Phosphate-Sparing Solution to Prevent Hypophosphataemia in Patients Undergoing CRRT

Phosphate-based solutions used during continuous renal replacement therapy (CRRT) significantly reduce the incidence of hypophosphataemia in critically ill patients. These solutions are safe, improve phosphate balance, and may shorten ICU stay and ventilation duration, though further multicentre trials are needed to confirm these benefits.

Introduction

Phosphate plays a vital role in energy metabolism, cellular signalling, and the maintenance of cell membrane integrity through phospholipid synthesis (Wadsworth and Siddiqui 2016). These processes can be compromised by the acute physiological stress and specific pathophysiological changes observed in critical illness (Bellomo et al. 2014). Various conditions, including sepsis, gastrointestinal losses, diuretic use, and prolonged mechanical ventilation, can lead to intracellular redistribution, reduced absorption, and increased renal excretion of phosphate (Wadsworth and Siddiqui 2016).

Consequently, hypophosphataemia is a common complication in critical illness (Suzuki et al. 2013). Moreover, continuous renal replacement therapy (CRRT) can further lower systemic phosphate levels, exacerbating hypophosphataemia. Given the association between hypophosphataemia and adverse outcomes in critically ill patients (Kjellstrand et al. 2011; Lim et al. 2017), phosphate-containing solutions have been incorporated into CRRT protocols to mitigate this risk (Broman et al. 2011; Chua et al. 2012; Chua et al. 2013; Godaly et al. 2016).

Clinical Implications of Hypophosphataemia

The association between hypophosphataemia, acute kidney injury (AKI), and mortality remains controversial. A large retrospective study (Suzuki et al. 2013) found no independent association between hypophosphataemia and worse outcomes, whereas a more recent study reported that hypophosphataemia was associated with increased 90-day mortality in patients with higher disease severity. In general, hypophosphataemia is independently associated with numerous complications, including respiratory failure, myocardial dysfunction, haemolysis, and impaired inotropic response (Agusti et al. 1984; Melvin and Watts 2002; Rajaram and Subramanian 2018; Cohen et al. 2004).

Susceptibility to hypophosphataemia varies among critically ill patients. It is particularly prevalent following cardiac and abdominal aortic procedures (Geerse et al. 2010), with an even higher risk in patients with acute hepatic injury (e.g., acute liver failure and hepatic surgery), where the incidence reaches 100% in some studies (Buell et al. 1998; George and Shiu 1992; Salem and Tray 2005). Consequently, maintaining adequate serum phosphate levels becomes even more challenging in certain diseases and their subsequent clinical management.

CRRT-Induced Hypophosphataemia

Conventional CRRT dialysate and replacement fluids do not contain phosphate; therefore, the sieving coefficient for phosphate (i.e., the ratio of its concentration in the effluent to that in plasma) is approximately 1.0 (Troyanov et al. 2003). When higher effluent flow rates are used to achieve the desired solute clearance, the risk of iatrogenic phosphate loss increases further. However, while CRRT-induced hypophosphataemia has shown limited consequences in many retrospective studies, potentially due to prophylactic phosphate administration and replacement (Reintam et al. 2021), it remains associated with extended respiratory failure and prolonged ventilatory and vasopressor requirements (Lim et al. 2017).

A post hoc analysis of the Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement trial (Bellomo 2009) found that although higher CRRT intensity did not directly delay extubation, it was associated with a higher incidence of hypophosphataemia, which, in turn, was associated with a reduced likelihood of successful extubation (Serpa Neto et al. 2023). Additionally, prolonged CRRT further predisposes patients to phosphate depletion. Reported rates of hypophosphataemia during CRRT range from 27% to 78%, with variability likely reflecting differences in patient aetiology and treatment parameters (Bellomo 2009; Demirjian et al. 2011; Yang et al. 2013).

Phosphate Replacement

Some studies suggest clinical benefits from phosphate replacement in the ICU setting, including reduced arrhythmias and complications across various patient populations (Kahn et al. 2015; Schwartz et al. 2014). However, the optimal phosphate replacement strategy for hypophosphataemia in critically ill patients remains poorly defined in the literature, despite clear serum laboratory targets (Reintam et al. 2021). Although hypophosphataemia can be safely corrected through intravenous infusion of up to 45 mmol/kg of phosphate, it can still lead to variability in serum phosphate levels, hypomagnesemia, hypocalcaemia, and hypotension (Geerse et al. 2010). Similarly, adding phosphate to CRRT fluids off-label can result in calcium precipitation, compromise sterility, and increase the risk of administration errors, supporting the use of pre-formulated, phosphate-containing fluids (Chua et al. 2012).

