓ cell volume) (to maintain equal
osmolality inside and outside the cell)
Also ADH is released- renal conservation of water
Sodium is unique among electrolytes…
because water balance, not sodium balance, usually determines its concentration.
Cause of Hyponatremia by Urine Specimen
Cause Urine Na Urine
Hypovolemic renal Na loss ↑ >20mEq/L ↑ ↓ ↓
Hypovolemic extrarenal loss ↓ ↓ ↑ ↑
Hypervolemic HypoNa- CHF,edema ↓<20mEq/L ↓ ↑ ↑
Hypervolemic HypoNa- Renal Failure varies ↓ varies varies
SIADH-like syndrome ↑ >20mEq/L ↓ ↑ ↑
History can tell us most of the story
Laboratory studies: Urine Na and Osm compared to Serum Na and Osm
Calculate Osmolar Gap: Difference between measured & calculated osm
Gap is high with mannitol, glycerol, lactate, methanol, EtOH,
Calc Osm= 2( Serum Na + serum K+) + (BUN/2.8) + (glucose/18)
HYPONATREMIA IN CHF
Excessive / inappropriate AVP secretion in
response to nonosmotic stimuli
Solute losses from diuretic therapy
Hyponatremia in CHF is not an isolated
event, rather is a part of the syndrome.
creatinine, and serum sodium were
related to progressive heart failure
death….serum potassium were
related to sudden cardiac death
Multivariate analysis identified three
variables that were statistically significant
and independent predictors of outcome…
In order of importance these were plasma
sodium level, left ventricular ejection
fraction and peak oxygen consumption.
By regression analysis, pretreatment serum sodium
concentration was the most powerful predictor of cardiovascular
mortality, with hyponatremic patients having a substantially
shorter median survival than did patients with a normal serum
sodium concentration. The unfavorable prognosis for
hyponatremic patients appeared to be related to the marked
elevation of plasma renin activity, since hyponatremic patients
fared significantly better when treated with angiotensin
converting-enzyme inhibitors than when treated with vasodilator
drugs that did not interfere with angiotensin 2 biosynthesis. In
contrast, there was no selective benefit of converting-enzyme
inhibition on the survival of patients with a normal serum sodium
concentration, in whom plasma renin activity was low.
is not as
forward as the
means of extra
The failure to treat hyponatremia promptly, as
well as too rapid correction can lead to adverse
The presence or absence of neurologic
symptoms and signs must guide treatment
The rate at which sodium concentrations should
be corrected depends on whether the sodium
imbalance is acute or chronic
THERAPY GUIDED BY 3
Although the therapeutic distinction between
symptomatic and asymptomatic
hyponatremia is clear at the extremes of
symptomatology, in reality many patients with
hyponatremia are somewhere between these
poles, with chronic hyponatremia and mild or
subtle manifestations of neurologic
It is often difficult to ascertain whether
symptoms are due to hyponatremia or to
Therapeutic Options for Hyponatremia
Due to Congestive Heart Failure
LIMITATIONS OF EXISTING THERAPY
slow onset of action,
compliance issues, and
AVP IN CHF
In many studies, it has been shown that AVP levels are higher
in presence of CHF
AVP values typically are not suppressed appropriately with a
water load in CHF patients
The elevated or ‘‘normal’’ levels of AVP in the presence of
hyponatremia suggest that non-osmotic mechanisms for
vasopressin release are essential factors in the hyponatremia
which characterizes the complex heart failure syndrome
A more rational approach to the treatment of hyponatremia in
CHF, therefore, would be to address the issue of excessive
AVP secretion or its effects.
Apart from reduction in body weight and increased urine
output, patients with hyponatremia had increases in
serum sodium levels that were maintained throughout the
study... There were no significant differences in outpatient
outcome of worsening CHF (defined as death,
hospitalization, or unscheduled visits for CHF) at 60 days
between the tolvaptan and placebo groups… Event-free
survival tended to be longer for the tolvaptan groups
combined when compared with placebo.
Post hoc analysis of ACTIVE in CHF
Total mortality was lower in the tolvaptan groups
combined compared with placebo in patients with
---elevated blood urea nitrogen levels (10.35
mmol/L [29 mg/dL]) and
---severe systemic congestion at randomization
(defined as presence of dyspnea, jugular venous
distention, and edema)
Serum sodium concentrations increased more in the
tolvaptan group than in the placebo group during the
first 4 days (P<0.001) and after the full 30 days of
therapy (P<0.001). The condition of patients with mild
or marked hyponatremia improved (P<0.001 for all
comparisons)… During the week after discontinuation
of tolvaptan on day 30, hyponatremia recurred.
Tolvaptan significantly improved secondary end
points of day 1 patient-assessed dyspnea, day 1
body weight, and day 7 edema. In patients with
hyponatremia, serum sodium levels significantly
increased… Tolvaptan caused increased thirst
and dry mouth, but frequencies of major adverse
events were similar in the 2 groups.
Development of the oral formulation was discontinued to
limit the potential for drug interactions resulting from
cytochrome P-450 enzyme inhibition.
Blockade of the V1a receptor causes vasodilation of
vascular smooth muscle, leading to increased cardiac
output and lower systemic vascular resistance.
V1a receptor blockade may also prevent AVP-induced
coronary artery vasoconstriction and a direct myocardial
remodeling stimulus, all of which may be beneficial in
patients with hyponatremia caused by CHF.
