Use of Diuretics in the Newborn




Abstract


Diuretics increase salt and water renal excretion. They do it by acting mainly on electrolyte and water transport across renal tubules. The sites of action of diuretics include the proximal tubule, the ascending limb of Henle loop, the distal tubule, and the collecting duct. The effects of diuretics vary according to their site of action, and their adverse effects are frequently extensions of their primary effects. Although diuretics may have specific indications, sodium retention states remain the primary target of diuretics. The rational use of diuretics in neonates requires a thorough knowledge of developmental renal physiology and physiopathology.




Keywords

newborn kidney, neonatal renal physiology and pathophysiology, natriuretic and aquaretic agents, site of actions of diuretics, adverse effects of diuretics

 





  • Body Fluid Homeostasis



  • Mechanisms and Sites of Action of Diuretics



  • Clinical Use of Diuretics



  • Adverse Effects of Diuretics





Introduction


Diuretics are pharmacologic agents that increase the excretion of water and electrolytes. They are primarily used in states of inappropriate salt and water retention. Such states can be the consequence of congestive heart failure (CHF), renal diseases, or liver disease. Diuretics are also used in various conditions not evidently associated with salt retention. Such conditions include oliguric states, respiratory disorders, electrolyte disorders, and nephrogenic diabetes insipidus. Diuretics can also be valuable tools in the laboratory differential diagnosis of congenital tubulopathies.


The rationale use of diuretics in newborn infants requires a clear understanding of the physiology and physiopathology of immature kidneys.




Body Fluid Homeostasis


The kidney is responsible for maintaining the extracellular fluid (ECF) volume and osmolality constant despite large variations in salt and water intake.


Extracellular Fluid Volume


NaCl, the major osmotically active solute in ECF, determines its volume. The overall balance between sodium intake and its urinary excretion thus regulates ECF volume and consequently cardiac output and blood pressure. Volume receptors are distributed in the low-pressure capacitance vessels (great veins and atria), as well as in the high-pressure resistance vessels (arterial vascular tree). Arterial sensors perceive the adequacy of blood flow in the arterial circuit, a parameter coined as effective arterial circulating volume. This volume is also monitored by baroreceptors located in the juxtaglomerular apparatus of the kidney. When sensed by these receptors, a decrease in renal perfusion pressure leads to the activation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone stimulates sodium reabsorption and potassium excretion. Although aldosterone is the main hormone regulating long-term changes in sodium excretion, other hormones and paracrine factors, including angiotensin II, the prostaglandins, dopamine, the catecholamines, and atrial natriuretic peptide (ANP), also modulate sodium renal handling. The release of the latter, a potent vasodilator and natriuretic agent, is modulated by sensors (the stretch receptors) that sense the atrial filling volume.


Plasma Osmolality


The plasma osmolality is maintained within narrow limits. Small (2%–3%) changes in plasma osmolality are sensed by osmoreceptors located in the hypothalamus, which by stimulating or inhibiting the release of vasopressin lead to increases or decreases in the excretion of free water. By acting on the baroreceptors, the effective circulating volume also influences the release of vasopressin. Dilution of urine depends on sodium delivery to the distal nephron diluting site; concentration of urine, modulated by vasopressin, requires the presence of a hypertonic renal medullary interstitium.




Clinical Use of Diuretics


Sodium-Retaining States


Sodium retention is the primary target of diuretics. Salt and water retention with or without edema formation can occur as a primary event or as a consequence of reduced effective circulating volume with secondary hyperaldosteronism. CHF is the main neonatal condition associated with sodium retention. The increased pressure in the venous circulation and capillaries favors the movement of fluid into the interstitium and leads to the formation of edema. Failure of the heart to provide normal tissue perfusion is sensed as a decrease in effective circulating volume by the kidney, which retains sodium and water. Treatment of the condition consists in restoring normal cardiac output. By mobilizing the edematous fluid, diuretics improve the symptoms of CHF. The pulmonary edema secondary to heart failure requires the urgent use of diuretics to reduce the life-threatening pulmonary congestion. The use of diuretics can be lifesaving when the ECF volume is expanded.


