Optimal diuretic dosing strategies following cardiac surgery: a retrospective cohort study

Introduction

Background

Diuretics are a class of drugs used to treat oedema and fluid overload, and are the 12^th most commonly prescribed drug in the United Kingdom (1). Loop diuretics are the most common given their potency (2-4), with furosemide the most frequently prescribed by a tenfold margin. These drugs are utilised commonly following cardiac surgery to relieve fluid overload and oedema (5). Sub-optimal diuresis can lead to extended hospitalisation (6,7) or rehospitalisation (8,9) especially in patients with heart failure. Despite this, the pharmacokinetics and pharmacodynamics of loop diuretics are not well understood.

Unlike many drugs, loop diuretics do not induce a sliding scale action: low doses do not produce a weak response and higher doses a stronger response. They are classed as threshold drugs which means a therapeutic level must be reached to achieve the desired effect as seen in the dose-response curve in Figure 1. This has been interpreted to mean that once the drug reaches a therapeutic level a dose change is usually not required (10).

Figure 1 Furosemide dose-response curve.

Much of the research underpinning the pharmacodynamics of loop diuretics are based on small series experiments of predominantly normal volunteers from the 1970s and 1980s (11), which has been open to misinterpretation (12). This original research gives little information about titrating doses or precise administration. Further research is required in all aspects of diuretic management including, dosing and effectiveness monitoring, particularly in multi-comorbid patients and those with acute fluid overload following cardiac surgery.

Objective

The purpose of this study is to investigate diuretic prescribing behaviours and efficacy in the postoperative cardiac patient in a specialist cardiac centre. We aim to identify trends in decision making and to investigate factors associated with effectiveness of dose adjustments in the postoperative period. We present this article in accordance with the STROBE reporting checklist (available at https://asj.amegroups.com/article/view/10.21037/asj-23-29/rc).

Methods

We undertook a single-centre retrospective cohort study, conducted at a tertiary cardio-thoracic hospital. All consecutive post-operative cardiac surgery inpatients during a 4-week period in October 2022 (01/10/22–31/10/22) were included. Any inpatients from different specialities or ward attenders were excluded from this study.

Data collection

The data were prospectively collected electronic patient records and ward lists, and analysed retrospectively. The inclusion criteria were any patient that underwent cardiac surgery in October 2022. Exclusion criteria were any patient admitted for reasons other than cardiac surgery, patients belonging to a different speciality, patients discharged without operation. Baseline data including age, body mass index (BMI), past medical history and existing medication was collected. Data relating to the operation was also collected, including type of operation, urgency of operation, cardiopulmonary bypass (CPB) usage and aortic cross-clamp time.

The use of post-operative diuretics in patients was measured, and we specifically noted which patients had been prescribed furosemide in this period. Starting dosage, delivery method, day started post-operatively, and any additional diuretic adjunct were recorded. Decisions regarding diuretics were made on daily ward rounds, and were based on a variety of factors. Diuresis, fluid balance, and patient weight were all considered, in addition to clinical signs like increasing oedema and pleural effusions. Throughout, renal profile bloods (urea and electrolytes) were monitored closely to ensure safe renal function while using diuretics.

The number of diuretic dose adjustments as an inpatient was the primary outcome measure recorded. Logistic regression was also undertaken to analyse any factors affecting the need for furosemide dose escalation.

Data analysis

Data analysis was undertaken using R (R Core Team) (13). Visual inspection and Kolmogorov-Smirnov tests were used to assess for normal distribution. Descriptive statistics were presented as median and interquartile range for continuous non-parametric data or mean and standard deviation for continuous parametric data. Categorical data were presented as numbers and percentage of total. Where subgroup comparisons were undertaken, Mann-Whitney U tests were used for continuous non-parametric data and t-tests for normally distributed data. Fisher’s exact was used for categorical data due to the small numbers in some groups. P values were reported as a two-sided test.

No data is missing from this report. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Following review from the local institution’s research board, ethical approval was waived, and as this was a retrospective study without intervention, no patient consent was required.