Safety and Efficacy of Phosphate-Based CRRT Solutions

Previous studies have demonstrated that phosphate-based solutions are safe and effective in preventing hypophosphataemia across various CRRT modalities. The main findings of key retrospective studies on phosphate based CRRT are summarised in Table 1. While many of these studies are retrospective and subject to selection bias and confounding, crossover studies provide stronger evidence by controlling for patient-specific covariates. In a crossover study (Chua et al. 2012), switching to phosphate-based solutions significantly improved serum phosphate levels after 36–42 hours of treatment in patients receiving continuous veno-venous haemofiltration. Similarly, phosphate-based solutions effectively prevented hypophosphataemia in patients undergoing different continuous veno-venous haemodiafiltration (Broman et al. 2011; Besnard et al. 2016). This effect was more pronounced when phosphate-based solutions was used as both a dialysate and a replacement solution (as opposed to just one or the other), possibly due to increased phosphate delivery and reduced convective removal. However, its use in either role generally stabilised phosphate levels. These studies may be confounded by heterogeneous patient populations with varying diagnoses (e.g., sepsis, cardiogenic shock, hepatorenal syndrome) that affect phosphate dynamics, as well as the lack of reporting on AKI stages, which influence renal phosphate excretion. Furthermore, small sample sizes may limit the generalisability of the findings and introduce bias and variability, making it challenging to isolate the treatment effect.

Phosphate-based solutions have been associated with improved patient outcomes. Thomson Bastin et al. (2022) reported that phosphate-containing solutions were independently associated with a reduced ICU length of stay and a shorter duration of mechanical ventilation, suggesting a meaningful patient-centred benefit (Thompson et al. 2022). Although limited by its single-centre design, the study’s large sample size provides strong statistical power. However, the generalisability of these findings may be constrained by the study’s setting, highlighting the need for multicentre trials to confirm the broader applicability of phosphate-containing CRRT fluids in the ICU.

Phosphate-containing fluids have been associated with mild iatrogenic metabolic acidosis and mild hypocalcaemia (Chua et al. 2013: Besnard et al. 2016; Lee et al. 2019). Metabolic acidosis may occur because phosphate acts as a non-volatile weak acid (Chua et al. 2012), while hypocalcaemia may result from phosphate’s ability to complex with ionised calcium, particularly in critically ill patients with an altered

calcium-phosphate balance (Sutters et al. 1996). However, calcium precipitation may be less pronounced with phosphate-based CRRT than with intravenous phosphate supplementation, as CRRT provides gradual 24-hour replacement. Instead, the hypocalcaemia observed with phosphate-based solutions may be due to its lower calcium content compared to standard CRRT fluids.

Despite physiological phosphate concentrations in phosphate-based solutions, patients often experience relatively higher rates of hyperphosphataemia, with half of the patients in one study developing it (Chua et al. 2012). Additionally, maximum serum phosphate levels were similar between the phosphate-solution and standard-solution cohorts, suggesting that hyperphosphataemia may not be attributable to the specific composition of the fluid (Chua et al. 2012). Instead, the increased risk of hyperphosphataemia may be associated with an excessively catabolic state, exacerbated by cytokine and hormonal derangements common in many critical illnesses, which accelerate protein breakdown (Chua et al. 2012; Rennie 2009). The optimal aetiology-specific strategy for CRRT patients, therefore, remains poorly understood. Finally, reducing phosphate supplementation requirements also decreases clinical staff workload. A recent survey indicates that nurses find phosphate-containing CRRT fluids safer and less burdensome than conventional CRRT fluids (Besnard et al. 2016).

Conclusion

Hypophosphataemia is a frequent complication in critically ill patients, and the negative phosphate balance associated with prolonged CRRT using phosphate-free solutions is the most common cause of phosphate depletion in those with severe AKI. The clinical efficacy of phosphate-containing solutions in reducing hypophosphataemia has been demonstrated in multiple retrospective trials. As persistent hypophosphataemia, particularly in severe cases, is associated with adverse outcomes, any strategy aimed at reducing its incidence and severity appears reasonable.

Conflict of Interest

None.