Diuretics may on the contrary further compromise the patient’s condition when sodium retention occurs in response to homeostatic mechanisms mobilized to defend the circulating volume. The same reasoning applies to states of nephrotic or liver cirrhosis edemas. The use of diuretics (loop diuretics, thiazides, and potassium-sparing diuretics) in these conditions requires a clear understanding of the patient’s underlying pathophysiologic condition and careful monitoring of the hemodynamic state.


Oliguric States


Loop diuretics are often administered to patients with oliguric renal insufficiency in the hope of promoting diuresis and improving renal perfusion and glomerular filtration rate (GFR). When present, the diuretic response may actually worsen the renal hypoperfusion.


Respiratory Disorders


Interstitial and alveolar edema is present in idiopathic respiratory distress syndrome (RDS) of preterm babies, as well as in transient tachypnea of term neonates. Inadequate fetal lung fluid clearance is partly responsible for the edema. Administration of diuretics (loop diuretics) could accelerate the reabsorption of lung fluid and pulmonary recovery in these patients with lung edema.


Central Nervous System Disorders


Large hemorrhages into the brain ventricles may result in fluid retention and dilatation of the fluid-producing brain cavities. Diuretics (acetazolamide, furosemide) are sometimes used to prevent or reduce the accumulation of fluid in the ventricles.


Electrolyte Disorders


Diuretics can be used in various situations associated with dyselectrolytemia. They can increase potassium excretion in hyperkalemic states (loop diuretics, thiazides), increase calcium excretion in hypercalcemia (loop diuretics), or decrease the rate of calcium excretion in hypercalciuric states (thiazides). Increased bicarbonate excretion can be achieved by acetazolamide, and increased excretion of hydrogen ions can be stimulated by loop diuretics.


Nephrogenic Diabetes Insipidus


Diuretics (thiazides) can paradoxically decrease urine output in nephrogenic diabetes insipidus.


Arterial Hypertension


Arterial hypertension may be a consequence of, or aggravated by, sodium retention and consecutive expansion of the ECF volume. This type of hypertension responds to diuretic-induced natriuresis.


Differential Diagnosis of Congenital Tubulopathies


Diuretics such as acetazolamide, furosemide, and hydrochlorothiazide can be used to test distal tubular acidification or distal sodium reabsorption defects in patients with congenital tubulopathies.




Classification of Diuretics According to the Site of Action


Diuretics can be classified according to their site and mode of action ( Fig. 15.1 and Table 15.1 ). They all increase sodium and water excretion and variably modify the excretion of other electrolytes ( Table 15.2 ). Filtration diuretics increase salt and water excretion by primarily increasing GFR. Osmotic diuretics depress salt and electrolyte reabsorption in the proximal tubule and in Henle loop. Carbonic anhydrase inhibitors act primarily on the proximal tubule. Loop diuretics, the most potent diuretics, inhibit Na + reabsorption in the ascending limb of Henle loop. The thiazide and thiazide-like diuretics act in the distal convoluted tubule and potassium-sparing diuretics in the late distal tubule and collecting duct. New diuretics with different modes of action ( vasopressin antagonists, adenosine antagonists, natriuretic peptides, etc.) are being developed and tested. All diuretics share adverse effects that are actually extensions of their primary effects on electrolyte excretion ( Table 15.3 ), as well as nonelectrolyte adverse effects ( Table 15.4 ).




Fig. 15.1


Sites 1 to 5: sites of sodium transport along the nephron. Numbers 1 to 5 represent the sites and mechanisms of Na + transport. The group of diuretics acting at the different sites is indicated. 1, Na/H exchanger 1 (NHE1). 2, Na-glucose cotransporter 2 (SLGT2). 3, Na-K-2Cl cotransporter (NKCC2) (furosemide receptor). 4, Na-Cl cotransporter (NCC) (thiazides receptor). 5, H + ,K + -ATPase and epithelial sodium channel (amiloride receptor): ENaC (potassium-sparing diuretics). The aquaretics act on the collecting duct vasopressin type 2 receptor (V 2 R). CAI, Carbonic anhydrase inhibitor; ENaC, sodium epithelium channel.


