关于呋塞米的10个传说（10 myths about frusemide）

10 myths about frusemide

关于呋塞米的10个传说（译文）

Joannidis, M., Klein, S.J. & Ostermann, M. 10 myths about frusemide. Intensive Care Med 45, 545–548 (2019). https://doi.org/10.1007/s00134-018-5502-4

再好的翻译都不比原文，以下请中英文对比阅读！

Background

Frusemide is the most frequently used diuretic in critically ill patients . It exerts its action by selectively blocking the Na+/K+/2Cl− co-transporter in the luminal membrane of the thick ascending limb of the loop of Henle (Supplementary Fig. S1). To reach the site of action, it is first taken up by the proximal cells via organic anion transporters and then secreted into the luminal space from where it is transported to the distal tubule. Frusemide generates greater loss of water than sodium loss, resulting in the production of hypotonic urine. Diuretic resistance is not uncommon in patients receiving prolonged therapy with loop diuretics. Furthermore, concern has been raised that diuretic use may be associated with harmful effects, including acute kidney injury (AKI). This has led to uncertainty among clinicians about when and how to use frusemide safely and effectively in critically ill patients with and without AKI. Here, we address ten common myths about frusemide and its application in critically ill patients (Fig. 1).

背景

速尿是危重病人最常用到的利尿剂。它通过选择性的抑制位于肾小管髓袢升支厚壁段内膜上的钠/钾/2氯联合转载体而发挥利尿作用。它先被近端小管细胞摄取，再分泌到肾小管管腔内，随后被转运至远端小管。速尿产生的作用是失水大于失钠，从而产生低渗尿。利尿剂抵抗在长期使用袢利尿剂治疗的患者中并不少见。此外，人们对利尿剂相关性损害的顾虑在增加，包括AKI等。这已导致临床医师无法确定在有AKI或无AKI的危重病患者中该如何安全有效地使用速尿了。

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在本文中，我们主要讲述了十个关于速尿的常见神话及其在危重病人中的应用（图1）。

• Myth #1:

• Frusemide causes AKI.

  No, it does not.

Frusemide promotes diuresis and is particularly useful in patients with fluid overload. However, it is a common conception that diuretics may cause AKI. In fact, few studies have identified diuretic use as a risk factor for AKI. However, most reports did not distinguish between different aetiologies of AKI and included patients with AKI due to hypovolaemia. It is very likely that inappropriate use of diuretics in this patient population contributes to the development of AKI. However, when used appropriately in patients with fluid overload, frusemide may actually resolve AKI, presumably due to resolution of intrarenal congestion and reduction of renal oxygen consumption .

传说1  
速尿可导致AKI的发生。不，它不会

速尿可以促进利尿，尤其是液体过负荷的患者，特别有效。然而，有一个普遍的观点认为利尿剂可能会导致AKI的发生。事实上，能证实利尿剂是AKI的危险因素的相关研究几乎没有。然而，大多数文章并没有把不同的AKI病因进行区分，包括因低血容量所致的AKI患者在内。似乎就像在这些患者人群中不恰当地使用了速尿导致了AKI的发生一样。但是，对于液体过负荷的患者来说，速尿的使用或许还避免了AKI的发生。这可能的机制是减少了肾瘀血和肾的耗氧量。

• Myth #2:

• Frusemide and fluids together can prevent AKI in high-risk patients.

  Probably not.

There is a common belief that the co-administration of frusemide and fluids increases diuresis without causing hypovolaemia. In fact, automated matched hydration systems using diuretics and fluids together exist for the prevention of contrast-associated AKI (CA-AKI). While some authors found a reduction in the incidence of CA-AKI, studies in patients with AKI did not demonstrate a beneficial effect on progression of AKI . In general, fluids should be considered as therapy for patients with intravascular hypovolaemia and diuretics should be reserved for patients with intravascular hypervolaemia.

传说2 
对于高风险患者，速尿与液体联合可以预防AKI。可能并不是这样

有一个很常见的观点认为，液体和速尿一起联合治疗，可以增加尿量同时又避免低血容量。事实上，使用利尿剂和补液水化的疗法是用来预防造影剂相关的AKI的。虽然一些作者发现该疗法可使造影剂相关AKI的发病率有所下降，但一些针对AKI患者的研究，该疗法并没有显示出对预防AKI进展有任何获益。总之，补液治疗应该是针对血管内低血容量的患者，而利尿剂应该主要针对血管内高容量的患者。

• Myth #3:

• Frusemide is contraindicated in AKI.

