How to define parenteral nutrition

In the context of an international, multicentre observational study—the GUTPHOS study [1]—the investigators documented the use of parenteral nutrition (PN), including daily energy intake via this route. A secondary outcome, “days free of PN," was planned to validate a gastrointestinal dysfunction score. During data quality check, we observed that the definition of PN varied among the participating sites. This observation was further confirmed in a subsequent survey, in which the sites were asked to report the approach they used to document PN. All 28 GUTPHOS study sites (21 from Europe, four from Asia, one from North America, one from South America and one from Oceania) responded and reported their approach (Fig. 1A). In addition to some expectable differences in practice (e.g., using multi-chamber bags vs. separate components), relevant conceptual variability was observed, leading the steering committee to develop a consensus definition for PN in GUTPHOS: “The administration of intravenous amino acids or lipids alone, or any combination of at least two macronutrient components is considered as being PN, whereas administration of only glucose in any concentration is not.” Sites adjusted their data accordingly.

Fig. 1

Results of the survey among 28 sites participating in the GUTPHOS study. A Frequency of Positive Responses for PN Options. Bubble chart representing the frequency of responses for different Parenteral Nutrition (PN) options in the survey with 28 sites. Each bubble represents a PN option. Each bubble's size and colour intensity correspond to the number of positive responses for that option, with larger and brighter bubbles indicating more frequent selection. The number inside each bubble indicates the exact count of positive responses. PN options are labelled beneath each bubble. AA amino acids. B Summary of minimum requirements to label a solution as PN. Bar chart illustrating the diversity in defining Parenteral Nutrition (PN) among survey respondents. The x-axis shows five categories of increasing complexity in PN definition, from "Any single component" to "Only commercial preparations." The y-axis and bar heights represent the number of responses in each category. The sites were categorised according to the minimal definition (left-to-right on the x-axis)

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In this correspondence, we aim to draw attention to the unclear definition of PN and call for action.

Despite numerous guidelines and studies addressing PN in the literature, clear guidance on which components and amounts are necessary to define PN for clinical studies still needs to be provided. The European Society for Clinical Nutrition and Metabolism (ESPEN) defines PN as a nutrition therapy provided through intravenous (central or peripheral) administration of amino acids, glucose, lipids, electrolytes, vitamins and trace elements [2]. The American Society for Parenteral and Enteral Nutrition (ASPEN) defines PN as nutrition provided when patients cannot use the gastrointestinal (GI) tract or nutrition needs cannot be met through the GI tract alone [3]. ESPEN guidelines on ICU nutrition mention that parenteral and enteral feeding preparations differ because commercially available PN solutions contain amino acids and glucose with or without lipids (multi-chamber bags) but no micronutrients for stability reasons [4]. While it is clear that providing all macronutrients and micronutrients intravenously is considered PN, the minimum requirements for defining PN in clinical studies need to be clarified (Fig. 1B).

When PN was first introduced in the 1960s, it was initially called “total parenteral nutrition (TPN)”, designed to cover all nutrition needs, i.e. to provide fluid, protein, carbohydrate, fat, vitamins, trace elements and minerals. The term was simplified to PN after the start of the millennium, and this abbreviation has led to different interpretations. Our current observation suggests the need to define PN more precisely for clinical studies. In the ongoing GUTPHOS study, the question of the PN definition was never raised during the study protocol development nor by sites during data collection, although the Case Report Form manual listed dextrose-based maintenance solutions as non-nutritional calories, yet without further specification and guidance. Our observation suggests a high confidence level in personal or local interpretations, whereas, in reality, these interpretations are widely different. In randomised controlled trials (RCT) investigating specific PN products, the variation in definition may be less important than in observational studies. The most recent large NUTRIREA-3 RCT defined PN as “ternary admixture bags containing three groups of macronutrients used according to standard practice” [5]. However, in the NUTRIREA-2 and CALORIES RCTs that compared enteral nutrition (EN) vs. PN, PN was defined as nutrition provided through a central venous catheter [6, 7], leaving considerable space for different interpretations. Accordingly, RCTs would benefit from a detailed definition of PN.

