Diuretics and the kidney

Learning objectives.

By reading this article, you should be able to:

• •Recall the basic anatomy and physiology of the nephron.
• •Explain the mechanism of action of commonly used diuretic agents.
• •Discuss the relationship between diuretic therapy and renal function.
• •Know when to consider initiation of diuretic therapy for patients in intensive care.

Key points.

• •Diuretics work in various ways, often interacting with different ion transport systems throughout the nephron to influence renal tubular sodium and water reabsorption.
• •Diuretic resistance in heart failure or chronic kidney disease may result in larger doses of diuretic drugs being needed to achieve the same effect.
• •Acute kidney injury is not a contraindication to the use of diuretics.
• •Fluid overload causes harm.
• •Diuretics can be beneficial for critically ill patients who have excess extracellular fluid.

The main function of the kidney is to preserve homeostasis by regulating fluid and electrolyte balance, filtering and eliminating waste products, and controlling acid-base status. In addition, the kidneys are responsible for the formation or production of several hormones, including erythropoietin; the control and regulation of blood pressure via the renin–angiotensin–aldosterone system (RAAS); and they play a key role in calcium homeostasis.¹

Diuretic agents increase the excretion of water and electrolytes and are prescribed for a wide range of pathologies, diseases and clinical conditions, including fluid overload, hypertension and glaucoma. They exert their effects in various ways, often by affecting ion transport systems throughout the nephron. In this review, we summarise relevant renal physiology with respect to the pharmacological actions of diuretic agents and describe commonly encountered situations relating to the use of these agents in the perioperative setting and in the ICU.

Renal anatomy and physiology

The glomerulus and formation of ultrafiltrate

The average kidney contains between 800,000 and 1,000,000 nephrons, with each nephron supplied with blood by an afferent arteriole (Fig. 1). The afferent arteriole forms a glomerulus, which is a bundle of capillaries situated within the Bowman's capsule. The glomerulus acts as the filtering unit of the kidney. Under normal conditions, in healthy individuals the kidneys can generate a glomerular filtration rate (GFR) up to 125 ml min⁻¹ of ultrafiltrate into the Bowman's capsule.¹

Fig 1.

Sites of action of diuretics along the nephron. ADH, Antidiuretic hormone; PTH, parathyroid hormone. From Barratt and Bell,¹ with permission from Elsevier.

The formed ultrafiltrate passes through the fenestrated endothelium of glomerular capillaries, the glomerular basement membrane and visceral epithelial cells (podocytes).² These layers act as a semipermeable membrane allowing the passage of fluid, solutes and proteins of <70 kDa, whereas the negatively charged glycocalyx limits the filtration of negatively charged proteins such as albumin. Starling forces are responsible for the formation of the ultrafiltrate and movement of water across the glomerular capillaries. The final ultrafiltrate consists of fluid with a similar composition of small molecules and ions to that within the afferent arteriole.²

Proximal convoluted tubule and reabsorption

Up to 70% of the ultrafiltrate is reabsorbed in the proximal convoluted tubule (PCT), which is the site of numerous adenosine triphosphate (ATP)-driven processes. The Na⁺/K⁺-ATPase pump within the basolateral proximal tubule epithelial cells is responsible for the reabsorption of sodium ions (Na⁺) and water. Other solutes, including amino acids, bicarbonate (HCO₃^–), organic cations, anions, glucose and phosphate (PO₄^3–) are, to a degree, reabsorbed in the PCT through ATP-dependent processes.

