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Pathophysiological course and vicious cycle of HF until clinical congestion,including renal dysfunction by cardio-renal interaction,subdivided in phases of preclinical medical interventions and hospitalization, suggesting a window for earlier intervention on hemodynamic congestion

The vicious cycle of HF progression with mutual involvement of left and right

sides of the heart and the kidney : key role of congestion

Potential factors contributing to the

development of congestion in acute heart failure.

LVEDP left ventricular end-diastolic

pressure, PCWP pulmonary capillary wedge pressure

Congestion in heart failure

Nephron parts and functions.

Renal handling of sodium and water

DCT diuretic

Diuretic therapy.

(1) Acetazolamide functions in the proximal tubule by blocking carbonic anhydrase and increasing NaHCO3 excretion. (2) Mannitol functions in both the proximal tubule and the loop of Henle by increasing H2O excretion. (3) Loop diuretics function in thick ascending limb of the loop of Henle by blocking the sodium–chloride–potassium cotransporter and increasing sodium, potassium, and chloride excretion. (4) Thiazide functions in the distal convoluted tubule by blocking the sodium–chloride transporter and increasing sodium chloride excretion. (5) Mineralocorticoid-receptor antagonists function in the collecting duct of the distal tubule and antagonize the aldosterone receptor, hence increasing sodium excretion and potassium retention.

Diuretics: A Friend or a Necessary Evil?

The use of loop diuretics is essential in the management of HF, particularly during episodes of acute decompensation, therefore more than 90% of patients admitted with HF receive this drug. The administration of intravenous loop diuretics to patients with heart failure and congestion typically results in the improvement of dyspnea, pulmonary congestion and in the reduction of Left Ventricular (LV) filling pressures. Several side effects may result from the administration of high diuretics dose, including worsening kidney function, diuretic resistance and sympathetic overdrive.

Do diuretics do more harm than good?

SNS+

Effects of renin-angiotensin-aldosterone and sympathetic overdrive in different kidney sites

RAAS Activation During Decongestion in Acute HFFriend or Foe?

Adverse effects of major diuretics

Symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction

Patients with heart failure with preserved ejection fraction and heart failure with mid-range ejection fraction

Hypertension in patients with symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction

Patients with acute heart failure

Renal replacement therapy in patients with acute heart failure

Ultrafiltration involves the removal of plasma water across a semipermeable membrane in response to a transmembrane pressure gradient. There is no evidence favouring ultrafiltration over loop diuretics as first-line therapy in patients with AHF. At the present time, routine use of ultrafiltration is not recommended and should be confined to patients who fail to respond to diuretic based strategies

No single accepted definition of diuretic resistance has been described.

Of the several definitions proposed, the most frequently cited is “failure to decongest despite adequate and escalating doses of diuretics”

DIURETIC RESISTANCE

Why Diuretics Fail Failing Hearts.

Persistent congestion despite adequate and

escalating doses of diuretic with >80 mg

furosemide per day

Amount of sodium excreted as a percentage

of filtered load <0.2%

Failure to excrete at least 90 mmol of sodium

within 72 h of a 160 mg oral furosemide dose

given twice daily

Less clinically applicable definitions that include variables not routinely obtained by clinicians have also

been suggested

Metrics of diuretic response

Weight loss per unit of 40 mg furosemide (or equivalent)

Net fluid loss per milligram of loop diuretic (40 mg of furosemide or equivalent) during hospitalization

Natriuretic response to furosemide as the ratio of urinary sodium to urinary furosemide

Unresponsiveness to diuretic therapy leading to persistent signs and symptoms of congestion is usually

considered diuretic resistance.

During diuretic-induced extracellular volume depletion, short-term and long-term adaptive processes serve to protect the intravascular volume

There are two forms of diuretic tolerance: (1) Short-term tolerance occurs when the diuretic effect is attenuated after the

first dose has been administered; this can be prevented by restoring diuretic-induced loss of volume. (2) Long-term

tolerance is observed after prolonged administration of a loop diuretic, which leads to avid sodium reabsorption at more

distal sites. This phenomenon argues for the use of sequential nephron blockade with combinations of loop and

thiazide diuretics in patients who do not have adequate responses to optimal doses of a loop diuretic.