Developing a precise PN definition is challenging. On the one hand, any substrate (glucose, amino acid, lipid) delivered intravenously, independent of the amount and indication, are parenteral nutrients that could be considered PN. On the other hand, from the perspective of sustaining life over an extended period of time, PN would be defined as covering the body’s requirement for all macro- and micro-nutrients. Therefore, another relevant question arises: Should supplemental PN (SPN), used in conjunction with oral or enteral intake, be defined differently regarding its composition? With such differentiation, PN administered together with EN is not always considered SPN when capturing different feeding routes in studies or databases.

Taken together, despite a simple initial definition of PN that seemed intuitively clear to most clinicians, a precise, unified definition for data comparison in clinical studies is not available and needs to be developed. The above definition, retrospectively applied to the GUTPHOS study, should only be understood as a compromise aiming at unifying results from different sites in a particular study rather than a consensus definition proposal. We wish to draw attention to varying interpretations of "PN" as a pitfall hindering comparisons between sites or studies. We call critical care and nutrition societies for a joint effort to find a global consensus on a detailed definition of PN.

Data will be made available on reasonable request.

ASPEN:

American Society for Parenteral and Enteral Nutrition

EN:

Enteral nutrition

ESPEN:

European Society for Clinical Nutrition and Metabolism

ICU:

Intensive care unit

PN:

Parenteral nutrition

RCT:

Randomized controlled trial

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Download references

We thank all collaborators in all study sites.

the GUTPHOS study sites and investigators: Gelderse Vallei Hospital, Ede, The Netherlands: Yvonnen Swaen-Dekkers; Tartu University Hospital, Tartu, Estonia: Anna-Liisa Voomets; Karolinska University Hospital Huddinge, Stockholm, Sweden: Rebecca Lindström; Karolinska University Hospital Solna, Solna, Sweden: Jonas Blixt; Luzerner Kantonsspital, Luzern, Switzerland: Benjamin Hess; CHUV, Centre hospitalier universitaire vaudois, Lausanne, Switzerland: Olivier Pantet; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia: Yasir Alzoubi; UZ Leuven, Leuven, Belgium: Liese Mebis; Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Anaesthesiology and Intensive Care Medicine (CCM/CVK), Berlin, Germany: Linus O. Warner; Klinikum rechts der Isar Technische Universität München, Munich, Germany: Kristina Fuest; Azienda Ospedaliero Universitaria “Policlinico Riuniti”, Foggia, Italy: Francesco Cardinale; Beijing Hospital, Beijing, China: Zhigang Chang; University Hospitals of North Midlands, North Midlands, UK: Ramprasad Matsa; H.I.G.A. San Martin de La Plata, Buenos Aires, Argentina: Cecilia Loudet; General Hospital of Atikki, KAT, Athens, Greece: Maria Theodorakopoulou; USL Romagna: Azienda USL della Romagna, Cesena, Italy: Giuliano Bolondi; Královské Vinohrady University Hospital, Prague, Czech Republic: František Duška; Hospital Clínic de Barcelona, Barcelona, Spain: Juan Carlos Lopez-Delgado; Auckland City Hospital, Auckland, New Zealand: Varsha Asrani; Univerity Cinical Center Niš, Niš, Serbia: Natalija Vukovic; North Estonia Medical Centre, Tallinn, Estonia: Oskar Appelberg; The Methodist Hospital Research Institute, Houston, USA: Raul Sanchez Leon; CHU de Besançon, Besançon, France: Guillaume Besch; Universität Leipzig, Leipzig, Germany: Sirak Petros; Södersjukhuset AB, Stockholm, Sweden: Rebecka Rubenson Wahlin; West China Hospital, Chengdu, China: Qin Wu; University Clinical Centre of Serbia, Belgrade, Serbia: Jovana Stanisavljevic; The First Hospital of Jilin University, Jilin, China: Zhang Dong

The GUTPHOS study was funded through an ESICM Fresenius Kabi Clinical Nutrition Award 2023 and the Estonian Research Council (PRG1255).