Loop of Henle and further concentration of the ultrafiltrate

Solute and water reabsorption continues in the loop of Henle, which is responsible for further concentrating the urine through its counter-current multiplier system. Up to 20–25% of filtered solutes and water are reabsorbed here through the thin descending, thin ascending and the thick ascending limbs of the loop.¹ Upon entering the loop of Henle, the filtrate has an osmolarity of 300 mOsm L⁻¹. As the filtrate passes through the loop of Henle, water diffuses down a concentration gradient out of the filtrate, into the interstitial fluid through aquaporin (AQP-1) channels, increasing the osmolarity of the filtrate to approximately 1200 mOsm L⁻¹ once it reaches the inner medulla. The thin ascending limb of the loop of Henle is only permeable to solutes and not to water. Solute reabsorption in the thin ascending loop of Henle consequently leads to a reduction in the osmolarity of the filtrate before it reaches the thick ascending loop of Henle. The Na⁺/K⁺/2Cl^– cotransporter and Na⁺/K⁺ ATPase transporter present in the thick ascending loop are responsible for the reabsorption of Na⁺, potassium ions (K⁺) and chloride ions (Cl^–).¹

Distal convoluted tubule; further reabsorption and excretion

The distal convoluted tubule (DCT) is situated distal to the macula densa and is primarily responsible for fine tuning of ion homeostasis (Na⁺, K⁺, HCO₃^– and calcium ions [Ca²⁺]). Around 5–10% of the filtered Na⁺ is reabsorbed in the DCT, predominantly via the thiazide-sensitive Na⁺/Cl^– symporter, which reabsorbs Na⁺ and Cl^– ions from tubular fluid.³ Aldosterone, produced in the adrenal cortex in response to low tubular flow at the macula densa, has some effect on Na⁺ reabsorption in the DCT (in exchange for K⁺).

Collecting duct; fine tuning

The collecting duct (CD) contains both principal cells and intercalated cells, which are responsible for further concentration of the urine before it passes to the renal calyx. Principal cells contain epithelial Na⁺ channels (ENaC), which mediate Na⁺ entry into cells and increase the driving force for K^+– secretion.⁴ Principal cells also contain AQP-2 channels through which water reabsorption occurs under the influence of antidiuretic hormone (ADH, or vasopressin).

Diuretic agents

Diuretics are prescribed for a wide range of clinical situations with the aim of increasing water and electrolyte excretion. Sixteen individual diuretics are listed in the British National Formulary, with various mechanisms of action (Table 1). Most of these agents influence renal tubular Na⁺ reabsorption, which reduces the osmotic gradient, thereby reducing water reabsorption in the nephron. As different diuretic agents exploit various specific ion transport systems and the degree of Na⁺ reabsorption varies throughout the nephron, the indications, pharmacodynamics and diuretic efficacy are specific to each class of diuretic.

Table 1.

Classification and characteristics of diuretics.

Drug	Mechanism of action	Site of action	Indications	Dose	Electrolyte abnormalities
Loop diuretics (e.g. furosemide, bumetanide)	Inhibit Na+/K+/2Cl– symport (NKCC2)	Thick ascending loop of Henle	Oedematous disorders (e.g. heart failure, nephrotic syndrome, ascites), hypertension, hypercalcaemia	Furosemide: 0.1–1 mg kg−1 i.v. or 0.75–3 mg kg−1 p.o. Bumetanide: 0.5–3 mg i.v. or p.o. 1–5 mg)	Hypokalaemia, hypernatraemia, Hypocalcaemia Metabolic alkalosis
Thiazide diuretics (e.g. bendroflumethiazide, indapamide)	Inhibit Na+/2Cl– symport	Distal convoluted tubule	Hypertension, hypercalciuria, nephrogenic diabetes insipidus	Bendroflumethiazide: 2.5–10 mg p.o. o.d. Indapamide: 2.5 mg p.o. o.d.	Hyponatraemia
					Hypokalaemia
					Hypomagnesaemia
					Hypochloraemic metabolic alkalosis
					Hyperuricaemia
					Hyperglycaemia
Potassium-sparing diuretics (aldosterone antagonists, e.g. spironolactone)	Aldosterone antagonists	Collecting duct	Primary or secondary hyperaldosteronism, resistant hypertension	Spironolactone: 25–200 mg day−1 p.o. in divided doses	Hyponatraemia
					Hyperkalaemia
Pteridine derivatives (e.g. amiloride)	Inhibit Na entry through epithelial sodium channels (ENaC)	Collecting duct	Hypertension	Amiloride: 5–10 mg p.o. b.d.	Hyperkalaemia
					Hyponatraemia
					Metabolic acidosis
Carbonic anhydrase inhibitors (e.g. acetazolamide)	Inhibit carbonic anhydrase	Proximal convoluted tubule	Glaucoma, acute mountain sickness, metabolic alkalosis	Acetazolamide: 250–1000 mg day−1 i.v. or p.o. in divided doses	Hypokalaemia
					Hyperchloraemia
					Metabolic alkalosis
Osmotic diuretics (e.g. mannitol)	Increase in tubular fluid osmolality	Proximal convoluted tubule	Raised intracranial pressure and intraocular pressure	Mannitol: 0.25–2 g kg−1 i.v.	Hypernatraemia
			Certain surgeries (e.g. cardiac, vascular)

