Intensive Care Med (2019) 45:545–548
10 myths about frusemide
Background
Frusemide is the most frequently used diuretic in criti- cally 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).
在危重病人中，呋塞米是最常用的利尿劑。它通過選擇性地阻斷Na/K/2Cl−通道在亨氏攀的粗支升段腔中發揮作用。為了到達作用部位，它首先由近端細胞通過有機陰離子轉運蛋白吸收，然後分泌到管腔內，從那裡轉運到遠端小管。呋塞米利尿作用比利鈉作用更大，導致低滲尿液的產生。利尿劑抵抗在長期接受袢利尿劑治療的患者中並不少見。此外，人們還擔心利尿劑的使用可能與有害影響有關，包括急性腎損傷(AKI)。這導致了臨床醫生對何時以及如何安全有效地在患有AKI和不患有AKI的危重病人中使用呋塞米的不確定性。在這裡，我們討論了關於呋塞米及其在危重病人中的應用的十個常見誤區(圖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.
1.呋塞米會導致AKI，不會
呋塞米促進利尿，對液體過負荷患者特別有用。然而，一般的概念是利尿劑可能導致AKI。事實上，很少有研究發現利尿劑的使用是AKI的危險因素。然而，大多數報告沒有區分導致AKI的不同病因，特別是因低血容量的AKI患者。在這種病人中使用利尿劑很可能有促進AKI的發展。然而，在液體過負荷患者中恰當使用呋塞米可能會解決AKI，這可能是通過減少腎充血和降低腎氧耗所致。
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.
2.液體與呋塞米聯合使用能阻滯高危人群的AKI發生，可能不是
有一個共同的概念，即液體+呋塞米的聯合使用促進利尿而不會引起低血容量。 事實上，使用利尿劑和液體及機體自動匹配水化系統以防造影劑相關的AKI(CA-AKI)。雖然一些作者發現CA-AKI的發生率降低，但對AKI患者的研究並沒有顯示出對AKI[6]進展的有益影響。一般情況下，液體應被用於治療血管內低血容量患者，利尿劑應用於血管內高血容量的患者。
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).
3.呋塞米在AKI中禁忌使用，不是
在液體過負荷包括合併AKI的患者中，呋塞米的使用時適應症。 然而，在AKI中可能需要更高的劑量，特別是在利尿劑抵抗的高風險的嚴重AKI患者。呋塞米在高鉀血症的管理中也發揮作用。最後，在評估腎小管功能和AKI進展較高階段風險時，呋塞米可以作為診斷工具。（呋塞米負荷試驗）
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.
4.呋塞米可以啟動腎功能，事實並非如此
在AKI患者中，呋塞米可能導致明顯的利尿。然而，這必須被認為是功能腎小管細胞的反映，而不是呋塞米對腎功能的直接有益作用。重複使用呋塞米，特別是在高劑量和無尿患者中，可能導致副作用的顯著增加，特別是耳毒性。在液體過負荷的患者，若對利尿劑無反應，沒有重複使用的必要。在這種情況下，應考慮體外液體清除。
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 crossover 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.
5.呋塞米與白蛋白聯合使用效果更好 ，看情況而定
在血漿中，呋塞米蛋白結合率高，嚴重的低蛋白血症與呋塞米向管腔分泌受損有關。支持聯合使用白蛋白和呋塞米的臨床證據不足。在一項包括肝硬化和腹水患者在內的研究中，預混利尿劑和白蛋白（40mg呋塞米+25g白蛋白）的使用並不能增強尿利鈉反應。相比之下，一項針對24例慢性腎病(CKD)和低白蛋白血症患者的隨機對照交叉研究顯示，呋塞米和白蛋白的聯合使用使尿量顯著增加。然而在24小時後，不再有任何顯著差異。包括10項研究在內的Meta分析顯示，在低血容量患者中，聯合使用呋塞米和白蛋白，更好地控制液體平衡。對正常血蛋白水平的患者的研究是不確定的，這表明此類患者無法從聯合輸注中獲益。
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.
6.呋塞米持續輸注比間斷負荷更有效，並非如此
幾項RCT和Meta分析表明，與呋塞米間斷負荷治療相比連續輸注更容易實現持續的利尿，但沒有證據表明其能獲得更好的預後，包括病死率，住院時間，對腎功能的影響或電解質紊亂。
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.
7.呋塞米可預防腎臟替代治療(RRT)，不能
呋塞米在液體過負荷患者的利尿誘導中起作用。如果對利尿劑有反應，呋塞米的使用可以為RRT的啟動爭取時間。一項薈萃分析報告稱，攀利尿劑的使用能縮短RRT的時間。然而，呋塞米對腎臟恢復的機率沒有直接影響。一項引導試驗(SPARK研究)對早期AKI患者中使用小劑量呋塞米和安慰劑的對比研究，發現在AKI進展及RRT需求沒有差異。
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.
8.呋塞米能夠幫助無尿患者撤機（RRT），不能
在接受RRT治療的患者中，尿量增加是終止RRT的常見原因，而利尿劑經常用於這一目的。然而，沒有證據表明利尿劑有效地改善肌酐清除率或促進腎臟恢復。然而，應該指出的是，呋塞米還存在較高的耳毒性發生率，這種風險可能與無尿患者呋塞米累積效應特別相關。
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.
9.在AKI後，呋塞米誘導的利尿意味著腎功能完全恢復，並不是這樣 雖然給予利尿劑後可能導致AKI患者尿量增加(UO)，但AKI後呋塞米誘導的利尿不能被認為是完全和持久腎恢復的跡象。即使只經歷一次AKI發生並且已恢復排尿功能的患者，CKD的風險也會增加，死亡率也會增加。
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 .
10.如果血清肌酐升高，表明腎功能惡化，應停止使用呋塞米。
許多急性心力衰竭患者在利尿劑治療時血清肌酐升高0.3mg/dl或更高。然而，這絕不能被自熱而然的認為與不良預後相關的腎功能真正惡化的跡象（WRF）。由於所測肌酐為血清中的濃度，單一血清肌酐的增加同時紅細胞壓積的增加可能只是血管內容量減少和充血性心衰減輕的跡象。重要的是，它也可能與較好的預後相關。這種現象被稱為偽WRF。在FACTT試驗中也觀察到了類似的效果，其中使用大量利尿劑的限制性液體治療增加呼吸機撤機成功率，但此類患者血清肌酐升高近0.3mg/dl，儘管如此，此類患者對RRT需求甚至更低。