Results

Baseline characteristics

A total of 103 patients were included. Two patients were subsequently excluded as post-operative cardiac surgery patients who had previously been discharged but readmitted for wound management. Baseline characteristics for included patients are presented in Table 1. The incidence of comorbidities was high, as expected in a cardiac surgical population. In the population analysed, 101 patients underwent a range of cardiac operations summarised in Table 2. Two patients in the initial cohort were excluded from further analysis as they did not undergo a surgical procedure, and were admitted for other reasons (Figure 2).

Figure 2 Flowchart demonstrating selection of patients.

Post-operative diuretics

In total, 92.1% (N=93) of patients were given post-operative diuretics after leaving theatre, of which 92.5% (86/93) were initially prescribed furosemide alone, and 7.5% (7/93) were prescribed furosemide and another diuretic (eplerenone, spironolactone). The initial doses were prescribed as intravenous in 25.8% (24/93) of patients and orally in 74.2% (69/93) of patients. Day 1 post-operatively was the most common day for diuretics to be started, with 77.4% (72/93) being started on diuretics then. The dosage of furosemide ranged from 20 to 60 mg, with the most common starting dose for furosemide was 40 mg daily, with 76.3% (71/93) of patients receiving this initial dose.

Of those prescribed diuretics, 49.5% (46/93) required no adjustment to their diuretic dose, while 50.5% (47/93) required at least 1 dose adjustment. Of this group, 42.6% (20/47) patients required 1 change to furosemide prescription, 42.6% (20/47) required 2 changes, 8.5% (4/47) required 3 changes, 4.3% (2/47) required 4 changes, and 2.1% (1/47) required 5 changes (Figure 3). The dose adjustments were absolute increases, usually by increasing 20 to 40 to 80 mg, or these were increases from once daily dosing to twice daily dosing.

Figure 3 Sankey diagram of furosemide dose adjustments. Nodes indicate dosing history (Base, baseline furosemide from surgery; Up, dose escalation, Down, dose reduction; Disc, discontinued; e.g., Base > Up > Down: 20 shows number of patients who were given baseline furosemide, then dose escalated, then dose reduced is 20).

CPB

All patients that underwent off-pump operations (N=14) required postoperative diuretic, and 85.7% (12/14) were prescribed on day 1 post-operatively, and 14.3% (2/14) were prescribed on day 2. Those that did undergo CPB (N=87), 92.0% (80/87) required postoperative diuretics. However, the patients that did not have CPB required fewer dose adjustments, compared to patients that did (Table 3).

Other factors

In patients with congestive cardiac failure (CCF) (N=6), defined by the Framington Heart Failure Diagnostic Criteria (14), 66.7% (4/6) required dose adjustments post-operatively, and of the patients with chronic kidney disease (CKD) [based on baseline estimated glomerular filtration rate (eGFR)] (N=14), 57.1% (8/14) required adjustments. Adjunct diuretics were used alongside furosemide in 7.5% (7/93) of patients from day 1 post-operatively, and of these 57.1% (4/7) required dose adjustments.

Patients that required a dose escalation were compared to those who did not, based on specific characteristics (Table 3). Results showed that of the various characteristics, patients with a higher BMI were more likely to require a dose increase of furosemide (P=0.01).

Logistic regression was used to evaluate the effects of which factors increase probability of needing a dose escalation (Table 4). It showed that only diabetes was a predictive factor in the need to have dose escalations (P=0.03).

Length of stay was evaluated, and for patients with no dose escalations (N=75) the average length of hospital was 8.65 days, for those with 1 dose escalation (N=25) with average stay was 13.28 days, and for patients who had 2 dose increases the average stay was 25.67 days.

Discussion

Furosemide is a natriuretic drug that inhibits the Na⁺-K⁺-2Cl⁻ cotransporter in the ascending limb of the loop of Henle, resulting in the elimination of sodium and fluid from the circulation (15). It reduces fluid overload, the side effects of which are increased urine output and loss of potassium (16). Because of this complex interplay, the diuretic effect of furosemide is second order kinetics, with absorption affecting plasma concentrations, but response being determined by the renal tubular concentration (6). Subtherapeutic doses might therefore be accumulated to create a prolonged and sustained diuresis (17).

