Volume overload and congestion are the cardinal features of most patients with acute heart failure. Controlling fluid retention and reducing volume overload are important measures to relieve symptoms of heart failure, reduce rehospitalization rate, and improve quality of life, and are one of the cornerstones in the treatment of congestive heart failure. However, improper application of diuretics may also lead to hypovolemia and increase the risk of hypotension. So, how to rationally apply diuretics and drugs with diuretic effect. Some time ago, at the 33rd Great Wall Cardiology Conference (GW-ICC 2022), Professor Zhang Yao from The Second Affiliated Hospital of Harbin Medical University gave a detailed explanation. Some key points are now sorted out for readers.
The dangers of volume overload and congestion?
Capacity Overload and congestion can lead to abnormal physiological functions of multiple organs:➤Pulmonary congestion causes gas exchange dysfunction and is prone to secondary lung infection;➤Myocardial congestion can lead to myocardial ischemia and decreased contractility;➤Kidney congestion can lead to decreased glomerular filtration rate and renal insufficiency; ➤Intestinal congestion can lead to digestive dysfunction and intestinal flora disturbance; ➤Hepatic congestion can lead to liver Abnormal function.
< p>Assessment of volume status and congestion in heart failure1. Non-invasive testing evaluation
The diagnostic accuracy, sensitivity, and specificity of noninvasive assessment parameters are shown in Table 1. On physical examination, the jugular venous pulse (JVP) is the most useful sign to determine volume status.
Table 1 Sensitivity and specificity of different congestion assessment parameters
2. Invasive inspection parameters
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➤floating conduit : Direct measurement of right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) by cardiac catheterization is the gold standard for diagnosis and evaluation of heart failure congestion, but Invasiveness limits its routine application in clinic. •Hypotension with PCWP<14 mmHg, after proper rehydration, if blood pressure rises, urine output increases, and there is no moist rale in the lungs or the moist rale is not aggravated, it indicates the presence of Insufficient capacity. •Hypotension with significantly lower cardiac output index, pulmonary capillary wedge pressure>18 mmHg, suggesting pulmonary congestion. ➤Central venous pressure (normal range 5-12 cmH₂O): Monitoring central venous pressure through central venous catheter can reflect Right ventricular preload. Its operation is simple, but it is easily affected by many factors such as left ventricular function, heart rate, and cardiac compliance. The change trend of central venous pressure should be observed dynamically, and it cannot be judged based on a single measurement. ➤Pulse-Indicated Continuous Cardiac Output Monitoring (PiCCO): an available The monitoring method of continuous and real-time monitoring of hemodynamics at the bedside can measure indicators reflecting cardiac preload and pulmonary edema. Effect of changes in intra-abdominal pressure, but not a substitute for floating catheter examination.
< p>What are volume management goals in patients with acutely decompensated heart failure? < span>Treatment goals for acutely decompensated patients with congestion and volume overload include:➤Although it is difficult to determine when to stop treatment, it is recommended Realize thorough decongestion treatment to ensure that there is no residual volume overload;➤At the same time, ensure sufficient perfusion pressure of the body to maintain normal organ perfusion;➤Maintain guideline-directed drug therapy, as these drugs may increase diuretic response while improving long-term survival. It is worth noting that whether in patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), decompensation is clinically All had similar symptoms of congestion. Therefore, the treatment options for these types of heart failure patients to relieve congestion are similar.
< p>What do Chinese guidelines say about diuretic therapy for acute heart failure? 《 Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2018 recommends that all patients with acute heart failure with evidence of fluid retention should be treated with diuretics (Ⅰ, B).
“Guidelines for the Emergency Management of Acute Heart Failure in China (2022)” states:➤In patients with acute heart failure with evidence of volume overload, intravenous diuretics should be used as initial treatment (Ⅰ, A);➤In patients with acute heart failure with organ hypoperfusion, diuretics should be avoided until adequate perfusion is achieved (III, C);➤Loop diuretics as First-line drugs for the treatment of acute heart failure (Ⅰ, B); The first dose of diuretics can be doubled (Ⅱa, B); ➤Avoid excessive diuresis, otherwise it may cause hypovolemia, acute kidney injury (AKI) and electrolyte disturbance, such as low Potassium, etc. (Ⅲ, C); ➤Evaluate diuretic response early and identify diuretic resistance (Ⅰ, B);➤ Vasopressin receptor antagonists are suitable for patients with acute heart failure and hyponatremia (Ⅱa, B).