Pathophysiology and mechanisms of loop diuretic resistance

Organic anion transporter

Sodium delivery into tubular fluid is determined by GFR

Non-adherence to diuretics

Non-adherence to low sodium diet

Dose to low or too infrequent

Use of NSAIDs

Don’t Forget to Check for:

The Truth About Water Pills

Sequential nephron blockade

Combination Diuretic Therapy(CDT)

CDT

Combination Diuretic Therapy produces true synergism, the

combination of agents is more effective than the sum of the

responses to each agent alone.

Distal convuluted tubule (DCT) diuretics are the class of drug

most commonly combined with loop diuretics.

The distal convuluted tubule (DCT) diuretic is administered 1

hour before the morning dose of the loop diuretic to ensure

that NaCl transport in the distal nephron is blocked when it is

flooded with solute.

Metolazone is the distal convuluted tubule (DCT) diuretic most

commonly combined with loop diuretics, because its half-life is

relatively long and it has been reported to be effective when renal

failure is present. Other thiazide and thiazide-like diuretics

appear to equally effective, even in severe renal failure.

Important Considerations Regarding Combination Diuretic Therapy(CDT)

JACC Vol. 56, No. 19, 2010

Potential Benefits and Adverse Effects of combination diuretic therapy (CDT)

Stepped pharmacological care; treatment algorithm for patients with heart failure (HF) and volume overload. At each decision, clinical assessment should include an assessment of symptoms, volume assessment, and appropriate monitoring of vital signs, electrolytes, and creatinine. Daily weights are more easily and accurately assessed than urine output. *Assumes: (1) volume assessment with each step; (2) monitoring of electrolytes, renal function, symptoms, and vital signs; (3) daily weights; and (4) urine output not often accurate or obtainable. y Titrate progressively, according to the degree of hypervolemia, furosemide doses, and creatinine/kidney function. I.V., intravenous.

Outpatient diuretic management algorithm for patients with heart failure. At each decision, clinical assessment should include an assessment of symptoms, volume assessment, and appropriate monitoring of vital signs, electrolytes, and creatinine. Daily weights are more easily and accurately assessed than urine output. Reassess serum potassium and creatinine 3-5 days after each diuretic dose change, earlier if concerned, other medication changes, or significant volume changes. Lowest dose of a diuretic that allows for optimal symptoms is the ideal dose. Dose reductions or increases should take into account previous response if known, and clinical scenario.

Furosemide urinary response tests tubular integrity. TAL, thick ascending limb.

The effects of diuretic agents depend on the delivery of loop diuretics to their intraluminal site of action (pharmacokinetics) and on the dynamics of interaction of the diuretic with its receptor at the site of action (pharmacodynamics).

Patients with heart failure require a higher serum diuretic concentration to elicit the same diuretic response (diuretic resistance) and have diminished responses to ceiling doses of loop diuretics. Providers should attempt to achieve a diuretic concentration that is on the steep part of the dose-response sigmoidal relationship.

Higher doses required to achieve same diuretic effect

Patients with heart failure typically demonstrate a rightward and downward shift of the sigmoid dose–response curve

If resistance to furosemide results or other factors (eg, a high salt meal) dictate that more diuresis is needed, 1 of 2 strategies may be used: First is to administer a higher dosage, as shown with the red pharmacodynamic curve. The increase in dosage increases the urine level of the diuretic but provides only a small increase in time in the effective range, enhancing diuresis (red arrow) but increasing risk for toxicity. A better approach, although problematic in terms of owner compliance, is to administer multiple doses throughout the day. As shown in this figure, administering the same dosage 3 times triples the time in the effective range and avoids the risk for toxicity.

Standardized IV Diuretic Administration Protocol : Patients were assigned to 1 of 4 protocol groups based on their total daily dose of home oral diuretic (maintenance dose).

JACC VOL. 69, NO. 19, 2017

Comparative Characteristics of Loop Diuretic Agents and Isolated ultrafiltration(UF)