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Early phosphate changes as potential indicator of unreadiness for artificial feeding: a secondary analysis of the EPaNIC RCT

Critical Care volume 29, Article number: 48 (2025) Cite this article

Abstract

Background

As compared to withholding parenteral nutrition (PN) until one week after intensive care unit (ICU) admission, Early PN prolonged ICU dependency in the EPaNIC randomized controlled trial (RCT). The Refeeding RCT showed improved outcome by temporary macronutrient restriction in ICU patients developing refeeding hypophosphatemia, defined as a phosphate decrease of > 0.16 mmol/L to levels < 0.65 mmol/L. We hypothesized that early phosphate changes may identify critically ill patients who are harmed by Early PN, and that dynamic phosphate changes are more discriminative than an absolute threshold for hypophosphatemia.

Methods

In this secondary analysis of the EPaNIC RCT, we studied whether absolute hypophosphatemia (AHP; < 0.65 mmol/L on the second ICU-day), relative hypophosphatemia (RHP; > 0.16 mmol/L decrease over the first 2 ICU-days), or a combination of both (CHP) interacted with the randomized nutritional strategy for its impact on outcome, adjusted for risk factors. In case of significant interaction, we studied whether the respective change could be predicted by baseline characteristics.

Results

Of 3520 patients with available phosphate measurements, AHP developed in 9.1%, RHP in 23.7%, and CHP in 5.3% of patients. RHP, but not AHP or CHP, interacted with the randomized intervention for its impact on outcome (p = 0.01). In RHP patients, Early PN independently associated with a lower likelihood of an earlier discharge alive from ICU (adjusted HR 0.75 [0.65–0.87]). In patients without RHP, Early PN did not significantly associate with this outcome (adjusted HR 0.93 [0.86–1.00]). Development of RHP was only poorly predicted by admission characteristics (adjusted pseudo R-squared = 1.7%).

Conclusion

Development of RHP may identify patients who are particularly harmed by early PN. Future studies should prospectively validate the potential of including RHP in a ready-to-feed indicator.

Background

The optimal timing, dose and composition of artificial nutrition in critically ill patients remains unclear [1,2,3,4]. Over the last 15 years, several large randomized controlled trials (RCTs) have not shown any benefit of early enhanced nutrition [5,6,7,8,9], and several RCTs even demonstrated harm as compared with relative macronutrient restriction [6,7,8,9,10,11,12,13,14,15]. In this regard, the EPaNIC RCT was the first trial to demonstrate that early supplementation of insufficient enteral nutrition (EN) with parenteral nutrition (Early PN) prolonged intensive care unit (ICU) and hospital dependency as compared with postponing PN until one week after ICU admission (Late PN) [10]. Prespecified subgroup analyses of this RCT did not identify heterogeneity of treatment effects by multivariable interaction models and revealed harm by Early PN in all studied subgroups [10, 14, 16].

Recent evidence indicates that phosphate levels declining upon feeding may be an easily accessible read-out of metabolic intolerance to nutrition [17, 18]. Indeed, in the Refeeding RCT (n = 339), continuing and advancing nutritional support in critically ill patients developing hypophosphatemia within 72h after initiation of nutrition was associated with excess mortality as compared with temporary macronutrient restriction [17]. Interestingly, this phenomenon occurred despite adequate phosphate and vitamin provision, with rapid correction of hypophosphatemia. Likewise, an observational study found that increased macronutrient intake was associated with increased mortality exclusively in patients with refeeding hypophosphatemia [18]. Remarkably, in both studies, phosphate levels were adequately corrected within 48 h [17, 18]. Moreover, in univariate analysis, both refeeding hypophosphatemia and the magnitude of the phosphate decrement did not associate with impaired outcome [18]. Altogether, this suggests that refeeding hypophosphatemia may be a marker of unreadiness for nutritional support rather than a direct mediator of poor outcomes.

The Refeeding trial defined refeeding hypophosphatemia as a phosphate decrease of at least 0.16 mmol/L to levels below 0.65 mmol/L after initiation of nutritional support [17, 18]. It remains unclear whether absolute hypophosphatemia and a decrease in phosphate levels are both necessary criteria to detect patients at risk for poor outcomes by enhanced nutritional support. Considering the dynamic interaction of phosphate with nutrition, a relative decrease in phosphate could be more informative than a fixed hypophosphatemia threshold to detect patients at risk for macronutrient-induced harm.