Loop diuretics

Loop diuretics (e.g. bumetanide and furosemide) are indicated for patients with salt and fluid overloaded states such as pulmonary oedema, peripheral oedema or cirrhosis with ascites (although they should be avoided in the patient with cirrhosis and hypovolaemia). To exert their effect, they must reach the luminal surface of the renal tubule. They are first taken up by organic anion transporters (OATs) followed by secretion into the proximal tubule. In addition to their diuretic effect, they may cause venodilation through prostaglandin synthesis. This causes a reduction in cardiac preload with consequent relief of symptomatic dyspnoea in patients with acute pulmonary oedema, before diuresis takes effect. They are known as ‘high ceiling’ diuretics, as a progressively increased dose accompanies an increase in diuresis.⁵ Loop diuretics are 96% protein bound and therefore not filtered by the glomerulus, arriving at their target in the PCT via the peritubular capillaries. Their mechanism of action is through blockade of the Na⁺/K⁺/2Cl^– symport (NKCC2) in the thick ascending loop of Henle, which prevents reabsorption of filtered Na⁺ ultimately leading to Na⁺ and water loss. The NKCC2 symport is responsible for a net positive electrical potential difference between the lumen and interstitium, a potential difference that influences Ca²⁺ and Mg²⁺ reabsorption. Thus, by inhibiting this symport, these agents can precipitate marked electrolyte disturbances (e.g. hypokalaemia, hyponatraemia, hypocalcaemia, hypomagnesaemia and metabolic alkalosis). Other adverse effects include ototoxicity, which is a dose-dependent consequence resulting from blockade of a Cl^– channel present in the inner ear which is similar to the NKCC2 symport.⁵

Thiazides

Thiazide diuretics are used in the management of essential hypertension. Like loop diuretics, thiazides are protein bound and are delivered by the peritubular capillaries to their site of action, located on the ascending loop of Henle and the DCT. Here they inhibit Na⁺ and Cl^– reabsorption through inhibition of the Na⁺/Cl^– symport.⁵ As around 5% of Na⁺ reabsorption occurs through this mechanism, the diuretic effect of thiazide diuretics is modest compared with loop diuretics, and yet they achieve better natriuresis compared with the former.¹ Despite this, thiazides are helpful in patients exhibiting resistance to loop diuretics, in whom hypertrophy of epithelial cells as a result of chronic loop diuretic therapy increases the Na⁺ transport capacity in the DCT.⁶ The increased Na⁺ load in the lumen also results in K⁺ and H⁺ ion loss, through the presence of the Na⁺/K^– exchanger in the DCT. Thiazide use may lead to hyperuricaemia and gout because of reduced urate secretion. Other adverse effects include hypomagnesaemia, hyperglycaemia and hyperlipidaemia.