The pharmacokinetics of furosemide were established initially around half a century ago, with healthy volunteers and “functionally anephric” patients in small numbers making up the subjects of experimentation (18). More recently, there has been a resurgence of interest in the dosing and management of loop diuretics, but much of the literature relates to heart failure. In the presence of heart failure, it is necessary to start at a higher dose of loop diuretic as the dose-response curve is shifted downwards and to the right bringing about diuretic resistance (19). Additionally, the presence of CKD may also contribute to diuretic resistance as the amount of diuretic entering the nephron is reduced (20,21). Furthermore, consideration should be given to otherwise healthy individuals where there is potential for the diuretic effect to be diminished as the renin-angiotensin-aldosterone system may be activated causing an increase in retention of sodium and fluid (19).

There does not appear to be a consistent approach to prescribing loop diuretics or measuring their effects. Various optimal strategies have been posited, including frequent dosing (4); changing drug within the loop-diuretic class to one with greater bioavailability; adding a thiazide or potassium sparing diuretic along with a fluid restriction (8); or utilising as-needed doses of diuretic to prevent hypovalemia. When comparing intravenous use of furosemide with oral, the instantaneous bioavailability of the intravenous bolus exceeds the maximally efficient excretion rate (MEER) of the renal tubules where diuresis occurs, thus “wasting” much of the dose. For this reason, there may be little difference between oral and intravenous doses in diuretic effect (18). It should be noted, however, that initial studies concentrated on drug clearance rather than urine output, often replacing diuresed volume with intravenous fluid. More recently, diuretic effectiveness is measured as urine output and body weight changes, although patient-reported increases in urine volume are also suggested as a measure of effectiveness (9).

In the results, over 50% of patients prescribed furosemide post-operatively require adjustments in their initial dose, and of these 65.9% needed a dose increase, highlighting that for a significant group of patients they were potentially under-dosed initially. Most dose adjustments occurred in the first few days immediately post-operatively, however for patients that required increased adjustments this went on through the admission. Studies looking at the furosemide dose-response curve (22) indicate that one of the most important factors in determining response is assessing how much of the drug reaches the nephron, meaning that in some patients a higher dose is required to achieve the desired effect. However, there is a degree of unknown interpatient variability that likely affects the adequate dose required, making it difficult to predict who needs a higher dose (3).

Of the seven patients in this study with CCF, 66.7% (N=4) required dose escalations. Meticulous fluid balance in this group of patients is key, particularly in the post-operative period. In this study, all patients received bolus injection of furosemide, and there is much debate throughout the literature as to which is more effective, bolus or continuous infusion (23). Due to loop diuretics being filtered and secreted in the loop of Henle on the luminal side, continuous infusion is said to give a more consistent plasma concentration (24). However, infusions are associated with lower plasma concentrations compared to a bolus injection (18). Indeed, we were able to see adequate diuresis achieved in this study without the need to escalate to continuous infusion. This is supported by a systematic review that found no clinical benefit to continuous infusion, when evaluating mortality and duration of hospitalisation (25). Furthermore, in patients with CCF, studies have looked at adding hypertonic saline as an adjust to furosemide, with the rationale that it increased furosemide delivery in the nephron (26). This specifically looked at patients with refractory CCF, and aimed at looking at ways of reducing diuretic resistance that can occur over time. While most patients we reviewed were not on long-term furosemide, or diuretics prior to surgery, there were 27% (N=21) of patients already on diuretics that may have had an element of diuretic resistance.

The dose people were discharged home on aimed to be the lowest dose that still gave adequate diuresis and management of oedema. This is particularly important, as it has been shown that patients discharged on high doses of diuretic, can be a predictor of cardiovascular mortality (26). However, it could be argued that this more likely due to patients requiring higher doses, are more likely to have poorer cardiac and renal function and increased comorbidities. During their post-operative period, 35% of the diuretic cohort required a dose reduction, and this was usually once they had reached or were approaching their target admission weight, due to renal impairment or following assessment of fluid balance, or de-escalation of aggressive therapy prior to discharge.

These dosage decisions were made from assessing a combination of factors, including; fluid balance.