Authors and Affiliations

1. Department of Anaesthesiology and Intensive Care, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia

   Annika Reintam Blaser, Martin Padar, Joel Starkopf & Kaspar F. Bachmann

2. Lucerne Cantonal Hospital, Lucerne, Switzerland

   Annika Reintam Blaser & Benjamin Hess

3. Department of Anesthesia and Intensive Care, University Hospital of Foggia, Foggia, Italy

   Antonella Cotoia

4. Faculty of Medicine and Biology, Lausanne University, Lausanne, Switzerland

   Mette M. Berger

5. Tartu University Hospital, Tartu, Estonia

   Martin Padar, Joel Starkopf & Anna-Liisa Voomets

6. College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Intensive Care Department, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia

   Yaseen M. Arabi

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

   Michael P. Casaer & Jan Gunst

8. Gelderse Vallei Hospital, Ede, The Netherlands

   Imre W. K. Kouw, Arthur R. H. van Zanten & Yvonnen Swaen-Dekkers

9. Division of Human Nutrition and Health, Nutritional Biology, Wageningen University and Research, Wageningen, The Netherlands

   Imre W. K. Kouw & Arthur R. H. van Zanten

10. First Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, Lublin, Poland

    Manu L. N. G. Malbrain

11. Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Division of General Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Vienna, Austria

    Stefan J. Schaller

12. Department of Anaesthesiology and Intensive Care Medicine (CCM/CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin, Germany

    Stefan J. Schaller & Linus O. Warner

13. Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden

    Martin Sundström Rehal

14. Division of Anaesthesia and Intensive Care, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden

    Martin Sundström Rehal

15. Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Kaspar F. Bachmann

16. Karolinska University Hospital Huddinge, Stockholm, Sweden

    Rebecca Lindström

17. Karolinska University Hospital Solna, Solna, Sweden

    Jonas Blixt

18. CHUV, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Olivier Pantet

19. King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    Yasir Alzoubi

20. UZ Leuven, Leuven, Belgium

    Liese Mebis

21. Klinikum Rechts der Isar Technische Universität München, Munich, Germany

    Kristina Fuest

22. Azienda Ospedaliero Universitaria “Policlinico Riuniti”, Foggia, Italy

    Francesco Cardinale

23. Beijing Hospital, Beijing, China

    Zhigang Chang

24. University Hospitals of North Midlands, North Midlands, UK

    Ramprasad Matsa

25. H.I.G.A. San Martin de la Plata, Buenos Aires, Argentina

    Cecilia Loudet

26. General Hospital of Atikki, KAT, Athens, Greece

    Maria Theodorakopoulou

27. AUSL Romagna: Azienda USL Della Romagna, Cesena, Italy

    Giuliano Bolondi

28. Královské Vinohrady University Hospital, Prague, Czech Republic

    František Duška

29. Hospital Clínic de Barcelona, Barcelona, Spain

    Juan Carlos Lopez-Delgado

30. Auckland City Hospital, Auckland, New Zealand

    Varsha Asrani

31. Univerity Cinical Center Niš, Niš, Serbia

    Natalija Vukovic

32. North Estonia Medical Centre, Tallinn, Estonia

    Oskar Appelberg

33. The Methodist Hospital Research Institute, Houston, USA

    Raul Sanchez Leon

34. CHU de Besançon, Besançon, France

    Guillaume Besch

35. Universität Leipzig, Leipzig, Germany

    Sirak Petros

36. Södersjukhuset AB, Stockholm, Sweden

    Rebecka Rubenson Wahlin

37. West China Hospital, Chengdu, China

    Qin Wu

38. University Clinical Centre of Serbia, Belgrade, Serbia

    Jovana Stanisavljevic

39. The First Hospital of Jilin University, Jilin, China

    Zhang Dong

Authors

1. Annika Reintam BlaserView author publications

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2. Antonella CotoiaView author publications

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6. Michael P. CasaerView author publications