Figure 1 Patients with acute heart failure Diuretic use flowchart What are diuretics and drugs that have a diuretic effect?
< span>1. Loop diuretic
➤Acute heart failure diuretic treatment It is widely used in more than 90% of heart failure patients. ➤It can inhibit the Na⁺-K⁺-2Cl⁻ cotransporter in the ascending branch of the loop of Henle, promote the excretion of sodium and chloride, and the potassium excretion effect is smaller than that of thiazide diuretics . ➤The protein binding rate is higher (>90%), needs to be secreted into the proximal tubule by several organic anion transporters, and requires adequate dose and plasma concentration. ➤Reduced plasma protein can also lead to decreased secretion of loop diuretics. ➤In view of the edema of the gastrointestinal mucosa in congestive heart failure, which may lead to reduced absorption of oral diuretics (especially furosemide), the guidelines recommend that patients with acute heart failure use Intravenous loop diuretics. ➤Determining an individual upper diuretic dose in patients with heart failure is often difficult and is influenced by many factors, including previous loop diuretic therapy, body composition, degree of volume overload and renal function status. ➤Intravenous injection of 400-600 mg furosemide and 10-15 mg bumetanide is usually the maximum total daily dose beyond which natriuretic effect occurs The increase is limited, but side effects will continue to increase. ➤Intravenous loop diuretics should be administered as early as possible to reduce in-hospital mortality in patients with heart failure.
Table 2 Pharmacological effects of loop diuretics
loop Pharmacological effects of diuretics |
Action site | Ascending branch of Henle of Henle < /td> |
Initial dose/long-term recommended dose | Furosemide: 20-40/40-240 mg Bumetanide: 0.5- 1.0/1-5 mg Torasemide: 5-10/10-20 mg |
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Maximum recommended total daily dose | Furosemide: 400-600 mg Bumetanide: 10-15 mg < span>torasemide: 200-300 mg | half-life | Furosemide: 1.5-3.0h Bumetanide: 1-1.5h Torasemide: 3-6h |
effective | PO: 0.5-1h IV: 5-10 min SC: 0.5h |
Oral bioavailability | Furosemide: 10%-100% Bumetanide: 80%-100% Torasemide: 80%-100% |
Effect of food on gastrointestinal absorption | Furosemide: Yes (delay) Bumetanide: Yes (delay) Torasemide: No |
Efficacy (FE Na%) | < span>20%-25% |
2. Thiazide diuretics
➤In theory, thiazide diuretics can partially overcome the decreased affinity of distal tubules for sodium caused by long-term loop diuretic use. ➤There are large regional differences in the use of thiazide-like diuretics. Distal convoluted tubular sodium-chloride cotransporter (NCC) blocking effects of different drugs are similar, but the half-life and diuretic effect are different. ➤Due to the slow absorption of metolazone and chlorthalidone from the gastrointestinal tract (peak time is about 8 hours), and the long half-life, they should be injected with loop diuresis after intravenous injection Oral low-dose thiazide-like diuretics several hours before the dose. ➤Chlorthiazide has a short half-life, so you can take chlorothiazide orally while giving loop diuretics. ➤In healthy people, the maximum diuretic effect of thiazide diuretics is limited, and the maximum diuretic response of monotherapy is 30%-40% of that of loop diuretics. ➤Thiazide diuretics are also bound to plasma proteins and thus require adequate renal blood flow distribution into the renal tubules. ➤Thiazide diuretics may cause significant hypokalemia, and this potassium-losing effect is especially pronounced in hyperaldosterone states (such as heart failure). ➤Thiazide diuretics reduce glomerular filtration rate (GFR<30mL/min) is still effective in heart failure patients. ➤ Considering the relative safety of high-dose loop diuretics in the DOSE-AHF trial, initial intensified loop diuretics may be prioritized before adding thiazide diuretics dosage of the agent. However, the CARRESS-HF trial showed that loop diuretics combined with thiazide diuretics are effective in stepwise drug therapy, so current guidelines recommend thiazide diuretics as second-line therapy.