The results showed all patients who underwent surgery ‘off-pump’ required postoperative diuretics, but required fewer dose escalations compared to those that underwent surgery with CPB. While there is no study comparing CPB vs. off-pump surgery specifically related to fluid balance outcomes, there is some evidence that patients undergoing a CABG off-pump have fewer issues associated with diuresis (27). However, given the small sample size in this population, and limitations to wider research it is difficult to fully assess this. When patients undergo CPB there is significant inflammatory response (28), given that this is likely to cause some increase in peripheral vasodilation and accumulation in excess interstitial fluid (29), meaning the dosages of diuretic are likely to be higher.

The results showed diabetes was an independent risk factor for the need for dose adjustments. While there is limited literature looking specifically at furosemide and diabetic patients alone, there is evidence that diabetic patients with heart failure can require higher doses of furosemide (30). However, this study has a small sample size, and further, similar studies would need to be undertaken to assess diabetes as an independent predictor of furosemide dosage (31). In diabetic patients, higher doses are often required (32) and is thought to be related to increased insulin-mediated sodium reabsorption, leading to diuretic resistance (30). Moreover, in patients with obesity may have an attenuated response to furosemide, considered to be related to the larger volume of distribution (33).

Patients that had fewer dose escalations or adjustments had a shorter length in hospital stay, and those that required more escalation had a higher mean hospital length of stay (34). This highlights the importance of starting with a dose that is able to give desired therapeutic effect. This benefits not only patients, with reduced length of stay, but also helps to become more cost-effective. Studies have shown that issues with positive fluid balance was a direct predictor of prolonged hospital and intensive therapy unit (ITU) stay (35). However, what is not able to be investigated from our data is if there were any other issues that also contributed to longer length of stay, like social issues for example. Therefore, being an inpatient longer may have allowed for further optimisation of fluid balance, rather than being an effect of it.

There is evidence that prescribing furosemide with other diuretics as an adjunct, can enhance the effects, in addition to reducing the risk of diuretic resistance (36). In our results, there was a limited number of adjuncts used alongside the furosemide, highlighting an area for further study, looking at how this could benefit patients.

Strengths & limitations

When it comes to diuretic prescribing following cardiac surgery, there is still clinical equipoise, and that was the basis of this pilot study. The aim was to review prescribing practices, with the aim of a larger study in the future.

The retrospective nature of this study is a limitation, particularly when making inferences about how dosages were adjusted and why. There is significant heterogeneity in prescribing practices and rationale for adjusting dosage, which has made some comparisons difficult. Moreover, given how decisions regarding diuretic dosages and adjustments are sometimes recorded in medical records, it makes it hard to review retrospectively. Patients are typically cared for in the post-operative critical care unit (POCCU) immediately post-operatively, before being stepped down to the ward, and therefore this will also further increase the differences in prescribing practices. Moreover, the furosemide in this cohort was given as a bolus, it did not look into different methods of administration, for example continuous infusion, to see if this had any effect on the results.

This was a single-centre study, and therefore there is potential for possible sampling bias. However, as a large tertiary centre receiving referrals from all over the region, it can be presumed that there is a wide range of patients, comparable to other similar centres.

Conclusions

Optimisation of diuretic use for fluid management is vital to ensure effective euvolemia in post-operative patients. This not only helps to reduce complications associated with fluid overload in patients, but can also support a timely discharge and prevent delays due to fluid balance. Loop diuretics, particularly furosemide, are widely prescribed worldwide, and are effective and safe methods of diuresis in post-operative cardiac patients. Despite this however, there is still limited research on the most effective dosage regimes. Further research, in the form of a randomised control trial, would enable further investigation to find the optimal doses for furosemide, and look at differences in patient characteristics that affect differing responses. This would potentially help ensure both overuses, leading to electrolyte imbalance and renal impairment, but also help to ensure patients are not undertreated, leading to delays in discharge.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://asj.amegroups.com/article/view/10.21037/asj-23-29/rc

Data Sharing Statement: Available at https://asj.amegroups.com/article/view/10.21037/asj-23-29/dss

Peer Review File: Available at https://asj.amegroups.com/article/view/10.21037/asj-23-29/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-23-29/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Following review from the local institution’s research board, ethical approval was waived. As this was a retrospective study without intervention, no patient consent was required.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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