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• How does Lasix’s mechanism of action contribute to its protective effect in acute lung injury (ALI) compared to other diuretics?
• What are the latest clinical findings regarding Lasix’s effectiveness in reducing mortality rates in patients with acute kidney injury (AKI)?
• How does the PAL technique utilizing Furosemide improve fluid balance outcomes in critically ill patients?
• What are the key indicators for discontinuing Lasix therapy in patients undergoing fluid removal in intensive care settings?
• How does the Lasix stress test (FST) compare to other diagnostic methods in predicting the progression of AKI?

The Use of Lasix in Critically Ill Patients
Mayang Indah Lestari, Yohannes WH George

Abstract
Critically ill patients face life-threatening conditions that, without prompt medical intervention, could lead to severe morbidity or even mortality. One common cause of morbidity and mortality in critically ill patients is distributive or vasogenic shock. After extensive fluid resuscitation, microvascular hydrostatic pressure increases, leading to fluid accumulation in the interstitial compartment and impaired organ function. This phase, known as the ebb phase, typically transitions into the flow phase, where inflammatory mediators stabilize, plasma oncotic pressure is restored, diuresis occurs, and excess extravascular fluid is mobilized, resulting in a negative fluid balance. However, some patients experience persistent systemic inflammation, plasma leakage, and failure to spontaneously transition into the flow phase, leading to fluid overload and global increased permeability syndrome (GIPS). GIPS causes venous resistance in organs, reducing perfusion pressure and potentially resulting in organ failure. In such cases, active fluid removal becomes necessary, and one of the commonly used medications is Lasix. This literature review discusses the physiological processes in critically ill patients, the mechanism of action of Lasix, its benefits, side effects, and potential toxicities.

Lasix plays a critical role in preventing interstitial edema formation by reducing compartment pressure. It is a widely prescribed diuretic in intensive care units (ICUs), acting on the sodium-potassium-chloride transporter in the thick ascending limb (TAL) of the loop of Henle, thereby inhibiting sodium, chloride, and water reabsorption. Additionally, Lasix exerts direct effects on vascular beds. Despite its benefits, improper use can lead to side effects and toxicities. This review explores the pharmacokinetics, pharmacodynamics, benefits, and risks of Lasix in critically ill patients.

Pharmacokinetics of Lasix
Lasix, a loop diuretic, was first approved by the FDA in 1966. Its chemical composition is 4-chloro-N-[2-furyl methyl]-5-sulfamyl-anthranilic acid. It can be administered orally or intravenously, with a bioavailability range of 10-100% (average 50%), which may be affected by food intake. The onset of action is approximately 30-60 minutes when taken orally and around 5 minutes when administered intravenously. Metabolism occurs primarily through liver conjugation, with about 50% of the drug being metabolized. The half-life of Lasix is 1.5-2 hours in healthy individuals, 2.8 hours in patients with renal dysfunction, 2.5 hours in those with liver dysfunction, and 2.7 hours in cases of cardiac failure.

Continuous administration of Lasix, compared to intermittent bolus dosing, allows for better drug titration to achieve the desired effect. However, initiating therapy with a loading dose is recommended to reach effective plasma levels. Yeh et al. compared continuous infusion (10 mg loading dose followed by 2 mg/h continuous infusion) with intermittent administration (10-20 mg bolus) and found no significant differences in 24-hour fluid balance, ICU length of stay, ventilator-free days, or mortality rates. Systematic reviews and meta-analyses by Ng et al. and Zangrillo et al. corroborated these findings, showing no mortality benefit with continuous administration but indicating increased urine output.

Albumin levels can influence Lasix pharmacokinetics, as low albumin levels may increase the drug’s distribution volume and impair its transport to renal tubules. However, this relationship remains controversial. Lasix is eliminated via renal glomerular filtration and tubular secretion, with non-steroidal anti-inflammatory drugs (NSAIDs) and probenecid potentially reducing its secretion by competing for low acidity transport in proximal tubules. The metabolites of Lasix lack diuretic activity.