  No, it is not.

Frusemide is indicated in patients with fluid overload, including those with AKI. However, higher doses may be needed in AKI, especially in severe AKI where the risk of diuretic resistance is higher, too. Frusemide also has a role in the management of hyperkalaemia. Finally, frusemide can be used as a diagnostic tool in AKI when assessing tubular function and risk of progression to higher stages of AKI (i.e. frusemide stress test).

传说 3 
速尿对AKI来说，是禁忌。非也

速尿适用于液体过负荷的患者，包括AKI的患者。只不过对于AKI患者来说，可能需要更大的剂量罢了，尤其是严重AKI的患者，他们对利尿剂抵抗的风险更高。另外，速尿也可用于高钾血症的治疗。最后，当需要评估AKI患者的肾小管功能以及患者进展为AKI更差阶段的风险时，速尿还可以作为其诊断工具（例如：速尿应激试验）。

• Myth #4:

• Frusemide can kick-start kidney function.

  No, this is not the case.

Frusemide may lead to significant diuresis in patients with AKI. However, this has to be regarded as an indication of functioning tubular cells, rather than a direct beneficial effect of frusemide on renal function. Repeated doses of frusemide, especially in high doses and in anuric patients, may lead to a significant increase in side effects, in particular ototoxicity. In patients with fluid overload, who are not diuretic-responsive, there is no role for repeated frusemide application. In this situation, extracorporeal fluid removal should be considered.

传说 4  
速尿可以恢复肾功能。不，不是这样子的

速尿可以使AKI患者的尿量明显增加。然而，这只能反映肾小管细胞的功能，而不能说明速尿对肾功能有直接的正面影响。速尿反复使用，特别是高剂量用于无尿的患者，可能会使副作用明显增加，尤其是耳毒性。对于液体过负荷、同时对利尿剂又无反应的患者，反复给予速尿治疗并无作用。在这 种情况下，则应考虑体外液体清除。

• Myth #5:

• Frusemide works better if given together with albumin.

  It depends.

In plasma, frusemide is highly protein-bound, and severe hypoalbuminaemia is associated with impaired frusemide secretion into the tubular lumen. The evidence supporting the combined use of albumin and frusemide is sparse. In a study including patients with liver cirrhosis and ascites, the administration of premixed loop diuretic and albumin (40 mg frusemide and 25 g albumin) did not enhance the natriuretic response. In contrast, a randomized controlled cross-over study in 24 patients with chronic kidney disease (CKD) and hypoalbuminaemia showed a significant increase in urine volume with frusemide and albumin. However, at 24 h, there were no longer any significant differences. A meta-analysis including 10 studies demonstrated better control of fluid balance with co-administration of frusemide and albumin in hypoalbuminaemic patients. Studies in patients with normal blood protein levels are inconclusive, pointing to no direct benefit of combined infusion in these patients.

传说 5   
如果与白蛋白联用，速尿利尿效果更佳？这要视情况而定

在血浆中，速尿与蛋白的结合率很高，严重低蛋白血症时将使速尿排入肾小管内受到影响。支持把白蛋白和速尿联合使用的证据还非常少。在一项针对肝硬化腹水患者的研究中发现，把袢利尿剂与白蛋白（速尿40mg，白蛋白25克）联合给药，并不能增加尿钠的排出。相反，一项随机对照交叉研究，纳入了24例慢性肾病合并低蛋白血症的患者，结果发现速尿与白蛋白合用明显增加了患者的尿量。然而，在24小时内，却没有任何显著性差异。一项Mate分析，纳入了10项研究，结果显示在低蛋白血症的患者当中，联用速尿和白蛋白，可以使液体平衡的控制更胜一筹。一些针对血浆白蛋白水平正常患者的研究结果仍无定论，但它们指出在这些患者中联合速尿和白蛋白并无直接获益。

• Myth #6:

• Frusemide infusion is more effective than frusemide boluses.

  No, it is not.

Several randomized controlled trials (RCTs) and meta-analyses showed that sustained diuresis is easier to achieve with continuous frusemide infusion compared to intermittent bolus therapy , but there is no evidence of better outcomes, including mortality, length of hospital stay, effect on renal function or electrolyte disturbances.

传说 6   
速尿连续泵入比间断顿推更有效？不，不是

几项随机对照试验和Meta分析表明，连续泵入速尿比间断顿推更容易获得连续性的利尿作用，但并不改善预后，包括死亡率，住院时间，对肾功能或电解质紊乱的影响。

• Myth #7:

• Frusemide can prevent renal replacement therapy (RRT).