We hypothesized that early phosphate alterations would allow identification of patients who are harmed by Early PN in the EPaNIC RCT, and that dynamic changes are more discriminative to detect unreadiness to nutritional support than a fixed threshold for hypophosphatemia. To that purpose, we investigated whether there was a statistical interaction between the randomized treatment and the development of early phosphate alterations for the impact of randomization on outcome. Early phosphate changes were studied as the occurrence of absolute hypophosphatemia, a decrease in phosphate levels irrespective of the absolute value (relative hypophosphatemia), or the combination of both. In case of a significant interaction, we studied whether the respective phosphate alteration could be predicted by admission characteristics.

Methods

Study design and participants

This is a secondary analysis of the EPaNIC RCT (Clinicaltrials.gov: NCT00512122), following the STrengthening the Reporting of Observational studies in Epidemiology (STROBE) statement [10, 19]. The protocol of the study was approved by the Ethical Committee Research UZ/KU Leuven (ML4190). Written informed consent was requested from the patient or the patient’s representative. The study protocol and primary results have been published previously [10, 20]. In brief, 4640 patients were randomized to receive early (N = 2312) versus delayed (N = 2328) supplementation of insufficient or contraindicated EN by PN. After randomization, a glucose infusion was started (20% glucose infusion in patients receiving Early PN, 5% glucose in patients randomized to Late PN), and EN was initiated on the evening of the second ICU day, unless contraindicated. In patients randomized to Early PN, PN was initiated on the morning of the third ICU day, and continued until enteral/oral intake covered at least 80% of the calculated energy target [20]. In patients randomized to Late PN, PN was only initiated after one week in ICU, if EN was still insufficient or contraindicated at that time. Patients in both groups received parenteral micronutrients until sufficient enteral/oral intake, to prevent deficiencies. Metabolic tolerance was monitored in both groups, including (among others) monitoring of blood glucose and urea. Per protocol, all patients received tight blood glucose control to target 80–110 mg/dL (4.4–6.1 mmol/L) [10, 20]. Plasma phosphate concentrations were measured daily by the central laboratory at the time of the routine morning blood sampling (6 ± 2 am). Early PN prolonged the dependency on intensive care -the primary endpoint-, with a prolonged dependency on mechanical ventilation and an increased incidence of new infections. Mortality at 90 days -the safety endpoint-, and mortality at 2 and 5 years were not affected [16, 21].

For this study, we included all EPaNIC patients with an ICU stay of at least two days and available phosphate measurements (Supplementary Fig. 1). Based on previous studies, we defined combined hypophosphatemia (CHP) as a plasma phosphate declining by at least 0.16 mmol/L to levels below 0.65 mmol/L on the second day in ICU, absolute hypophosphatemia (AHP) as a plasma phosphate below 0.65 mmol/L on the second day in ICU, and relative hypophosphatemia (RHP) as a decrease of plasma phosphate by minimum 0.16 mmol/L, regardless of the baseline value [17, 18]. The primary endpoint was the duration of ICU dependency, which we studied as the time to being discharged alive from ICU to correct for mortality as competing risk. To that purpose, data from non-surviving ICU patients were censored at a time point beyond that of the last surviving patient. Mortality at 90 days after randomization was the safety endpoint. Secondary outcomes included the time to successful weaning from mechanical ventilation, the incidence of new infections in ICU, the time to discharge alive from hospital, and mortality after 2 and 5 years. We first investigated, for the primary and safety outcomes, whether there was a statistical interaction between randomization and the occurrence of CHP, AHP and RHP through multivariable regression analyses, adjusted for baseline characteristics. In case of a significant interaction, we studied the impact of the randomized intervention on secondary outcomes in the respective subgroups, and we investigated whether development of the respective phosphate change could be predicted by ICU admission characteristics. Moreover, as exploratory sensitivity analysis, we studied the interaction between randomization and the occurrence of CHP, AHP and RHP for the effect of the randomized intervention on the primary endpoint in subgroups with or without early renal dysfunction. Patients having received renal replacement therapy pre-admission or in the first 2 ICU days,, and patients with a plasma creatinine ≥ 2 mg/dL on the first or second day in ICU were considered to have early renal dysfunction.