Table 15.1

CLINICAL USE OF DIURETICS IN NEONATES



























Filtration Diuretics



  • Oliguric prerenal failure

Osmotic Diuretics



  • Oliguric prerenal failure



  • Elevated intracranial pressure

Carbonic Anhydrase Inhibitors



  • Production of alkaline diuresis



  • Posthemorrhagic ventricular dilatation



  • Assessment of distal urinary acidification

Loop Diuretics



  • Edematous states (congestive heart failure, renal and liver diseases)



  • Respiratory disorders (transient tachypnea, respiratory distress syndrome, chronic lung disease in preterm neonates, compromised lung mechanics)



  • Prerenal failure (asphyxia)



  • Posthemorrhagic ventricular dilatation



  • Indomethacin-induced oliguria



  • Electrolyte disorders (hyperkalemia, hypercalcemia, severe hyponatremia)



  • Assessment of distal urinary acidification

Thiazides



  • Edematous states (congestive heart failure, renal and liver diseases)



  • Respiratory disorders (chronic lung diseases in preterm neonates)



  • Hypercalciuria



  • Proximal renal tubular acidosis



  • Nephrogenic diabetes insipidus



  • Diagnosis of renal tubular hypokalemic disorders

Potassium-Sparing Diuretics



  • Adjunctive therapy with loop or thiazide diuretics



  • Prevention of hypokalemia



  • Nephrogenic diabetes insipidus



  • Cystic fibrosis



Table 15.2

ACUTE EFFECTS OF DIURETICS ON ELECTROLYTE EXCRETION






















































Na + K + Ca 2+ Mg 2+ H + Cl HCO 3 H 2 PO 4
Carbonic anhydrase inhibitors ↑↑ = ~ (↑) ↑↑ ↑↑
Loop diuretics ↑↑ ↑↑ ↑↑ ↑↑ ↑↑
Thiazide diuretics ↑↑ ~ (↑)
K + -sparing diuretics (↑) =

In the absence of significant volume depletion, which would trigger complex adjustments.

(↑), Slight increase; ↑, moderate increase; ↑↑, marked increase; ↓, decrease; =, no change; ~, variable effects.


Table 15.3

ELECTROLYTE DISTURBANCES INDUCED BY DIURETICS COMMONLY USED IN NEONATES
































































Loop Thiazides K + -Sparing
Hypovolemia +++ + +
Hyponatremia ++ +++
Hypokalemia +++ ++
Hyperkalemia ++
Hypercalciuria ++
Hypercalcemia +
Hypomagnesemia + +
Hypophosphatemia + +
Hyperuricemia ++ ++
Metabolic acidosis +
Metabolic alkalosis ++ ++

Adapted from Chemtob S, Kaplan BS, Sherbotie JR, Aranda JV. Pharmacology of diuretics in the newborn. Pediatr Clin North Am . 1989;36:1231-1250.

+++ , Marked increase in electrolyte disturbances; ++, moderate increase in electrolyte disturbances; +, mild increase in electrolyte disturbances; − indicates no effects.



Table 15.4

GENERAL NONELECTROLYTE SIDE EFFECTS OF DIURETICS





























Diuretic Nonelectrolyte Side Effects
Carbonic anhydrase inhibitors CNS depression, paresthesia, calculus formation
Loop diuretics Ototoxicity (usually reversible), nephrocalcinosis in neonates, PDA in neonates, hyperuricemia, hyperglycemia, hyperlipidemia, hypersensitivity
Thiazides Hyperglycemia, insulin resistance, hyperlipidemia, hypersensitivity (fever, rash, purpura, anaphylaxis, interstitial nephritis), hyperuricemia
K + -sparing Amiloride Diarrhea, headache
Triamterene Glucose intolerance, interstitial nephritis, blood dyscrasias
Spironolactone Gynecomastia, hirsutism, peptic ulcers, ataxia, headache

CNS, Central nervous system; PDA, patent ductus arteriosus.