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8. Imre W. K. KouwView author publications

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9. Manu L. N. G. MalbrainView author publications

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10. Stefan J. SchallerView author publications

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11. Joel StarkopfView author publications

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12. Martin Sundström RehalView author publications

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13. Arthur R. H. van ZantenView author publications

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14. Kaspar F. BachmannView author publications

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Consortia

the GUTPHOS study sites and investigators

• Yvonnen Swaen-Dekkers
• , Anna-Liisa Voomets
• , Rebecca Lindström
• , Jonas Blixt
• , Benjamin Hess
• , Olivier Pantet
• , Yasir Alzoubi
• , Liese Mebis
• , Linus O. Warner
• , Kristina Fuest
• , Francesco Cardinale
• , Zhigang Chang
• , Ramprasad Matsa
• , Cecilia Loudet
• , Maria Theodorakopoulou
• , Giuliano Bolondi
• , František Duška
• , Juan Carlos Lopez-Delgado
• , Varsha Asrani
• , Natalija Vukovic
• , Oskar Appelberg
• , Raul Sanchez Leon
• , Guillaume Besch
• , Sirak Petros
• , Rebecka Rubenson Wahlin
• , Qin Wu
• , Jovana Stanisavljevic
•  & Zhang Dong

Contributions

ARB, AC, MMB, MP and KFB conceptualised and drafted the manuscript, KFB visualised the results, and all the co-authors reviewed and revised the manuscript.

Corresponding author

Correspondence to Annika Reintam Blaser.

Ethics approval and consent to participate

The GUTPHOS study was primarily approved by the University of Tartu Ethics Committee on May 29th, 2023 (approval number 377/T-15), and each participating site obtained local ethics committee approval according to local site country and institutional regulations.

Consent for publication

Not applicable.

Competing interests

ARB received a consultancy fee from VIPUN Medical and is holding a grant from the Estonian Research Council (PRG1255). MMB received lecture honoraria from Baxter, Fresenius Kabi and Nestlé Health Int. SJS received grants and non-financial support from Reactive Robotics GmbH (Munich, Germany), ASP GmbH (Attendorn, Germany), STIMIT AG (Biel, Switzerland), ESICM (Geneva, Switzerland), grants, personal fees, and non-financial support from Fresenius Kabi Deutschland GmbH (Bad Homburg, Germany), grants from the Innovationsfond of The Federal Joint Committee (G-BA), personal fees from Springer Verlag GmbH (Vienna, Austria) for educational purposes and Advanz Pharma GmbH (Bielefeld, Germany), non-financial support from national and international societies (and their congress organisers) in the field of anaesthesiology and intensive care medicine, outside the submitted work. SJS holds stocks in small amounts from Alphabet Inc., Bayer AG, and Siemens AG; these holdings have not affected any decisions regarding his research or this study. MLNGM is member of the medical advisory Board of Pulsion Medical Systems (now fully part of Getinge group), Sentinel Medical and Baxter. He consults for BBraun, Becton Dickinson, Spiegelberg, Medtronic, MedCaptain, and Holtech Medical, and received speaker's fees from PeerVoice. He holds stock options for Sentinel, Serenno and Potrero. AvZ reported receiving honoraria for advisory board meetings, lectures, research, and travel expenses from AOP Pharma, Abbott, Baxter, Cardinal Health, Danone-Nutricia, DIM3, Dutch Medical Food, Fresenius Kabi, GE Healthcare, InBody, Mermaid, Rousselot, and Lyric. MPC and JG receive a senior clinical investigator fellowship funded by Research Foundation-Flanders. AC, YA, JS, MSR, MP and IWKK report no conflicts of interest.

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Reintam Blaser, A., Cotoia, A., Berger, M.M. et al. How to define parenteral nutrition. Crit Care 28, 372 (2024). https://doi.org/10.1186/s13054-024-05153-1

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• Received: 24 October 2024

• Accepted: 29 October 2024

• Published: 19 November 2024

• DOI: https://doi.org/10.1186/s13054-024-05153-1

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