A simulation-based study was conducted to assess the adequacy of the macronutrient (protein, glucose, and lipid) and caloric content of commercially available 3CPNB formulations across different clinical scenarios in Spain. The study took place between March and June 2025.

No ethical approval was required, as the study was based on simulated patients and did not involve humans.

Inclusion: This study was focused exclusively on adults (≥ 18 years old) with standard nutritional requirements.

Exclusion: Patients with complex conditions that could significantly alter macronutrient requirements were excluded, namely body mass index (BMI) <18.5 or >30 kg/m2; renal or liver impairment; severe metabolic disturbances (e.g., uncontrolled glucose intolerance, hypertriglyceridemia); risk of refeeding syndrome; pregnancy; burns; or any other condition requiring individualized nutritional management.

Four common clinical scenarios were defined to represent a broad range of hospitalized adult patients requiring PN:

— Scenario I1 (acute early phase of intensive care): defined as the first 3–4 days following admission to the intensive care unit (ICU), typically characterized by hemodynamic instability and initial caloric restriction, with relatively high protein intake.17

— Scenario I2 (acute late phase of intensive care): representing the subsequent days of ICU stay, during which full nutritional targets are pursued.17

— Scenario Q (uncomplicated surgical patients): postoperative patients without organic failure, sepsis, or significant metabolic disturbances, typically requiring higher protein intake.18

— Scenario M (uncomplicated medical patients): stable medical patients without acute inflammatory conditions or critical illness.19

Based on these scenarios, two complementary sub-studies were conducted:

— 3CNPB-centered analysis: Evaluation of the macronutrient profiles of each 3CPNB to determine their theoretical suitability for each predefined clinical scenario, based on guideline-defined energy and protein targets.

— Patient and scenario-centered analysis: Assessment of 1000 simulated patients per scenario (total: 4000 simulations) to determine which 3CPNBs could meet their individual nutritional requirements within each scenario. Energy and protein needs were calculated for each patient based on body weight, according to ESPEN-recommended targets for each scenario. The utilization rate of each 3CNPB was calculated per scenario.

In all calculations, a deviation of ±5% from target values was considered acceptable.20

A detailed breakdown of these sub-analyses is available in Supplementary Fig. 1.

The 3CPNB formulations initially included in this study were those listed as commercially available in the CIMA (Centro de Información de Medicamentos) database of AEMPS (Agencia Española de Medicamentos y Productos Sanitarios – Spanish Agency of Medicines and Health Products, Ministry of Health)6 on April 2nd, 2025.

Nutritional composition data were obtained from the official manufacturer's datasheets available through the CIMA website.

3CNPBs from the same manufacturer with identical macronutrient composition but differing in micronutrient content (mainly electrolytes) were considered a single formulation for the purposes of this study.

To standardize values across different brands and presentations, total caloric content was calculated using the classical Atwater system: 4 kcal/g of glucose or protein, and 9 kcal/g of lipid. The Jones' factor (6.25 g of protein/g of nitrogen) was used to calculate the non-protein calorie-to-nitrogen ratio (NP kcal/g N). To quantify this standardization, the difference between the calculated kcal and those reported in the technical data sheet, as well as the corresponding percentage difference, was analyzed.

Each unique 3CNPB formulation was assigned a code based on its approximate total caloric and protein content (i.e., E[kcal/100]N[g protein/L]). When several manufacturers offered 3CNPBs with very similar macronutrient compositions, an additional letter (e.g., B, C, etc.) was appended to the code to distinguish between them. The composition of micronutrients (electrolytes, vitamins, and trace elements), as well as the total volume of PN, was considered beyond the scope of this study and was not considered.

It was assumed that 3CPNBs represented the only source of nutritional intake and contributions from concurrent intravenous fluids, enteral, or oral nutrition were not considered. It was also assumed that the entire content of a single bag was fully administered over a 24-h period, without combining or adjusting volumes between bags.

A cohort of 1000 simulated patients was generated and applied to each of the four predefined scenarios, resulting in a total of 4000 simulations.

Body weight was the variable used to calculate individual macronutrient and caloric requirements. The weight of 1000 patients was simulated through random number generation using a normal distribution, based on the published values for the Spanish population21. Height was not simulated, as nutritional targets are weight-based, and BMI was used only as to exclude underweight and obese profiles.

Patients' weights were grouped into 12 strata to facilitate the presentation of results.

A sample size of 1000 simulated patients per scenario was selected to ensure sufficient representation across the body-weight distribution. This number allowed each percentile to be represented by 10 individuals, enabling precise and interpretable estimates of nutritional adequacy across weight strata. A formal power calculation was not applicable, as this was a study without hypothesis testing or group comparisons.

Nutritional targets for each clinical scenario were based on current recommendations from the European Society for Clinical Nutrition and Metabolism (ESPEN).

The dosing targets used in this study were as follows:

— Scenario I1 (acute early phase of intensive care): Calorie intake: 14–17.5 kcal/kg/day; protein 0.91 g/kg/day (approximately 70% of the requirement in the subsequent phase).17

— Scenario I2 (acute late phase of intensive care): Calorie intake: 20–25 kcal/kg/day; protein 1.3 g/kg/day.17

— Scenario Q (surgical patients): Calorie intake: 25–30 kcal/kg/day; protein 1.5 g/kg/day.18

— Scenario M (medical patients): Calorie intake; 25–30 kcal/kg/day; protein 1.2–1.5 g/kg/day.19

The NP kcal/g N ratios were calculated from the caloric and protein goals recommended in the ESPEN guidelines for each clinical scenario. The resulting intervals were: 62.0–107.8 for both intensive care scenarios (I1 and I2), 69.2–113.2 for surgical patients (Q), and 69.2–147.7 for medical patients (M). 3CPNBs that did not meet any of those ratios would be excluded, as they failed to comply with ESPEN nutritional guidelines in all scenarios.