Pharmacodynamics of Lasix
Lasix inhibits the sodium-potassium-chloride transporter (NKCC2) in the TAL of the loop of Henle, reducing sodium, chloride, and water reabsorption. It also promotes the excretion of potassium (K+), magnesium (Mg2+), hydrogen ions (H+), and chloride (Cl-) through urine. As the most potent diuretic available, Lasix’s efficacy is linked to the high sodium chloride absorption capacity of the TAL. Unlike carbonic anhydrase inhibitors, Lasix’s action is not affected by acidosis. Huang et al. demonstrated that a 40 mg intravenous bolus of Lasix significantly increased urine production, urinary sodium, potassium, and chloride losses, while also causing hypochloremia and metabolic alkalosis.

Conclusion
Lasix is a vital therapeutic agent for managing fluid overload in critically ill patients, especially in cases of GIPS and refractory edema. While its benefits include increased diuresis and improved fluid balance, careful administration is necessary to prevent side effects and toxicities such as electrolyte imbalances and metabolic alkalosis. Further studies are needed to determine the optimal administration method and dosage to maximize therapeutic benefits while minimizing risks.

Lasix also impacts the vascular system by modifying vascular conductance. Increased sodium and water retention in the arterial walls of patients with heart failure can heighten vascular stiffness. Administering Lasix can swiftly improve this condition within 24 hours, primarily through diuresis rather than neurohormonal inactivation. However, after 24-48 hours, no further improvement in vascular compliance is observed, indicating that neurohormonal activation may contribute to the subsequent changes.

Research by Figueras et al. investigated blood volume before and after Lasix therapy in patients with cardiogenic pulmonary edema. The results demonstrated that Lasix administration increased intravascular volume, with the replenishment of intravascular fluid exceeding the volume excreted through urine. Another study by Schuster et al. revealed that diuresis induced by Lasix did not decrease intravascular volume but actually increased plasma volume. Additionally, Lasix directly influences blood flow in various vascular beds. It enhances renal blood flow through prostaglandin action on kidney vasculature. Before any measurable increase in urine production, Lasix was shown to alleviate pulmonary congestion and reduce left ventricular filling pressure in heart failure patients.

Furosemide is commonly prescribed to critically ill patients for indications such as reducing edema, enhancing gas exchange, correcting oliguria, mitigating acute kidney injury (AKI), achieving venodilatory effects, and lowering pulmonary arterial wedge pressure. In critically ill patients suffering from sepsis, inflammation, or heart failure, oncotic pressure often decreases, resulting in transcapillary fluid shifts, increased interstitial fluid volume, and reduced plasma volume. This process triggers the release of counter-regulatory hormones such as angiotensin II, sympathetic hormones, and vasopressin, leading to sodium retention. The administration of plasma albumin may improve the efficacy of diuretics by raising oncotic pressure.

Fluid balance is increasingly regarded as a critical biomarker in critically ill patients. Research by Cordemans et al. indicated that patients with global increased permeability syndrome (GIPS) benefit from fluid removal, with Lasix being one of the primary agents used. Malbrain et al. also found that a positive cumulative fluid balance correlates with intra-abdominal hypertension (IAH) and other adverse outcomes. The goal of active fluid removal is to achieve negative fluid balance through late goal-directed fluid removal (LGFR), also known as de-resuscitation.

Fluid removal typically begins during the stabilization or de-escalation phase following resuscitation in patients at risk of or suffering from fluid overload. Effective fluid management involves minimizing unnecessary fluid administration. However, no prospective studies have evaluated the clinical, physiological, or biochemical parameters to guide the timing of fluid removal or its relationship with organ function, adverse events, and survival rates. Goldstein et al. proposed fluid balance trajectory as a physiological endpoint during fluid removal, recommending close monitoring of this target, although the guidelines remain subjective and challenging to apply.

Assessing excess fluid and its impact on target organs involves various techniques such as transcardiopulmonary thermodilution (TPTD), bioelectrical impedance analysis (BIA), pulmonary vascular permeability index (PVPI), intra-abdominal pressure (IAP), extracellular water (ECW), intracellular water (ICW), total body water (TBW), and volume excess (VE). Malbrain et al. used EVLWI measurements via TPTD to estimate capillary leaks and fluid overload, highlighting the importance of comprehensive fluid assessment in critically ill patients.