Potassium-sparing diuretics

There are two types of potassium-sparing diuretics: aldosterone antagonists or drugs acting independently of aldosterone. Spironolactone and eplerenone are aldosterone antagonists, thereby inhibiting Na⁺ reabsorption and K⁺ loss through the blockade of aldosterone receptors in the DCT; these drugs are secreted from the peritubular capillaries. They are prescribed in primary hyperaldosteronism associated with bilateral adrenal hyperplasia and secondary hyperaldosteronism, where aldosterone production is increased in response to poor renal perfusion causing salt and water retention (e.g. heart failure or liver cirrhosis).⁶ Spironolactone can cause gynaecomastia and hirsutism owing to its steroidal molecular structure.⁵

Amiloride and triamterene act independently of aldosterone on the DCT and CD. They are predominantly used for the treatment of hypertension.⁶ They are freely filtered in the glomerulus, blocking Na⁺ entry through ENaC in the DCT and CD. This leads to reduced K⁺ and H⁺ excretion into the lumen.^5,6 Acidosis and hyperkalaemia are not uncommon with their use.

Carbonic anhydrase inhibitors

Acetazolamide, a carbonic anhydrase inhibitor, exerts its effect in the PCT. Carbonic anhydrase, an enzyme found in both luminal and basolateral membranes of the PCT, catalyses the interconversion between CO₂ and water leading to the formation of HCO₃^– and H⁺ ions:

H₂O + CO₂ = H₂CO₃ = H⁺ + HCO₃^– (1)

The Na⁺/H⁺ exchanger in the PCT is responsible for Na⁺ reabsorption in exchange for H⁺ ions, which react with HCO₃^– to form H₂CO₃. Under the influence of carbonic anhydrase, the H₂CO₃ dissociates to H₂O and CO₂. However, by inhibiting carbonic anhydrase and reducing H⁺ concentration, carbonic anhydrase inhibitors, such as acetazolamide, reduce Na⁺ reabsorption. Impaired neutralisation of luminal HCO₃^– leads to alkaline urine and increased Cl^– reabsorption to maintain ionic balance, resulting in hyperchloraemic metabolic acidosis.⁵ Increased Na⁺ concentration at the distal nephron results in increased K⁺ exchange, leading to increased K⁺ loss.⁶ The diuretic effect of carbonic anhydrase inhibitors is mild, partly caused by the fact that the remaining nephron compensates for a higher Na⁺ load and also because of activation of the tubuloglomerular feedback mechanism.⁶

Owing to their weak diuretic effect, carbonic anhydrase inhibitors are not usually used for their diuretic properties. They are indicated for the treatment for glaucoma (carbonic anhydrase contributes to aqueous humour formation), acute altitude sickness and selected cases of metabolic alkalosis.

Osmotic diuretics

Osmotic diuretics such as mannitol are pharmacologically inert and stay within the tubular lumen to remain osmotically active. Mannitol is filtered freely and generates an osmotic force that retains Na⁺ and water within the tubule by decreasing water reabsorption. Contrary to other diuretic agents, mannitol leads to a higher degree of diuresis than natriuresis or kaliuresis and can thus lead to hypernatraemia as proportionally more water than electrolytes is lost.⁵ It is commonly used as a rescue therapy to reduce intracranial volume (and pressure). It remains in use in cardiac and vascular surgery in an effort to maximise the GFR and theoretically avoid acute kidney injury (AKI).⁵ Recent evidence shows no benefit of this practice.⁷

Relationship between diuretic therapy and renal function

Diuretic use in chronic kidney disease and heart failure

In the setting of heart failure or chronic kidney disease (CKD), there is often development of ‘diuretic resistance’ requiring larger doses of diuretic to achieve the same effect. There are various reasons for this phenomenon. In patients with heart failure and CKD, the delivery of the diuretic to the tubule is decreased, leading to decreased secretion of the diuretics and lower concentration at their sites of action in the tubular lumen. With decrease in GFR there is less filtered plasma and Na⁺, which limits the maximal response to diuretic. For example, in patients with a GFR of around 15 ml min⁻¹ 1.73 m⁻², there is secretion of only around 10–20% of the furosemide that would be excreted in a patient with normal renal function. Thus an increased dose of diuretic must be given to deliver adequate amounts to the tubule.⁸ In addition, secretion of loop diuretics into the lumen of the tubule via OATs is impaired by metabolic acidosis (e.g. in patient with CKD and AKI) resulting in larger dose requirements.