Statistical analysis

Data were presented as median and interquartile range (IQR) or as number and percentage, as appropriate. For continuous variables, normality was assessed visually and by the Smirnov-Kolmogorov test. We used nonparametric testing (Mann–Whitney U or Wilcoxon rank-sum test) to compare continuous data, and chi-square test or Fisher’s exact test for categorical data, as appropriate. Kaplan–Meier curves visualize the time to discharge alive from ICU and survival in the different subgroups.

We applied multivariable Cox and logistic regression models to study whether the randomized intervention was associated with differences in the primary and safety endpoints, and to study whether there was a statistical interaction between randomization and development of an early phosphate change for the impact of randomization on outcome. Risk factors used for adjustment in multivariable models included age (per 1 year), body-mass index (BMI; between 25 kg/m2 and 40 kg/m2 versus other), history of malignancy, diagnostic category at admission (cardiac surgery or complications thereafter; other major surgery or complications thereafter; medical diseases; trauma/burns), Nutritional Risk Screening-2002 (NRS) score (NRS ≥ 5 versus other), and Acute Physiology and Chronic Health Evaluation II (APACHE II) score, as in the original RCT [10]. Hazard ratios and odds ratios were reported as appropriate, with the 95% confidence interval.

If the multivariable interaction model revealed a significant interaction between randomization and a particular phosphate change, we investigated by multivariable logistic regression whether the respective phosphate alteration could be predicted by baseline risk factors [22]. Apart from randomization, the studied ICU admission characteristics included age, BMI, history of malignancy, diagnostic category, NRS score and APACHE II score, as these factors may determine the risk of refeeding syndrome [23, 24]. A pseudo-R Square was calculated according to McFadden to approximate the proportion of variance estimated by the model [25]. Potential collinearity among variables in the regression models was assessed by the generalized variance inflation factor (GVIF). GVIF values < 4 were considered acceptable.

Statistical analyses were performed using R statistical software. (version 4.3.4, The R Project for Statistical Computing, Vienna, Austria) and the RStudio interface (version 2024.04.0, Boston, MA, USA). For interaction p-values, the threshold for statistical significance was set at 0.2 to avoid missing an interaction that could be clinically relevant. For other analyses, two-sided p-values below 0.05 were considered statistically significant, without correction for multiple comparisons.

Results

Baseline characteristics and nutritional intake of the study population

From the 4640 patients included in the EPaNIC RCT [10], 3520 patients had available plasma phosphate measurements on ICU day 1 and 2, and were included in this secondary analysis (Supplementary Fig. 1). CHP developed in 187 (5.3%) patients, AHP in 321 (9.1%) and RHP in 834 (23.7%) patients. Patients developing CHP and AHP were younger, with more frequently a history of malignancy, higher NRS scores, different admission diagnoses, and higher APACHE II scores than patients without these phosphate alterations (Table 1). Patients with AHP also had lower BMI than patients without AHP. Patients developing RHP were younger and more often male, with more frequently a history of malignancy and different admission diagnoses than patients without RHP (Table 1). Patients developing CHP and AHP more frequently belonged to the Early-PN arm, while RHP patients were more often randomized to Late PN (Table 2). In the CHP and AHP subgroups, baseline characteristics were comparable between Early and Late PN patients (Table 2). In the RHP subgroup, Early PN patients had different ICU admission diagnoses and higher APACHE II scores than Late PN patients (Table 2). Baseline characteristics of patients not developing early phosphate changes were comparable between Early and Late PN patients (Supplementary Table S1).

Table 1 characteristics of patients with and without early phosphate alterations
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Table 2 characteristics of Early and Late PN patients developing early phosphate alterations
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Regardless of the occurrence of early phosphate alterations, Early PN patients received a higher caloric intake in the first ICU week than Late PN patients (p < 0.0001 for all days, Supplementary Fig. 2). During the first 2 days in ICU, 490 patients (14.7%) received phosphate supplementation, and plasma phosphate levels were adequately corrected within days (Supplementary Fig. 2).