Table 3 Pharmacological effects of thiazide diuretics
Thiazide diuretics Pharmacological action of the agent |
Action site | Proximal distal convoluted tubule < /td> |
Initial dose/long-term recommended dose | HCTZ: 25/12.5-100 mg Metolazone: 2.5/2.5-10 mg Chlorthalidone: 25/25-200 mg Chlorthalidone: 500-1000 mg (IV) Chlorthalidone: 500-1000 mg (IV) span> |
Maximum recommended total daily dose < /td> | HCTZ: 200 mg Metolazone: 20 mg Chlorthalidone: 100 mg Chlorthiazide: 1000 mg | < /tr>
half-life | HCTZ: 6-15 h Methorazone: 6-20 m g Chlorthalidone: 45-60 mg |
Onset | PO: 1-2.5h IV: Chlorthiazide intravenously available, onset time 30 minutes |
Oral bioavailability | HCTZ: 65%-75% Metolazone: 60%-65% Chlorthalidone: Unknown Chlorthiazide: 9%-56% |
Effect of food on gastrointestinal absorption | HCTZ: Unknown Metolazone: Unknown Chlorthalidone: Unknown |
Efficacy (FE Na%) | 5%-8% |
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3. Mineralocorticoid receptor antagonist (MRA)
➤MRA has pleiotropic effects, and its renal effects include modulating the expression and activity of distal tubular sodium and potassium channels. ➤MRA is recommended in symptomatic patients with chronic HFrEF to counteract aldosterone escape caused by neurohormonal hyperactivation (Grade I). ➤High-dose MRA therapy is safe and does not cause hyperkalemia or worsening renal function, in addition, MRA therapy may help counteract loop diuretics and thiazide Hypokalemia due to diuretics due to excretion of potassium. ➤Early start of regular dose (25 mg) of MRA may help reduce diuretic-related hypokalemia and promote optimization of heart failure treatment, thereby improving HFrEF Patient’s prognosis. ➤In case of emergency, MRA needs to be applied individually, and it should be temporarily stopped when combined with hyperkalemia. ➤Current data indicate that MRA is significantly underutilized in HFrEF.
Table 4 Pharmacological effects of mineralocorticoid receptor antagonists
mineral cortex Pharmacological effects of hormone receptor antagonists |
Site of action | Distal end of the distal convoluted renal tubule |
Initial dose/recommended long-term dose | Spironolactone: 25/25-50 mg Eplerenone: 25/25-50 mg canrenoic acid Potassium: 25 -200 mg/not recommended for long-term use |
Maximum Recommended total daily dose | 50-100 mg (up to 400 mg for liver disease) |
half-life | Canrenone: 16.5 h Eplerenone: 3-6 h< /p> |
effective | PO: 48-72h IV: Potassium canrenoate 2.5h |
Oral bioavailability | Spironolactone: ~90% Eplerenone: 69% |
Effect of food on gastrointestinal absorption | Spironolactone: High-fat diet increases bioavailability Eplerenone: Unknown span> |
Efficacy (FE Na%) | 2% |
4. Acetazolamide
➤Carbonic anhydrase inhibitors inhibit carbonic anhydrase in renal tubular epithelial cells, reduce the formation of H₂CO₃, and the production of H⁺ decreases accordingly. Therefore, the exchange of H⁺ and Na⁺ is greatly slowed down, the excretion of HCO3⁻, Na⁺, and K⁺ increases, and the urine output increases. ➤From a pathophysiological perspective, targeted inhibition of proximal tubular sodium reabsorption has several potential benefits in the treatment of heart failure:①Most sodium is reabsorbed in the proximal tubule, especially in patients with decompensated heart failure. ② Delivery of more chloride to the macula densa inhibits renin secretion and reduces neurohumoral activation. ③ Endogenous natriuretic peptide (acting on the distal renal tubule) may restore its effect. ➤ADVOR multicenter, randomized controlled trial showed that acetazolamide combined with loop diuretics can reduce congestion and enhance diuretic effect in decompensated heart failure. ➤ Studies have shown that the combination of acetazolamide can enhance the diuretic effect of loop diuretics.
Table 5 Pharmacological effects of acetazolamide
Acetyl Pharmacological effects of oxazolamide |
Action site | Proximal renal tubule < /td> |
Initial dose/long-term recommended dose | Oral: 250-375 mg Intravenous: 500 mg < /td> |
Maximum recommended total daily dose | Oral: 500 mg 3x/day Intravenous: 500 mg 3x/day |
Half-life | 2.4-5.4h |
| < p>Take effect | PO: 1h < p>IV: 15-60 min |
Oral bioavailability | Dose-dependent, variable absorption when dose > 10 mg/kg | < /tr>
Effect of food on gastrointestinal absorption | It can be eaten with food, food can reduce GI symptoms |
Efficacy (FE Na%) | 2%< /p> |
5. Ami Loli
➤Amiloride inhibits distal renal tubular epithelium Sodium channel (ENAC), thereby reducing filling pressure, thereby relieving congestion. ➤ENAC is associated with volume overload mediated by oral thiazolidinediones in diabetic patients, which can be inhibited by amiloride.