142 patients…single intravenous dose of conivaptan or placebo…
Conivaptan 20 mg and 40 mg significantly reduced pulmonary
capillary wedge pressure at 3 to 6 hours, the primary end point….and
the right atrial pressure at 3 to 6 hours, a secondary end point. Dose-
dependent increases in urine output were observed during the first 4
hours...Changes in cardiac index, systemic and pulmonary resistance,
blood pressure, and heart rate at 3 to 6 hours (all secondary end
points) were not significantly different among groups… Hypotension
and thirst were the only treatment emergent adverse events that were
reported in 5% of patients.
Nesiritide, the synthetic BNP
A1-adenosine antagonists, which increase
natriuresis and diuresis
Corticosteroids, which improve natriuresis
and diuresis induced by diuretics
Ultrafiltration, when the other treatment
failed or is not available
Most potassium is intracellular
Distribution of between the intra- and extracellular compartments
alters serum levels
Na+, K+-ATPase maintains the high intracellular K+ concentration
Pumping Na+ out of the cell and K+ into the cell.
Insulin activates the Na+, K+-ATPase- drives K+ into the cell
Acidosis (high H+) drives potassium extracellularly; (H+ in for K+ out)
Alkalosis drives K+ into the cell
β-Adrenergic agonists stimulate the Na+, K+-ATPase, ↑cellular uptake of K+
α-Adrenergic agonists and exercise cause a net movement of K+ out.
Potassium is necessary for:
Electrical responsiveness of nerve and muscle cells
Contractility of cardiac, skeletal, and smooth muscle.
Homeostasis- controlled by EXCRETION
Kidney plays the most important role
90% is of K+ is resorbed before the distal tubule and collecting duct-
In distal tubule and collecting duct- K+ absorbed and secreted
Tubular secretion that regulates the amount of K+ in the urine
Regulating hormone- aldosterone (↑in hyperkalemia)
Acts on cortical collecting duct
Moves sodium into cells
Creates a negative charge in the lumen → K+ excretion.
↑ intracellular Na+ stimulates the basolateral Na+, K+-ATPase
Moves K+ into cells lining the cortical collecting duct from blood side.
Glucocorticoids, ADH, high urine flow, and high Na+ delivery to the
distal nephron also ↑ urine K+.
Alkalosis -↑ urine K+.
Acidosis ↓ urine K+.
Excretion is decreased by insulin, catecholamines, and urine ammonia
Initial serum potassium
treadmill exercise time
carried weak but
There did, however,
appear to be a reduction
in the frequency of sudden
death when angiotension
inhibitors were given.
Severe, symptomatic hypokalemia requires aggressive treatment
Because of the risk of hyperkalemia, use IV potassium
0.5–1 mEq/kg, usually given over 1 hr. The adult maximum
dose is 40 mEq.
Oral potassium is safer.
Potassium chloride is the usual choice for supplementation.
Potassium acetate or potassium citrate for patients with
acidosis and hypokalemia
Potassium phosphate if hypophosphatemia is present
ACE – Inhibitors/ARB
Hyperkalemia in CHF
“One of the few things one can die from
without any symptoms…”
K+ level, the ECG, and the risk determine the aggressiveness of
Stop all sources of additional potassium (oral, intravenous) and
If K+ level is believable at >6.0 mEq/L, get ECG
Stabilize the heart to prevent life-threatening arrhythmias
Calcium-stabilizes the cell membrane of heart cells
Rapidly decrease serum K+ level (even if only temporary)
Bicarbonate- K+ to move intracellularly, lowering the plasma K+ level
Insulin- K+ to move intracellularly, give with glucose
Albuterol neb- stimulates β1-receptors→rapid movement of K+ into
Remove potassium from the body.
Loop diuretic increases renal excretion of K+- only if
Kayexalate- exchange resin that is given either rectally
Dialysis for acute potassium removal
necessary if severe renal failure or high rate of endogenous K+
Hemodialysis better than Peritoneal dialysis
reducing dietary intake and eliminating or reducing medications
that cause hyperkalemia. May need meds to remove K+
Magnesium deficit is not infrequently
observed in CHF patients but its
pathophysiology remains less well-studied
There is evidence that early detection and
correction of magnesium abnormalities
could obviate potentially deleterious
Hypomagnesemia was found in 17.4% of
hospitalized CHF patients… Inappropriate
magnesiuria (fractional excretion of
magnesium > 4%) was evident in half of
them... A variety of associated conditions,
including poor dietary intake, also favored
Serum magnesium does not appear to be an independent
risk factor for either sudden death or death due to all causes
in patients with moderate to severe heart failure.
Hypomagnesemia is associated with an increse in the
frequency of certain forms of ventricular ectopic activity, but
this is not associated with an incrase in clinical events. The
higher mortality rate among the patients with
hypermagnesemia is attributable to older age, more
advanced heart failure and renal insufficiency.
Hyponatremia is an independent predictor
of morbidity & mortality in CHF
Hypokalemia is an independent predictor
of sudden cardiac death
Serum magnesium is not an independent
risk factor of death in patients with
moderate to severe CHF
The use of hypertonic saline solution for the treatment of acute
and chronic symptomatic hyponatremia involves complex
calculations and requires careful monitoring
Fluid restriction for the treatment of chronic asymptomatic
hyponatremia is only moderately effective and presents serious
therapeutic adherence issues for patients
Agents such as demeclocycline and lithium have potentially
serious side effects
AVP receptor antagonists, the vaptans, are a promising new
class of aquaretic agents that increase free-water excretion while
maintaining levels of sodium and other essential electrolytes.