الفهرس 
PATHOPHYSIOLOGY OF ELECTROLYTE DISTURBANCES IN CONGESTIVE HEART FAILURE: HYPONATREMIA, HYPOKALEMIA, HYPOMAGNESEMIAOnly 14 pages are availabe for public view
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Abstract
HF is defined as a clinical syndrome characterized by dyspnea and fatigue, at rest or with exertion, due to structural and/or functional abnormalities of the heart. Patients with systolic HF tend to have large, dilated ventricles and markedly impaired systolic function. They frequently manifest mitral regurgitation and tricuspid regurgitation, usually on the basis of dilated ventricles and disruption of the normal papillary muscle architecture.HF often passes through an asymptomatic, latent phase that is frequently concealed from the patient and the physician.As HF syndrome advances, patients become less physically active, and there can be substantial salt and H2O retention, leading to edema. Many patients eventually die from progressive pump dysfunction, which includes hypotension, low CO, and multiorgan dysfunction.
In patients with CHF, the mechanisms that play an important role on electrolyte metabolism are reduced renal blood flow and GFR, elevation of RAAS, enhanced SNS activity, and VP release. These factors evoke potent vasoconstriction, retain Na and H2O, and induce hyponatremia, hypokalemia and hypomagnesemia. The concomitant rise in plasma atrial BNP represents a major, but often unsuccessful, effort in CHF to normalize H2O and electrolyte balance. ATII(released by RAAS) stimulates the thirst center to foster continued H2O consumption in spite of already excessive H2O retention and hypo-osmolar hyponatremia and stimulates the central release of AVP which acts directly on the distal tubule and collecting duct to retain H2O.The net result of all of these mechanisms is a dilutional state with a net reduction in serum Na concentration in the face of a marked increase in total body Na. Hyponatremia should not be viewed as an index of whole body Na depletion; while the serum Na concentration may be reduced, total body Na is increased. Activation of the RAAS evokes Na retention by the kidney in exchange for K and H ions. Elevated levels of VP enhance the loss of K from the distal tubule by increasing the permeability to this cation. Metabolic alkalosis, a common condition in CHF patients receiving diuretics, provokes hypokalemia by preferentially exchanging K(rather than hydrogen ion) for Na at the level of the renal tubule. Plasma norepinephrine is elevated in most patients with moderate to severe CHF, while plasma epinephrine is increased primarily in those with the most advanced stages. Chronic elevation of these catecholamines plays a role in the pathogenesis of hypokalemia by driving K into cells and by augmenting renal loss. Mg depletion in CHF appears to be most closely tied to the use of diuretics. Hypomagnesemia in CHF could also result from the chronic activation of the RAAS.
The diagnosis of HF is often determined by a careful history and physical examination and characteristic chestradiograph findings. The measurement of serum brain natriuretic peptide and echocardiography have substantially improved the accuracy of diagnosis.
Hyponatremia has associated with higher mortality in CHF. In hypervolaemic hyponatraemia free H2O gain exceeds Na gain, resulting in hyponatraemia. This is seen mainly in the setting of increased total body H2O as occurs in oedematous states such as CHF, hepatic cirrhosis, nephrotic syndrome, and renal failure. In these conditions,although the total body H2O is increased, the effective arterial volume is decreased. Intravascular volume depletion triggers secretion of ADH, renin- angiotensin, norepinephrine, and thirst. So the intake and retention of water exceeds the intake of Na leading to dilutional hyponatraemia. The signs and symptoms of hyponatraemia depend not only on the serum Na levels but also on the rate of serum Na decline. chronic hyponatraemia is hyponatraemia for more than 48 hrs may be asymptomatic, acute hyponatraemia of duration <48 hrs, may result in severe neurological dysfunction. Those at extremes of age are less tolerant to hyponatraemia. The neurological manifestations are most likely related to diffuse cerebral oedeme. In severe cases, death can result from tentorial herniation and brain stem compression. The evaluation of volume status plays an essential role in the diagnosis and treatment. Clinical examinations focus on determining the volume status, because the cause of hyponatremia is identified based on the volume status. Because a patient with low GFR develops a low urinary Na＋, hypervolemic hyponatremia also results in a low urinary Na＋ level of less than 20 mmol/L as in CHF. Low CO leads to significant neurohumoral activation, including the nonosmotic release of AVP. This stimulation of AVP release results in enhanced reabsorption of urea through urea transporters in the collecting duct. This may be the explanation why BUN was found to correlate with 60-days mortality more than either serum creatinine or with GFR.
The importance of preventing hypokalemia is due to the finding that the risks of dysrhythmias, syncope, cardiac arrest, or death are greater in with HF. This result due to the cells of hypertrophied and failing hearts often having prolonged action potential duration, which in most cases is caused by a decrease in outward K+ currents. Hypokalemia predisposes a patient to digoxin toxicity by reducing renal clearance and promoting myocardial binding of the drug. This, in turn, produces increased automaticity and ventricular arrhythmias. K+ depletion exacerbates diastolic dysfunction in animal and human models. In Severe hypokalemia less than (2 mEq/L) flaccid paralysis and hyporeflexia may result. Respiratory depression from severe impairment of skeletal muscle function is found in many patients. The most common mechanisms leading to hypokalemia in CHF are increased urinary losses due to increased Na delivery to the distal nephron, as with diuretics. Most patients with HF have increased ventricular ectopy, and 50% exhibit non sustained ventricular tachycardia. A total of 50% of deaths from HF are sudden, presumably due to arrhythmias.