Table 6 Pharmacological effects of amiloride
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Amilori’s Pharmacological effects |
Action site | Distal tube of distal convoluted renal tubule < /td> |
Initial dose/long-term recommended dose | 5/10 mg |
Maximum recommended total daily dose | 20 mg |
Half-life | GFR normal: 6-9h; GFR<50 ml/min: 21-144h GFR<50 ml/min: 21-144h span> |
effective | PO: 2h IV: No IV < /td> |
| < p>Oral bioavailability | 30%-90%< /p> |
Effect of food on gastrointestinal absorption < /td> | Unknown |
Efficacy (FE Na%) | 2% |
6. Vasopressin receptor antagonist (tolvaptan)
➤Tolvaptan, a selective V2 vasopressin receptor antagonist, can block the reabsorption of free water in the distal tubule, and combined with loop diuretics can improve filling pressure. ➤Tolvaptan may be a better choice for patients with hyponatremia and renal insufficiency. ➤TACTICS randomized controlled trial showed that tolvaptan can significantly reduce the weight of patients compared with placebo. The EVEREST outcome trial showed that although compared with placebo, tolvaptan did not improve the incidence of cardiovascular death, cardiovascular death or hospitalization, and the incidence of heart failure worsening in patients. However, tolvaptan significantly improved secondary endpoints, body weight and symptoms (dyspnea, edema), significantly increased serum sodium levels in patients with hyponatremia, and its effects on body weight and serum sodium persisted long after discharge. 7. Recombinant human brain natriuretic peptide (rhBNP)
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➤rhBNP reduces adverse effects of loop diuretics. ➤ Studies have shown that the nesiritide/furosemide combination and furosemide alone resulted in similar Na⁺ and water excretion, but furosemide alone resulted in plasma Aldosterone rises rapidly. The combination of nesiritide and furosemide blocks this neurohormonal response. Brain natriuretic peptide combined with diuretics has a better diuretic effect in patients with heart failure resistant to diuretics.
< p>Adverse effects of unreasonable use of diuretics➤The appropriate early dose of diuretics is the minimum dose that can effectively reduce volume load;➤use Unreasonable Adverse Effects:•If the amount of diuretics is insufficient, it will reduce the response to ACEI and increase the risk of using β-blockers;• Inappropriate large doses of diuretics can lead to hypovolemia and increase the risk of hypotension, renal function deterioration, and electrolyte disturbance.
➤Diuretic use and electrolyte abnormalities
Frequent primary effects during acute heart failure due to neuroendocrine activation due to diuretic use, renal dysfunction, or iatrogenic electrolyte disturbances Sodium and potassium metabolism. •Hyponatremia: plasma sodium concentration <135 mEq/L (the main abnormality of sodium homeostasis in acute heart failure). ✎The pathophysiology of hyponatremia: ① Unable to excrete free water (diluted hyponatremia) ,②Due to sodium depletion (exhausted hyponatremia),③A combination of the above two. •Hypokalemia (plasma K<3.5 mEq/L) usually occurs in acute heart failure secondary to diuretic-induced diuresis and potassium depletion. ✎In clinical practice, the use of loop diuretics is the most common cause of hypokalemia. ✎Treatment: Add upfront MRA therapy, add RAAS blockade, and potassium supplementation during decongestion. ✎In addition to potassium depletion, diuretic use often results in magnesium depletion or refractory hypokalemia. Although not supported by strong experimental evidence, appropriate magnesium supplementation may be considered during diuretic therapy.
➤Diuretics are the cornerstone of acute heart failure treatment;➤Rational use of diuretics is the key to successful heart failure drug therapy and foundation;➤ Fully understanding the mechanism of action of diuretics and guideline recommendations is conducive to more effectively improving the volume load of acute heart failure; < section>➤During the use of diuretics, pay attention to the adverse effects such as electrolyte disturbance and renal function damage, and adjust the medication strategy in time;
➤On the basis of diuretics, also Other drugs or device-related heart failure treatment under the guidance of guidelines should be fully carried out.