Impact of early PN in relation to early phosphate alterations

For the primary and safety endpoint, there was no interaction between the randomized intervention and development of CHP or AHP (Table 3, Fig. 1A–D). Development of RHP significantly interacted with the randomized feeding intervention for the primary endpoint (Table 3 and Fig. 1E). In patients with RHP, Early PN independently associated with a lower likelihood of an earlier discharge alive from ICU (adjusted HR 0.75 [0.65–0.87]). In patients without RHP, Early PN did not independently associate with this outcome, although the likelihood of earlier alive ICU discharge tended to be lower (adjusted HR 0.93 [0.86–1.00]). For 90-day mortality, there was no interaction between the randomized intervention and development of RHP, and Early PN did not independently associate with this outcome (Table 3 and Fig. 1F). In patients with RHP, Early PN independently associated with a lower likelihood of earlier successful weaning from mechanical ventilation (adjusted HR 0.74 [0.64–0.86]), a higher incidence of new infections in ICU (adjusted OR 1.48 [1.07–2.04]), and a lower likelihood of earlier discharge alive from hospital (adjusted HR 0.80 [0.68–0.93]). Early PN did not independently associate with mortality at 2 and 5 years (Table 4).

Table 3 primary and safety outcomes for patients with and without hypophosphatemia
Full size table
Fig. 1
figure 1

Kaplan–Meier estimates of the time to discharge alive from the intensive care unit (ICU) and survival for 90-days after ICU admission in patients randomized to Early and Late PN, and with/without combined hypophosphatemia (CHP) (panel A and B, resp.), absolute hypophosphatemia (AHP) (panel C and D, resp.) and relative hypophosphatemia (RHP) (panel E and F, resp.)

Full size image
Table 4 secondary outcomes for patients with relative hypophosphatemia
Full size table

In a post-hoc exploratory sensitivity analysis, we repeated the interaction analyses for the primary endpoint in the subgroups of patients with and without early renal dysfunction. Early renal dysfunction occurred in 283 (16.3%) patients receiving Early PN and in 318 (17.8%) patients receiving Late PN (p = 0.3). In patients without renal dysfunction, there was a significant interaction between randomization and development of RHP for the impact on the duration of ICU dependency, with more harm by Early PN in patients developing RHP as compared with those not developing RHP. Such significant interaction was not observed for patients with early renal dysfunction. Development of AHP or CHP did not associate with a differential impact of the randomized intervention in both patients with and without early renal dysfunction (Supplementary Table 2).

In all regression models, GVIFs were below 4, which excluded relevant collinearity.

Factors associated with development of RHP

Age (p = 0.003), diagnostic category at admission (p < 0.001), APACHE II (p = 0.02) and the randomized feeding intervention (p < 0.001) independently associated with the occurrence of RHP, whereas BMI, a history of malignancy and NRS score did not (Supplementary Table 3). Yet, the overall performance of the multivariable model was poor (pseudo R-Squared 1.7%). All variables in the prediction model had a GVIF below 2.1.

Discussion

In this secondary analysis of the EPaNIC RCT, an early phosphate decrease (RHP) occurred in 23.7% of patients, while AHP and CHP occurred less frequently (9.1%, respectively 5.3% of patients). There was a statistical interaction between the development of RHP and the effect of the randomized intervention on the primary outcome. Indeed, Early PN significantly prolonged ICU dependency in patients developing RHP, whereas there was no significant harm in patients without RHP. There was no interaction between development of AHP/CHP and the effect of the randomized intervention on the primary and safety outcome, suggesting that patients were equally harmed by the intervention, regardless of development of AHP or CHP. Altogether, these data suggest that an early phosphate decrease may identify patients who are particularly harmed by Early PN. Development of RHP was poorly predictable by baseline characteristics.