In the setting of CHF, Mg depletion stems from:- Reduced dietary intake, altered distribution of the ion, and excessive loss from diuretics.serum electrolyte disorders, such as hypokalemia, hyponatremia, hypophosphatemia, hypocalcemia, and especially refractory K depletion in CHF patients should alert the clinician to the possibility of coexisting Mg depletion and the need for Mg therapy. Even though serum Mg concentration is valuable in the evaluation of the Mg status of CHF patients, it may not always provide a precise estimate of the Mg homeostasis in this population. Intracellular K and Mg have been reported to be low in CHF patients. Mg is critically important in maintaining normal cell function, and symptomatic Mg depletion is often associated with multiple biochemical abnormalities, including hypokalemia, hypocalcemia, and metabolic acidosis. The organ systems commonly affected by Mg deficiency are the cardiovascular and neuromuscular. The earliest manifestations are usually neuromuscular and neuropsychiatric hyper-excitability. The normal renal response to Mg depletion is to lower Mg excretion to very low levels. Thus, daily excretion of more than 1 mmol or a calculated FE of Mg above 3% in a subject with normal renal function indicates renal Mg wasting. Hypomagnesaemia increased incidence of sudden death among patients with CHF, even a minor decrease in arrythmiogenic deaths will lead to an important decrease of mortality.
Treatment of HF categorized as (i) haemodynamic, neuroendocrine and metabolic disorders (ii) symptoms and quality of life, (iii) morbidity and mortality risks. Selection of anti-HF drugs used should be based on knowledge of the impact on the pathophysiological disorders and on the morbidity and mortality risks. Diuretics, vasodilators and ACEI are now accepted as standard treatment, particularly when used in combination.
Once the serum osmolality and volume status of the patient is determined, treatment should be initiated to correct the serum sodium by 8 to 12 mEq/L within the first 24 hours. AVP antagonists represent a new class of drugs indicated to treat hypervolemic and euvolemic hyponatremia. Conivaptan is a nonselective AVP antagonist that is available intravenously, and tolvaptan is a V2 selective AVP antagonist that is available as an oral tablet. Both agents produce highly effective and safe aquaresis to increase serum Na levels.
Serum K+ levels have important therapeutic and prognostic implication for HF patients. Maintenance of normal K+ homeostasis has become an important limiting factor in the therapy of HF. With the application of loop diuretics and digoxin, hypokalemia has become afeared side effect of treatment. Low serum K+ in HF may be also a marker of increased neurohormonal activity and disease progression. To gain the maximum benefit from treatment, we need to individualize drug use and carefully monitor electrolytes. Symptomatic HF patients should be prescribed the lowest dose of diuretic necessary to maintain euvolemia. Aldosterone blockade is effective in reducing death from all causes in patients after myocardial infarction complicated by left ventricular dysfunction and HF. Some HF patients may remain hypokalemic despite therapy with aldosterone antagonists and should be treated with K+ supplements.
Suppression of ventricular arrhythmias does not necessarily improve survival, Mg supplementation seems to be superior to pharmacological antiarrhythmic interventions in that it is devoid of serious proarrhythmic effects. CHF patients on diuretics should be routinely supplemented with both K and Mg or should be more often given K/Mg sparing diuretics
By decreasing the elevated circulating levels of angiotensin II and aldosterone and thus reducing their adverse renal and metabolic effects in CHF, the ACEI favorably influence electrolyte balance and are often useful in correcting hyponatremia and hypokalemia. It is important to recall that hyperkalemia can occur during ACEI therapy in CHF patients with renal insufficiency or with the concomitant administration of K sparing diuretic and K supplementation. Diuretics, a heterogeneous class of drugs, are widely utilized in the treatment of CHF. They can induce adverse effects on electrolyte balance, although it is often difficult to separate their effects from those provoked by HF mechanisms themselves. In general, the commonly employed diuretics in CHF, namely thiazide and loop diuretics, inhibit the tubular reabsorption of Na, decrease exchangeable total body k and Mg, reduce intravascular (and extracelluIar) volume, further activate the RAAS, and stimulate the nonosmolar release of VP
K-sparing diuretics often are administered with loop and thiazide diuretics. These agents increase urinary Na excretion, but reduce k loss and thus can blunt, to varying extents, the kaliuretic action of loop and thiazide diuretic
Moreover, the adverse effects of RAAS, heightened by loop and thiazide diuretics, can be reduced somewhat by the concomitant administration of the K-sparing diuretics. K sparing diuretics tend to retain Mg. Amiloride and spironolactone increase tissue Mg and K concentrations in patients with CHF treated with furosemide.
Disturbed intake of electrolytes probably is important in patients with advanced CHF and in those receiving diuretics and various cardioactive drugs (e.g., digitalis, antiarrhythmic agents). It is not uncommon for some of these patients to present with an excessive (absolutely or relatively) intake of NaCL and a deficient intake of K and/or Mg.
Of course, restricting Na consumption and increasing K and Mg intake, when needed, are important interventions in the overall management of CHF.