Can saline repletion be the true TARGET for achieving fluid balance in acute heart failure?

Abstract

This article refers to ‘Controlled decongestion by Reprieve therapy in acute heart failure: results of the TARGET-1 and TARGET-2 studies’ by J. Biegus et al., published in this issue on pages 1079–1087. Congestion is a complex clinical syndrome defined as signs and symptoms of fluid accumulation that often tracks with increased cardiac filling pressures and circulatory redistributions.1 With loop diuretic therapy being the primary strategy to remove salt and water, comparing strategies of initial dosing and routes of loop diuretics have been the focus of clinical research studies in acute decompensated heart failure (ADHF). Interestingly, only studies comparing diuretic therapy with ultrafiltration have prospectively set volume removal or urine output goals of net negative 3–5 L/day.2 The recently published position paper on the use of diuretics in heart failure with congestion from the Heart Failure Association of the European Society of Cardiology provides some best practice recommendations on how to achieve such goals.3 Based on the assumption that loop diuretics are often effective in relieving congestion by salt and water removal when adequately dosed, choosing an adequate initial and stepwise diuretic dosing needs to pair with assessing diuretic response, potentially with timely assessments of urine output and spot urinary sodium.3 How to best decongest and stabilize ADHF patients remains an ongoing challenge, since persistent congestion confers poorer outcomes.4 With lack of consensus on what constitutes ‘complete decongestion’, there has been suggestions that perhaps either under-dosing or overzealous use of diuretic therapy that surpass the plasma refill rate may contribute to residual congestion at the time of discharge. Indeed, the pathophysiology of diuretic resistance is likely multifactorial and varies over time, including the activation of the renin–angiotensin–aldosterone and sympathetic systems, nephron remodelling, pre-existing renal dysfunction, and importantly, fluid depletion due to slow plasma refilling.5 Therefore, beyond diuretic therapy, stabilization may involve appropriately targeting some of these pathways and may be necessary to reset renal sodium and water avidity and to normalize circulatory volume distributions. In this issue of the Journal, Biegus and colleagues report their findings of two single-arm, open-label, single-centre pilot studies that assessed the safety and tolerability of a proprietary platform that monitors urine output in real time (hourly) via a Foley catheter and delivers a matched volume of intravenous normal saline to maintain a pre-set fluid balance in patients with ADHF receiving intravenous (IV) loop diuretic therapy.6 Of note, the study population included those who have already been admitted to the hospital with ADHF (with congestive signs and symptoms, elevated natriuretic peptide levels, and ∼8.6 kg self-reported weight gain at admission) for ∼2 days. Characterized as ‘controlled decongestion’ with the concept of maintaining plasma refill rate to avoid over-diuresis, the investigators targeted a pre-determined negative fluid balance (∼200 mL/h) to allow the clinician to reliably achieve their clinically-determined ‘optimal’ negative fluid balance during treatment. The results were thought-provoking – there was significantly increased diuresis/natriuresis and improvements in markers of decongestion compared with the preceding 24 h before the system was operational, even though patients were given much higher diuretic doses at the discretion of the treating physicians in an open-label fashion without a parallel control group.6 These findings have perhaps shed some light on the fact that aggressive IV diuresis in ADHF is physiologically an intentional dehydration process that inevitably stimulates counter-regulatory responses to maintain a tightly-regulated blood tonicity. It is therefore logical to consider careful saline repletion as a rehydration approach even in the setting of ADHF to maintain (or even augment) IV loop diuretic therapy. Like the well-known complications of dehydration in endurance exercises and the need for water and electrolyte repletion to maintain adequate physiologic performance, the potential benefits of saline repletion during ADHF treatment may have been largely overlooked. The first important observation from these studies that supported the concept of saline repletion is that these ADHF patients were able to tolerate the large volume infused even in their congested state. This is in stark contrast with prior concerns regarding simultaneous IV fluid administration in the setting of ADHF that was linked to worse clinical outcomes.7 While the authors focused on reporting the urine outputs achieved, they did not highlight the impressive fact that these well-perfused ADHF patients received an average 2.5–3.5 L of 0.9% sodium chloride infusion over 24 h in the absence of haemodynamic compromise. In fact, when furosemide doses were increased in the TARGET-2 study, an average of ∼150 mL/h of normal saline infusion had to be given to maintain a steady negative diuresis and to achieve pre-defined fluid balance goals. Granted that the majority of patients enrolled in TARGET-2 were largely responsive to IV loop diuretics (those who do not achieve greater than >200 mL of diuresis in the first 4 h after receiving 40 mg IV furosemide