‘Tolerance’ of diuretic can occur with repeated dosing. Chronic treatment with loop and thiazide diuretics increases their target transporters; loop diuretic resistance occurs when there is distal nephron segment hypertrophy and enhanced Na⁺ reabsorption after increased exposure of the distal tubule to solutes not absorbed proximally. This can be overcome by adding a thiazide diuretic to block these distal nephron sites. Loop diuretics have short half-lives, with their effects wearing off after a number of hours. When this occurs, the kidney compensates by retaining the lost salt and water, leading to ‘post-diuretic NaCl retention’. This has led to the recommendation that loop diuretics be dosed at a minimum of twice daily in the critically ill.⁹

Loop diuretics have steep dose–response curves, with little effect below a given plasma threshold, but above which the response increases rapidly. In patients with CKD or AKI, it is impossible to predict at which dose this threshold lies.

Diuretics in patients with AKI

Diuretics are often stopped in patients with a decline in renal function because of the commonly held misconception that diuretics cause acute kidney injury. The danger from diuretics develops when the patient is hypovolaemic and diuretics are given. Enhanced diuresis can lead to a decrease in cardiac output, and renal hypoperfusion as a consequence. When used in patients with AKI, diuretics are not associated with increased mortality and AKI should not be seen as a contraindication to their use to treat hypervolaemic states.¹⁰

In patients with established AKI and oligoanuria however, using diuretics in an attempt to ‘kick-start’ the kidneys is ineffective and should not be undertaken.¹¹

Diuretics are not intrinsically toxic to the kidneys and may even have some theoretical protective properties to mitigate ischaemic injury by decreasing oxygen consumption, although this has not been shown to alter clinical outcomes when used as a preventative therapy in patients with AKI.¹²

In cardiac surgery, postoperative use of loop diuretics is not recommended for the prevention of AKI and is potentially harmful.¹³ Intraoperative use increases urine output by preventing concentration of urine at the loop of Henle, but there is little evidence that GFR is improved or AKI prevented. Diuretics do not directly affect renal function, as they do not alter the GFR at the glomerulus but rather alter the concentrating and fine-tuning of the ultrafiltrate after it has passed through the glomerulus and into the renal tubule, typically increasing the volume of urine or altering the electrolyte concentrations within it. Thus, although urine output may increase with diuretics, this does not reflect increased filtration and GFR, and can be falsely reassuring in patients with AKI.

A ‘furosemide stress test’ (FST) has been proposed in patients with AKI as a predictor of AKI progression, as the response to furosemide reflects glomerular filtration and degree of tubular damage. Typical regimens comprise a bolus of 1–1.5 mg kg⁻¹ furosemide i.v. and a urine output of <200 ml after 2 h used as a cut-off value. Urine output below this threshold may predict progression of early AKI. Questions remain regarding the use of FST: 25% of non-FST responders may not subsequently need RRT; therefore, it should not be used as a sole predictor of need for RRT.¹⁴ Meta-analysis of the use of FST shows a high degree of heterogeneity in the definition of AKI used, and indications for initiation of RRT making it difficult to interpret the results of an FST. Potential harm can result from injudicious use of diuretic in the hypovolaemic patient and an FST should be used and interpreted with caution.

Interstitial fluid accumulation in critically ill patients

As a result of the injury to the glycocalyx observed in critical illness, much of the fluid that is initially given in an effort to maintain tissue perfusion by expanding the intravascular volume will inevitably extravasate by capillary leakage into the interstitial space. This leads to tissue and organ oedema. Fluid overload has been defined as expansion of extracellular fluid volume with a positive fluid balance that produces a weight gain of >10% from baseline. It is common and occurs in >25% of patients in ICU.¹⁵ A hypervolaemic fluid state is associated with increased morbidity, and considered active evacuation of fluid can help mitigate these effects and allow for a more rapid discharge of the patient from the ICU.¹⁵ Attempts at restrictive fluid management can minimise a hypervolaemic state but patients are often left with significant positive fluid balance after initial treatment periods in critical care.

This manifests as pulmonary oedema, pleural effusions, ascites and peripheral or sacral oedema. Peripheral oedema and anasarca indicate excess interstitial fluid throughout the body.