The results are in line with previous studies that suggested that phosphate changes may identify patients who are harmed by high feeding doses. Indeed, the Refeeding RCT showed harm by continuing and increasing nutritional support in patients developing CHP within 72 h after initiation of feeding, as compared with temporary macronutrient restriction while correcting electrolyte and micronutrient deficiencies [17]. Similarly, an observational study associated harm by increased macronutrient doses solely in patients developing CHP after initiation of nutrition [18]. As in the current study, the latter study reported that these phosphate changes could hardly be predicted by clinical characteristics. Yet, in these preceding studies, phosphate changes were defined as decreases in phosphate to levels below the normal threshold. We found that an early phosphate decrease may be more discriminative than absolute hypophosphatemia in identifying vulnerability to higher nutritional doses. Indeed, only for RHP, there was a significant interaction with the randomized intervention for its effect on the primary outcome, which was not observed for AHP and CHP. Nevertheless, we may lack power to detect a significant interaction due to a lower number of patients developing the latter conditions. This may be especially so for CHP, since CHP is a form of RHP, and the point estimate of the mean effect of Early PN in CHP patients may suggest potentially more harm than in patients with RHP.

The reasons why a phosphate decrease could be an indicator of harm by higher feeding doses require further study. As phosphate was rapidly corrected in the current study, phosphate changes were likely a marker rather than a mediator of poor outcome with increased nutritional intake. Similarly, in the Refeeding RCT, an adverse outcome occurred in patients receiving higher feeding intake upon refeeding hypophosphatemia, although restoration of phosphate levels occurred rapidly and at the same speed than in the group with temporary caloric restriction [17]. Phosphate decreases are known to occur in hyperventilation [26,27,28,29]. In this condition, it is triggered by increased glycolytic flux due to respiratory alkalosis, leading to increased phosphate consumption and energy production that exceeds metabolic need [26, 27, 29]. Hence, phosphate decreases could be an indicator of unreadiness for high exogenous feeding doses, which requires further study.

Large RCTs in critically ill patients have shown harm by early high-dose nutritional support, regardless of the route [11, 12, 20]. Absence of benefit has been attributed to anabolic resistance, to suppression of beneficial repair pathways that are activated by fasting, and to iatrogenic hyperglycemia [13, 30,31,32]. As a result, current nutritional guidelines recommend to avoid early high feeding doses [1,2,3,4]. Nevertheless, prolonged fasting will expectedly come at a price, and the time when adequate feeding responsiveness occurs, likely varies over time in ICU and between patients. In non-critically ill patients, a large RCT showed benefit by enhanced nutritional support, although this benefit was not observed in patients with severe inflammation [33, 34]. Hence, there is an urgent need for validated biomarkers that can capture (un)readiness for nutritional support. Given the complexity of human biology, it seems unlikely that one single biomarker will suffice. Based on our findings, a phosphate decrease could be one promising biomarker, although it would likely need to be used in conjunction with other markers [35]. Indeed, in patients without RHP, point estimates for the primary endpoint, albeit non-significant, also were in the direction of harm. Hence, apart from markers clearly anticipating an untoward response to feeding, there is an urgent need for biomarkers that can predict a beneficial response to feeding. In the absence of such markers, and given the fact that a phosphate decrease was poorly predictable, it seems prudent to provide restrictive feeding in the acute phase to all critically ill patients, while awaiting further evidence.

The study is a secondary analysis of a large nutritional RCT with detailed prospective collection of data, which is a strength. Nevertheless, the study has several limitations. First, we cannot exclude selection bias, as we could only study patients with minimum ICU stay of 2 days and available phosphate measurements. However, from a clinical perspective, enhanced feeding is usually not considered on the first ICU day. Second, although we carefully adjusted for baseline characteristics, we cannot exclude residual confounding. Subgroup analyses should be interpreted cautiously as they may overinterpret potential effects. Per protocol, the initial glucose doses, and -as a consequence- the insulin doses differed between groups. This could have triggered phosphate decreases more rapidly in Early PN patients. However, RHP occurred more often in Late PN patients. Phosphate levels may be affected by renal function, drugs including diuretics, fluid management strategy, and use of renal replacement therapy, for which we did not adjust, as these are post-randomization characteristics. However, not taking these factors into account is expected to underestimate rather than overestimate a potential interaction. In a post-hoc exploratory subgroup analysis, the significant interaction between RHP and the effect of the randomized intervention on the primary endpoint was only observed in patients without early kidney dysfunction. Although the lower number of patients with early renal dysfunction may have induced lack of power, these data may suggest that early phosphate decreases in this subgroup are more reflective of other aspects of patient condition (e.g., initiation of renal replacement therapy) rather than a marker of metabolic unreadiness for nutrition. Based on previous studies, RHP was defined as a phosphate decrease of > 0.16 mmol/L. It remains unclear whether different cutoffs might be more discriminative for poor outcome associated with enhanced nutritional support. Moreover, we did not study whether harm associated with Early PN in patients with relative hypophosphatemia is due to increased caloric intake, or to harm by individual macronutrients. Previous studies in both general ICU patients and in patients with refeeding hypophosphatemia have suggested that increased protein delivery may be more important than overall caloric intake to mediate harm by enhanced feeding [14, 36]. Finally, we only studied the impact of a feeding intervention with specific timing, dose and macronutrient composition. Hence, the results require validation and may not necessarily be extrapolated to other feeding strategies.