were excluded), we simply do not know whether such replacement volumes would be equally tolerated in those with more cardiorenal impairment.8 The second important observation from the studies that should be considered hypothesis-generating is that saline repletion may benefit beyond restoration of intravascular volume and perfusion. Impaired urinary sodium excretion often preceded ADHF admissions.9 However, aggressive IV diuretic therapy during ADHF to overcome such changes may also artificially induce not only an intravascular volume-depleted state but also a sodium/chloride-depleted state. It is therefore noteworthy that in both TARGET studies, sustained net negative sodium balance with this saline repletion strategy tracked closely with weight loss and improvement in clinical status.6 This suggested that the kidneys are effective in handling excess electrolytes by means of greater urinary sodium excretion, rather than an expected urine electrolyte depletion with continuing diuresis.10 Also, unlike ultrafiltration that tracked with a fall in serum sodium following mechanical removal of isotonic fluid,11 serum sodium and osmolality appeared to increase (i.e. with appropriate haemoconcentration) when aggressive IV diuresis was matched with saline rehydration. This suggested sodium homeostasis can be adequately maintained by the kidneys when sodium and chloride are repleted, a physiologic response that has been demonstrated in classic dog studies even in the absence of volume depletion.12, 13 At this point, we simply do not know whether such maintenance of net sodium excretion by saline repletion is mediated by volume repletion or by salt repletion, but both may be at play. This proof-of-concept study only demonstrated that such a device can be used safely in a short term to allow clinicians to ‘pre-set’ the amount of net fluid balance to be achieved during ADHF therapy. It is conceivable the hourly feedback-response mechanism provided by the device may have some physiologic advantages in providing finer adjustments than if responded over a period of hours or without accurate urine output measurements by a Foley catheter. However, catheter-associated infection risks need to be acceptably low, and clinical endpoints like rehospitalization, length of stay, or incidence of acute kidney injury need to be better than not having the device. In other words, the invasiveness of such a strategy needs to be justified above and beyond the effects of standing saline repletion. This begs the logical question – would the effectiveness of a device like the Reprieve System™ be mitigated if a standing ‘saline rehydration protocol’ is implemented? Apart from the relatively controversial hypertonic saline infusion studies in the literature, there have been glimpses of such clinical responses from randomized controlled trials conducted in Japan where a standing 1.7% sodium chloride infusion was associated with better diuresis and symptomatic relief when routinely given during aggressive diuresis in ADHF, even in the absence of a diuresis-feedback mechanism.14 Like ultrafiltration studies, the same daily urine output goals should be set.2 Another question becomes – how to individualize the optimal net negative fluid balance for each patient? The current system conveniently left this key decision at the discretion of the treating clinician, but experience with ultrafiltration has demonstrated that a net negative balance of 200 mL/h is often tolerable and utilized in the TARGET trials and will likely need some adjustments for those with lower circulatory reserves.15 Prospective investigations may require a parallel group not only without saline repletion but also with a ‘sliding-scale’ algorithm of saline repletion protocol (similar to how clinicians adjust for heparin or insulin dosing) to adjust for varying diuretic efficiencies.2 Perhaps the more vexing problem with decongestion is not the inability to achieve target fluid balance, but the challenge in determining what the overall target fluid balance should be. While the Reprieve System™ may enable clinicians to initiate high-dose loop diuretics in all ADHF patients without worrying about ‘over-shooting’ their fluid balance goals, clinicians still need to consider multiple clinical variables to determine whether or not euvolaemia has been achieved. Also, the lack of insight into IV drug doses required to achieve diuretic efficiencies may potentially obscure the clinicians' ability to reliably estimate dosing needs during oral diuretic drug transition prior to discharge. It is unclear how this device can help with these important and challenging decisions. In summary, the prevailing diuresis paradigm in ADHF is still focused largely on the quantity rather than the quality of urine output, neglecting how aggressive IV diuresis may disrupt electrolytes and water homeostatic mechanisms. We should be mindful that potential benefits of such controlled decongestion may represent the facilitation of the kidneys to maintain effective diuresis and natriuresis in the setting of ADHF via saline repletion, rather than the intentional pre-set of target fluid balance that the device may conveniently provide. However, challenging the past assumptions in salt and water handling is the first step to progress. Conflict of interest: W.H.W.T. served as consultant for Sequana Medical Inc. and MyoKardia Inc., unrelated to the content of this paper. T.M. reports no relationships to disclose.