ELECTROLYTE DYSBALANCE IN CHF: PROGNOSIS & MANAGEMENT

Dr. Arindam Pande, MD, DMAssociate Consultant, CardiologyApollo 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 hyponatremia

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

gradually falling

glomerular filtration rate, due to CHF progression, medications or chronic kidney injury due to comorbidities, becomes more critical in sodium/water imbalance.

SODIUM

Sodium Homeostasis 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 renin-angiotensin-aldosterone system 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.

Hyponatremia- Diagnosis

Cause of Hyponatremia by Urine Specimen Cause Urine Na Urine

Volume Osmolarity Specific

Gravity 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 storyLaboratory studies: Urine Na and Osm compared to Serum Na and OsmCalculate Osmolar Gap: Difference between measured & calculated osm

Gap is high with mannitol, glycerol, lactate, methanol, EtOH, ethylene glycol

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.

Therapy for hyponatremia is not as straight forward as the picture by simply replenishing sodium by means of extra salt…

The failure to treat hyponatremia promptly, as well as too rapid correction can lead to adverse outcome

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 GENERAL PRINCIPLES:

Correction of Hyponatremia

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 symptoms.

It is often difficult to ascertain whether symptoms are due to hyponatremia or to underlying comorbidities.

Therapeutic Options for Hyponatremia Due to Congestive Heart Failure

LIMITATIONS OF EXISTING THERAPY

variable efficacy, slow onset of action, compliance issues, and toxicities.

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.

Unfortunately….

AVP RECEPTOR BLOCKERS (aquaretics)

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.

CONIVAPTANDevelopment 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 cardiacoutput and lower systemic vascular resistance.

V1a receptor blockade may also prevent AVP-induced coronary artery vasoconstriction and a direct myocardialremodeling 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

FUTURE DIRECTIONS…

POTASSIUM

Potassium Homeostasis 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 EXCRETIONKidney 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

Hypokalemia in CHF

Causes: Medication Increased losses: extrarenal and renal Transcellular shifts Decreased intake *Lab error- spurious

Initial serum potassium

concentration and treadmill exercise time carried weak but independent

prognostic information.

There did, however, appear to

be a reduction in the frequency of sudden death

when angiotension converting enzyme

inhibitors were given.

Treatment- HypokalemiaSevere, symptomatic hypokalemia requires aggressive treatment

Because of the risk of hyperkalemia, use IV potassium cautiously 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

Potassium-sparing diuretics-

ACE – Inhibitors/ARB

Hyperkalemia in CHF“One of the few things one can die from

without any symptoms…”

Causes

Medications

Spurious

Increased Intake

Decreased Excretion

Transcellular shifts

Hyperkalemia- TreatmentK+ level, the ECG, and the risk determine the aggressiveness of

therapy.

Stop all sources of additional potassium (oral, intravenous) and drugs

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

cells

Hyperkalemia- Treatment

Remove potassium from the body. Loop diuretic increases renal excretion of K+- only if

making urine. Kayexalate- exchange resin that is given either rectally

or orally Dialysis for acute potassium removal

necessary if severe renal failure or high rate of endogenous K+ release

Hemodialysis better than Peritoneal dialysis

Chronic management reducing dietary intake and eliminating or reducing medications

that cause hyperkalemia. May need meds to remove K+

MAGNESIUM

Hypomagnesemia (<1.4mEq/L)

Contributing factors:MalnutritionStarvationDiureticsAminoglcoside antibioticsHyperglycemia Insulin administration

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 arrhythmogenic effects

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 magnesium depletion.

Hypermagnesemia (>2.0mEq/L)

Contributing factors: Increased Mag intakeDecreased renal excretion

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.

Hypomagnesemia (<1.4mEq/L)

Interventions:Eliminate contributing drugsDiet Therapy IV MgSO4Assess DTR’s hourly with MgSO4

Hypermagnesemia (>2.0mg/dL)

InterventionsEliminate contributing drugsAdminister diureticCalcium gluconate reverses cardiac effectsDiet restrictions

CONCLUSION

PROGNOSIS 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

MANAGEMENT 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.