With the revised Starling model, it is recognised that return of interstitial fluid to the circulation is predominantly via the lymphatic system.¹⁶ Diuretics and mechanical ultrafiltration will remove fluid from the intravascular compartment, decreasing intravascular volume, which will be compensated for by returning fluid to the intravascular compartment through the lymph vessels being refilled by fluid as it is returned by the lymphatics.

Critically ill patients often receive large volumes of isotonic fluids beyond the recommended Na⁺ requirements of 1 mmol kg⁻¹ day⁻¹. This, in combination with the activation of the RAAS as the physiological response to stress, leads to decreased excretion of salt and water in the urine. In the patient who is in the early phase of recovery from critical illness these processes can be overcome with the use of diuretics, leading to a more rapid elimination of excess salts and water.

In critically ill patients, fluid overload is associated with worse renal outcomes.¹⁵ This is thought to result partly from the increased right atrial pressure in fluid overload states such as heart failure or generalised oedema; this causes venous congestion with impaired renal blood flow through glomerular beds and peritubular capillaries. Renal perfusion pressure is equal to mean arterial pressure minus intrarenal tissue pressure. An increase in intrarenal tissue pressure secondary to raised right atrial pressure or organ oedema causes renal congestion by a reduction in the arteriovenous gradient across the kidney. If a patient is volume overloaded and presenting with AKI, there is increasing evidence that fluid removal, either mechanically or by forced diuresis, may improve renal perfusion by decreasing renal congestion.^17,18

When diuretics are given to patients with fluid overload states such as heart failure, the development of an increase in serum creatinine was associated with better long-term outcomes with this increase in creatinine thought to be a sign of effective diuresis and haemoconcentration.^19,20

In patients with cardiorenal syndrome, it is often safe and effective to aim for 3–5 L of diuresis.²¹ It is, however, unclear what rate of fluid removal is safe each day in the critically ill. Careful observation for an increased requirement for vasopressor drugs, signs of poor tissue perfusion, increasing lactate concentrations or decreasing cardiac index should trigger a review of the fluid removal strategy.

Diuretic use in ICU

Loop diuretic

A typical first step in this process is to use furosemide. A typical starting dose is 40–80 mg or 1 mg kg⁻¹ furosemide i.v., with increased doses dependent on response. It is recommended that if there is little or no response within 1–2 h of an i.v. bolus, the dose is doubled and repeated until the required clinical effects are achieved.⁹

Furosemide is typically given twice to four times a day in ICU but can also be given as a continuous infusion in efforts to overcome the post-diuretic salt-avid state of the kidney. There are theoretical benefits to bolus dosing in that a higher peak dose is reached in the renal tubular system. A maximum dose of 1.5 g daily is recommended. The increased volume of urine produced is typically diluted with increased K⁺ concentration, and treatment is accompanied by hypokalaemia and hypernatraemia, as more water is lost than Na⁺. For this reason, furosemide is often combined with other diuretics, such as spironolactone or indapamide, to minimise serum electrolyte abnormalities.

Aldosterone antagonists

As the filtrate reaches the DCT, Na⁺ is reabsorbed in exchange for K⁺. To counteract these effects, an aldosterone antagonist such as spironolactone or the diuretic amiloride can be used as a K⁺-sparing diuretic. Both will lead to higher concentrations of serum K⁺ and increased Na⁺ loss in the urine. Spironolactone in the treatment of oedema is given orally in doses of 100–400 mg day⁻¹. Amiloride should be given orally as 10 mg o.d. up to a maximum of 20 mg day⁻¹. There is unfortunately no i.v. alternative for patients without gastrointestinal uptake.