Although diuretics are very widely used in neonatal intensive care units (NICUs), the extent of and expectations for diuretic therapy by neonatologists caring for low birth weight neonates may, as stated in a recent survey, exceed evidence for efficacy ( Table 15.5 ). The dosages of diuretics commonly used in neonates are given in Table 15.6 .



Table 15.5

SPECIFIC INDICATIONS WITH QUESTIONABLE BENEFITS IN CLINICAL TRIALS




















































Condition Diuretic(s) Reference
Oliguric prerenal failure Mannitol
Furosemide
Better et al., Rigden et al.
Kellum, Dubourg et al.
Respiratory distress syndrome Furosemide Jain and Eaton
Transient tachypnea of the newborn Furosemide Wiswell et al., Kassab M.
Chronic lung disease Furosemide
Thiazides
Thiazides + spironolactone
Furosemide + thiazides
Furosemide + metolazone
Intratracheal furosemide
Brion and Primhak, Brion et al.
Brion et al.
Brion et al.
Brion et al.
Segar et al.
Aufricht et al.
Posthemorrhagic ventricular dilatation Furosemide + acetazolamide International PHVD Drug Trial Group, Kennedy et al., International PHVD Drug Trial Group, Whitelaw et al.
Indomethacin-induced oliguria Furosemide
Dopamine
Eades and Christensen, Brion et al., Andriessen et al., Lee et al.
Barrington and Brion
Furosemide-induced nephrocalcinosis Thiazides Campfield et al.
Nephrocalcinosis secondary to the use of vitamin D in hypophosphatemic rickets Thiazides Seikaly and Baum
Compromised lung mechanics after cardiac surgery Intratracheal furosemide Aufricht et al.
Cystic fibrosis Aerolized amiloride Pons et al., Ratjen and Bush
Asthma Intratracheal furosemide Aufricht et al.

PHVD, Posthemorrhagic ventricular dilatation.


Table 15.6

DOSAGES OF DIURETICS COMMONLY USED IN NEONATES












































































Drug Route/Interval (qh) Dosage (mg/kg/day) Half-Life (h) Comments
Furosemide PO: 12–24
IV: 12–24
CIVI
1–2
0.5–1.5
100–200 µg/kg/h
≈1.5
idem
Effective at GFR <10
Doses may be increased up to 5 mg/kg in CRF
Hypokalemia; Mg, Ca depletion
Ototoxicity; metabolic alkalosis
Torasemide PO 0.5–1 ≈3.5 Longer half-life and larger duration than furosemide
Effective at GFR <10
Idem furosemide
Ethacrynic acid PO: 12–24 1–2 ≈1 Effective at GFR <10
Idem furosemide
Bumetanide PO: 12–24
IV: 12–24
CIVI
0.01–0.10
0.01–0.05
5–10 µg/kg/h
≈1
idem
Effective at GFR <10
Idem furosemide
Hydrochlorothiazide PO: 12–24 1–3 ≈2.5 Not effective at GFR <20
Hypokalemia metabolic alkalosis
Chlorthalidone PO: 24–48 0.5–2.0 45 Not effective at GFR <20
Hypokalemia metabolic alkalosis
Metolazone PO: 12–24 0.2–0.4 8–10 Effective at GFR <20
Hypokalemia
Spironolactone PO: 6–12 1–3 ≈1.6 Delayed effect. Cave CRF or K suppl.
Hyperkalemia, acidosis
Canrenoate-K IV: 24 4–10 ≈16 Single IV dose
Hyperkalemia, acidosis
Triamterene PO: 12–24 2–4 ≈4.2 Cave RF or K suppl.
Hyperkalemia, acidosis
Amiloride PO: 24 0.5 ≈21 Cave RF or K suppl.
Hyperkalemia, acidosis

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Apr 4, 2019 | Posted by in NEPHROLOGY | Comments Off on Use of Diuretics in the Newborn

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