Additional considerations included ensuring that carbohydrates provided between 50% and 80% of non-protein calories,22 limiting glucose dose to 7 g/kg/day (approximately 5 mg/kg/min),17 avoiding lipid emulsion based exclusively on soybean oil, due to their high content on pro-inflammatory omega-6 fatty acids,17,18 and restricting lipid dose to ≤1,5 g/kg/day.17

The random number generation and all data analysis were conducted using IBM SPSS Statistics, version 27 (Armonk, NY, USA), and Microsoft Excel, version 2019 (Redmond, WA, USA). To verify the adequacy of the simulated weight distribution, the Anderson-Darling test was used to assess normality, and a one-sample t-test was performed to compare the simulated population mean with the reference population mean. A two-sided p-value <0.05 was considered statistically significant.

Only descriptive statistics were used (frequencies, proportions, means and 95% confidence intervals). No hypothesis testing or between-group comparisons were performed, as the objective was to evaluate population-level coverage and adequacy rather than test statistical associations.

At the time of the study, a total of 50 commercially available 3CPNBs were identified. Of these, 12 bags (24.0%) provided less than 50% of non-protein calories from carbohydrates, and 3 bags (6.0%) contained a lipid emulsion based exclusively on soybean oil. These 15 bags (30.0%) were excluded based on predefined criteria. The remaining 35 formulations were included in the analysis (Table 1). These 3CPNBs ranged per bag from 725 to 2598 kcal, from 35 to 133 g of protein, and with NP kcal/g N between 57 and 141. The difference between the calculated kcal and those reported in the technical data sheet was 59 kcal (CI95%: 51–66), representing 3.60% of the total calories (CI95%: 3.42%–3.78%).

Table 2 shows, for each 3CPNB formulation, the body-weight ranges of patients for whom nutritional targets were met in each scenario.

Based on the NP kcal/g N thresholds derived from ESPEN guidelines, 18 3CPNB formulations (51.4%) met the criteria for both intensive care scenarios (I1 and I2), 20 (57.1%) for surgical patients (scenario Q), and 32 (91.4%) for medical patients (scenario M). Three 3CPNB formulations (8.6%) were unsuitable for any scenario.

Regarding scenario specificity, 12 bags (34.3%) were suitable for only one scenario, 2 (5.7%) for two, none for three, and 18 (51.4%) met the requirements of all four scenarios.

Supplementary Fig. 2 summarizes the scenario-based adequacy classification of each 3CPNB.

The 1000 simulated patients' weight followed a normal distribution (Anderson-Darling normality test, p = 0.706). The mean was 70.65 kg [95CI%: 69.85–71.44], which did not differ from the published mean of the Spanish population (one-sample t-test, p = 0.648). Fig. 1 illustrates this distribution and the number of individuals in each weight stratum who could be adequately covered by at least one 3CPNB in each scenario.

Figure 1.

Distribution of the 1000 simulated patient’s weights and the number of individuals in each weight stratum who could be adequately covered by at least one 3CPNB per scenario.

The solid line represents the distribution of the 1000 simulated adult patient weights (range: 27.5–113.0 kg).

Bars indicate the number of patients within each weight stratum whose nutritional requirements were met by at least one 3CPNB formulation.

Table 3 provides details on 3CPNB coverage adequacy across patient weight strata. In Scenario I1, most weight strata, except 58–63.99 kg, showed less than 50% coverage. A similar pattern was observed in Scenario I2, where only the 40–45.99 kg, 82–87.99 kg, and 88–93.99 kg strata achieved over 50% adequacy. In Scenario Q, coverage was below 50% in the 0–45.99 kg, 52–63.99 kg, and 88- ≥100 kg strata. In contrast, all weight strata in Scenario M were covered by at least one 3CNPB.

Across all scenarios, the weight strata most consistently undercovered were 0–39.99 kg, 52–57.99 kg, and 88- ≥100 kg. Notably, in the strata of 64–81,99 kg, around the population mean where the most patients were placed, nearly half of the patients (45.9%) lacked an appropriate 3CPNB option.

When analyzing the total number of patients that could not receive an appropriate 3CNPB, the following was observed: in Scenario I1, 693 patients (69.3%) were uncovered; in Scenario I2, 734 patients (73.4%); in Scenario Q, 382 patients (38.2%); and in Scenario M, only 1 patient (0.1%).

Table 4 presents the number of patients adequately nourished in each scenario by each 3CPNB formulation. Notably, 20 bags (57.1%) did not reach 10% coverage (i.e., fewer than 100 patients) in any scenario. Furthermore, four bags (11.4%) were found unsuitable for any patient, those aforementioned three formulations were unsuitable for any scenario, and an additional 3CNPB failed to be suitable for any of the simulated patients. Three formulations (8.6%) were exclusively adequate for scenario M.

Fig. 2 shows the cumulative patient coverage achieved in each scenario as additional 3CPNB formulations were included. The minimum number of 3CNPB formulations required to achieve the maximum possible patient coverage was estimated at 10 for Scenario I1 (307 patients); 11 for Scenario I2 (266 patients); 12 for Scenario Q (618 patients); and 7 for Scenario M (999 patients).

Figure 2.

Cumulative patient coverage achieved in each scenario as additional 3CPNB formulations are included.

The numbers under the graphic lines showed the maximum number of patients covered in each scenario and the position of the number indicated the number of the 3CNPB where this maximum was achieved.