Thiazide diuretics

Thiazide diuretics also act in the DCT causing increased loss of Na⁺ and Cl^– in the urine. Hydrochlorothiazide or bendroflumethiazide are examples of thiazide diuretics. Bendroflumethiazide 5–10 mg orally o.d. can be used in the treatment of oedema, but has a half-life in healthy individuals of only 2–5 h. Metolazone is a thiazide-like diuretic with potent diuretic effects and is often used in patients with CKD. Starting oral doses of 2.5 mg of metolazone often have significant diuretic effects. Indapamide 2.5 mg o.d. is another alternative with an oral bioavailability of 93% and a half-life of 15–25 h in healthy patients. Thiazides cause excess loss of sodium and chloride in the urine leading to hyponatraemia. This effect can be beneficial in the patient with hypernatraemia. Thiazide diuretics also increase K⁺ wasting and will worsen hypokalaemia.

Carbonic anhydrase inhibitors

Acetazolamide causes H⁺ excretion, and therefore Na⁺ and HCO₃^– ions stay in the renal tubule. This leads to alkaline urine with high sodium and bicarbonate. Delivery of this sodium to the collecting tubule will also lead to exchange and loss of potassium in the urine. Chloride is retained in exchange for the HCO₃^–, leading to a normal anion gap metabolic acidosis. This adverse effect can be useful in patients with persisting metabolic alkalosis and chronic hypercapnia, although it may not necessarily improve weaning from mechanical ventilation.²² The normal dose is 250–1000 mg day⁻¹ in divided doses.

Diuretic combinations

Several studies have been performed in critically ill patients with various combinations of diuretics to promote fluid evacuation. One trial used bolus furosemide i.v. up to 200 mg with a thiazide added if this dose was reached and without an adequate negative fluid balance or hypernatraemia occurred. This regimen resulted in increased requirements for K⁺ supplementation.²³ Patients taking chronic diuretics develop distal tubular hypertrophy to compensate for the Na⁺ loss, and addition of a thiazide diuretic at onset may be beneficial to limit development of hypernatraemia.²⁴ It has been suggested that we should aim for natriuresis rather than diuresis, and a more complete blockade of the majority of the nephron leads to urine loss of similar composition to plasma, avoiding the electrolyte abnormalities associated with single-agent diuretic regimens. In one case report, a combination of acetazolamide, furosemide, spironolactone and aminophylline (used to antagonise adenosine and cause natriuresis) has been shown to be effective in eliminating excess Na⁺ with accompanying water.²⁵

The most commonly used combination in clinical practice is a thiazide and a loop diuretic, with or without a K⁺-sparing diuretic.²⁶

Drug interactions

An exhaustive list of drug interactions is beyond the scope of this article but some are worth mentioning. Many drug interactions observed in the ICU are secondary to the electrolyte abnormalities encountered with diuretic agents. Hypokalaemia associated with loop diuretics and thiazides can potentiate the effects of non-depolarising neuromuscular blocking agents. Hypokalaemia and hypercalcaemia seen with thiazide diuretics can also precipitate digoxin toxicity. Concomitant use of loop diuretics and potassium-sparing diuretics with vasodilators enhances hypotension, which is likely to be attributable to a reduced circulating volume (a phenomenon that also explains a reduced effect of vasopressor agents in such cases).

Conclusions

Diuretics are widely used in patients encountered in the perioperative setting and critical care. For critically ill patients it is recognised that fluid overload is harmful and timely evacuation of fluid or ‘deresuscitation’ is an important therapy, which requires both water and total body Na⁺ loss. There is potential benefit from a combination of different diuretic agents in order to minimise electrolyte disturbances, but there remains a lack of robust evidence on which diuretic combinations produce optimal fluid and solute removal in such patients. Awareness of common drug interactions is important in the perioperative period.

Declaration of interests

The authors declare that they have no conflicts of interest.

Biographies

Ricky Bell FFICM, MRCP (Neph) is a consultant in intensive care medicine and nephrology at University Hospitals of Leicester. His interests include fluids stewardship, haemodynamic aspects of acute kidney injury and point-of-care ultrasound.

Rahil Mandalia BSc FRCA is a consultant anaesthetist at University Hospitals of Leicester. His major clinical interests are anaesthesia for hip fracture, frailty and perioperative medicine.

Matrix codes: 1A01, 2A05, 3C00

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