  No, it can’t.

Frusemide has a role in inducing diuresis in patients with fluid overload. If diuretic responsive, the administration of frusemide may buy time before RRT can be initiated. A meta-analysis reported that the administration of loop diuretics was associated with shorter duration of RRT. However, frusemide has no direct effect on chances of renal recovery. A pilot trial (the SPARK study) compared low-dose frusemide versus placebo in patients with early AKI and found no difference in the rate of worsening AKI or need for RRT.

传说 7
使用速尿治疗可以使患者免于接受 RRT？不，它不能

速尿在液体过负荷的患者中有诱导利尿的作用。如果对利尿剂有反应，在RRT启动之前使用速尿可能会为抢救赢得时间。一项Meta分析报导，袢利尿剂的使用可以缩短RRT的持续时间。然而，速尿对肾功能恢复的机会并没有直接影响。一项试验性研究，纳入的是AKI早期的患者，把小剂量速尿与安慰剂进行了对比，发现AKI恶化的机率或RRT的需求并无差异。

• Myth #8:

• Frusemide helps to wean anuric patients from RRT.

  No, it does not.

In patients treated with RRT, increasing diuresis is a common reason for discontinuing RRT, and diuretics are frequently used for this purpose. However, there is no evidence that diuretics are effective at improving creatinine clearance or inducing renal recovery . However, it should be noted that frusemide was also associated with a higher incidence of ototoxicity, a risk that may be particularly relevant to anuric patients at increased risk of frusemide accumulation.传说 8

速尿有助于无尿患者脱离RRT。不，并不能

在接受RRT的患者中，常常是为了停用RRT而增加利尿剂。然而，尚无证据表明利尿剂是可以提高肌酐清除率或肾功能的恢复的。而需要注意的是，速尿也有较高的耳毒性发生率，对于无尿的患者来说，这一风险可能是与速尿的累积作用有关。

• Myth #9:

• Frusemide-induced diuresis after AKI implies full renal recovery.

  No, it does not.

While frusemide administration may lead to increased urine output (UO) in patients with AKI, frusemide-induced diuresis after AKI must not be considered a sign of full and permanent renal recovery. Even patients who experienced only a single episode of AKI and recovered excretory function remain at increased risk of CKD and increased mortality.

传说 9  
在AKI之后，速尿的利尿效果出现，提示着肾功能完全恢复。不，不是

给予速尿治疗后，可能会使AKI患者的尿量增加，在发生AKI之后，速尿诱导出利尿效果并不能认为是肾功能已全面恢复。即使是只经历过一次AKI并恢复排泄功能的患者，他们进展为慢性肾衰的风险也会增加，死亡率也会增加。

• Myth #10:

• Frusemide should be stopped if serum creatinine is increasing, indicating worsening renal function.

  No, not necessarily.

Many patients with acute heart failure have a rise in serum creatinine of 0.3 mg/dl or more during diuretic therapy . However, this must not automatically be interpreted as a sign of true worsening renal function (WRF) associated with impaired outcome. Since creatinine is measured as a concentration in serum, an isolated increase in serum creatinine in combination with a rise in haematocrit may simply be a sign of reduction in intravascular volume and effective decongestion. Importantly, it may also be associated with better outcomes. This phenomenon is termed pseudo WRF . A similar effect was observed in the FACTT trial, where restricted fluid therapy using substantial diuretic dose improved weaning from respirator but was associated with increased serum creatinine by nearly 0.3 mg/dl. Despite that, the requirement of RRT was even lower in this group.

传说 10  
如果血清肌酐升高了，则应该停用速尿，因为肌酐升高提示着肾功能在恶化？不，没必要

许多急性心衰患者在利尿治疗过程中会出现肌酐升高达0.3mg/dl。然而，这不能自动的把它解读为肾功能出现真正恶化，同时带来更差的预后迹象。由于肌酐是以血清中的浓度来测量的，血清肌酐孤立地上升，再加上红细胞压积的升高，可能只是血管内容量减少和静脉系统瘀血减轻的一个迹象。重要的是，它可能与更好的预后相关。这种现象被称为假性肾功能恶化。在FACTT研究中同样观察到了类似的现象，纳入的是ARDS患者，研究中给予持续利尿、限制液体治疗，确实增加了脱离呼吸机的成功率，但血肌酐上升了差不多0.3mg/dl。尽管如此，在这个研究组中，需要RRT的机率还是非常低。
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