During fluid removal, tissue perfusion monitoring can be conducted using LiMON (Pulsion Medical Systems, Feldkirchen, Germany), gastric tonometry (Datex Ohmeda, Helsinki, Finland), microdialysis, hepatosplanchnic perfusion monitoring, and microperfusion with ScvO2, indocyanine green plasma disappearance rate (ICG-PDR), among others. (12) Research by Yeh et al. indicated that the target for fluid removal during Lasix administration is a net negative fluid balance of 100-300 ml over four hours. Discontinuation of Lasix is advised in cases of persistent hypotension (MAP<60 for more than 30 minutes), tachycardia (heart rate increase of 20% from baseline), recent vasopressor or fluid bolus administration (within the last 12 hours), myocardial infarction (based on electrocardiogram or troponin changes), acute renal failure (oliguria with creatinine >3.0 or oliguria with creatinine <3.0 but urine analysis indicating acute renal failure), refractory hypokalemia or arrhythmias due to electrolyte imbalances, metabolic acidosis (HCO3<18), or based on clinical judgment.

Lasix has shown protective effects in patients with acute lung injury (ALI), likely due to its role in reducing positive fluid balance. (38) Cordemans et al. utilized the PAL technique, which combines high levels of positive end-expiratory pressure (PEEP), small volume resuscitation with hyperoncotic albumin, and fluid removal with Lasix or continuous renal replacement therapy (CRRT). (10) The FACTT study demonstrated that a conservative fluid management strategy, aimed at reducing pulmonary edema and improving gas exchange, was more effective in patients with ALI and acute respiratory distress syndrome (ARDS) compared to a liberal fluid strategy. (44,45) In the conservative group, diuresis was used to maintain a pulmonary artery catheter pressure below 8 mmHg or a central venous catheter pressure below 4 mmHg, significantly shortening mechanical ventilation duration and ICU stay without increasing 60-day mortality or 28-day non-pulmonary organ failure. (44)

Teixera et al. found that patients with acute kidney injury (AKI) who died had a higher mean fluid balance. (46) The European Society of Intensive Care Medicine recommends controlling fluid resuscitation with crystalloids while avoiding excessive fluid administration. (43) For AKI prevention and renal protection, diuretics are recommended only in patients with a favorable response. (43)

The use of Furosemide in AKI prevention or management is supported by theories suggesting it helps flush cellular debris and casts from renal tubules while improving renal medullary oxygenation by reducing tubular oxygen utilization and promoting renal vasodilation. (47) However, in patients unresponsive to Lasix, the risk of in-hospital death increases by 68%, with a 77% higher odds ratio for death or failure to improve renal function. (47) Mehta et al. similarly reported that Lasix use was associated with increased risk of death or poor renal outcomes. (48)

The Lasix stress test (FST) can predict AKI severity by administering 1-1.5 mg/kg of Lasix and measuring urine output two hours later. Patients who had not previously received Lasix were given 1 mg/kg, while those who had were given 1.5 mg/kg. A urine volume of less than 200 ml (100 ml/hour) indicates a higher likelihood of progressive AKI, with 87.1% sensitivity and 84.1% specificity. (3) The FST serves as an AKI severity marker without delaying definitive treatment such as renal replacement therapy (RRT). Patients with AKI stage III and fluid overload complications should receive RRT immediately. (https://elegancehairtransplant.com)

Side effects of Lasix® include fluid, electrolyte, and acid-base imbalances. (4) Uncontrolled fluid removal can lead to hypovolemia, hypoperfusion, and tissue hypoxia. (12) However, studies have shown that Lasix can increase blood volume by shifting fluid from the interstitial to intravascular compartment more than it promotes urine output. (18-20) Electrolyte imbalances, such as hypokalemia, hypomagnesemia, and hypercalcemia, are common. Hypokalemia results from increased potassium and hydrogen ion excretion, while long-term use can cause hypomagnesemia, especially in those with magnesium deficiency. Hypercalcemia can be managed with loop diuretics and saline infusion to increase calcium excretion.