Conclusions

In this secondary analysis of the EPaNIC RCT, an early phosphate decrease, but not absolute hypophosphatemia, identified patients who were particularly harmed by Early PN. This opens perspectives for including phosphate changes in a ready-to-feed indicator, with the ultimate aim of implementing true individualized nutritional support, which requires further study in prospective validation studies.

Availability of data and materials

Datasets generated during and/or analyzed during the current study are not publicly available. Data sharing will be considered on a collaborative basis with the principal investigators, after evaluation of the proposed study protocol and statistical analysis plan. Data are stored on controlled access servers at KU Leuven.

Abbreviations

RCT:

Randomized controlled trial

EN:

Enteral nutrition

PN:

Parenteral nutrition

ICU:

Intensive care unit

STROBE:

STrengthening the Reporting of Observational studies in Epidemiology

AHP:

Absolute hypophosphatemia

RHP:

Relative hypophosphatemia

CHP:

Combined hypophosphatemia

IQR:

Interquartile range

BMI:

Body-mass index

NRS:

Nutritional Risk Screening-2002

APACHE II:

Acute Physiology and Chronic Health Evaluation II

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Acknowledgements

The authors acknowledge all authors and collaborators listed on the original EPaNIC study report for their efforts regarding patient recruitment, compliance to the protocol, and data collection.

Funding

This work was supported by KU Leuven (research project funding C24/17/070 to MPC and JG; STG/23/032 to JG), a European Research Council Advanced Grant (AdvG-2017–785806 to GVdB) from the European Union’s Horizon 2020 research and innovation program, the Methusalem program of the Flemish Government (METH/14/06 to GVdB and LL via the KU Leuven), Research Foundation—Flanders, Belgium (Grant G069421N to LL and GVdB; senior clinical investigator fellowship to JG [1842724N] and MPC [1832822N]), and the Clinical Research and Education Council of the University Hospitals Leuven, Belgium (postdoctoral fellowship to JG).

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Author notes

  1. M. P. Casaer and J. Gunst have contributed equally to this work.

Authors and Affiliations

  1. Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium

    C. Lauwers, L. Langouche, P. J. Wouters, G. Van den Berghe, M. P. Casaer & J. Gunst

  2. Department of General Internal Medicine, University Hospitals Leuven, 3000, Leuven, Belgium

    A. Wilmer

Authors
  1. C. Lauwers
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  2. L. Langouche
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  3. P. J. Wouters
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  4. A. Wilmer
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  5. G. Van den Berghe
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  6. M. P. Casaer
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  7. J. Gunst
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Contributions

CL, LL, MPC, JG and GVdB designed the study. CL, LL, MPC, JG, GVdB, AW and PJW participated in data collection. CL, LL, MPC and JG analyzed and interpreted the results. CL drafted the manuscript, which was revised by JG, MPC and LL, and thereafter reviewed by other authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to M. P. Casaer.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethical Committee Research UZ/KU Leuven as central ethical committee (ML4190), and by the local ethical committee of Jessa Hospital Hasselt as participating center. Written informed consent was obtained from all patients or their representative.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Lauwers, C., Langouche, L., Wouters, P.J. et al. Early phosphate changes as potential indicator of unreadiness for artificial feeding: a secondary analysis of the EPaNIC RCT. Crit Care 29, 48 (2025). https://doi.org/10.1186/s13054-025-05273-2

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  • DOI: https://doi.org/10.1186/s13054-025-05273-2

Keywords

Critical Care

ISSN: 1364-8535