- Email: [email protected]
Protein provision in the critically ill child: is less more?
Comment
Little is known about the appropriate amounts of fat, protein, and carbohydrate that critically ill patients should be given.1 Protein provision has come into the limelight in recent years, due to growing interest in and awareness of muscle wasting and weakness associated with stays in the intensive care unit (ICU),2,3 but evidence for protein supplementation has been inconsistent.4 In The Lancet Respiratory Medicine, Ilse Vanhorebeek and colleagues report the results of a pre-planned analysis of the PEPaNIC trial.5 By examining the provision of the three main macronutrients in the first 7 days of the paediatric intensive care unit (PICU) stay in great detail, this group of investigators demonstrated that higher provision of parenteral aminoacids, not glucose or lipids, was associated with worse clinical outcomes in the original study.5,6 Early provision of higher daily doses of aminoacid were associated with a higher risk of nosocomial infections (hazard ratio [HR] 1·04–1·13 for days 1–5 of PICU stay) and lower likelihood of weaning from mechanical ventilation (0·95–0·98 for days 3–7 of PICU stay) and lower likelihood of earlier PICU discharge (0·94–0·97 for days 1–7 of PICU stay). The investigators did not find any association of harm with glucose and lipids in these clinical outcomes. Instead, their results suggested some potential benefit of provision of glucose and lipids during the first week of PICU stay. The authors should be congratulated for undertaking this detailed analysis of the PEPaNIC trial. Because there was diversity in the orders in which parenteral and enteral nutrition were administered in the PEPaNIC trial, the investigators were able to conduct the statistical analyses required to examine the association between individual macronutrient provision with the clinical outcomes of interest. The analysis included covariates that potentially had an effect on clinical outcomes, such as age, diagnostic categories, illness severity, malnutrition risk, and clinical trial site. The reported harm associated with parenteral aminoacids might come as a surprise to PICU practitioners. Although it is not universal practice, many PICU practitioners believe that provision of protein is necessary to prevent depletion of body muscle stores.2 Prevention of overfeeding while providing adequate protein has become common practice in nutritional care in the ICU.1,3 However, protein recommendations are
based on the assumption that critically ill children have higher protein requirements due to higher turnover than healthy children,1,7 corroborated by observational studies that demonstrate better outcomes associated with a higher protein intake in the PICU.8,9 Before questioning this commonly accepted belief, albeit one without strong grade of evidence, the findings of this pre-planned analysis of the PEPaNIC trial should be considered in the context of its limitations. The main analysis was conducted using data from the whole cohort of patients regardless of the group to which they were randomly assigned. Although use of the whole cohort allowed for use of a larger dataset, and provided the necessary variability in macronutrients doses, it might not accurately reflect the effect of protein provision across the course of critical illness. From the description of the average macronutrient administration in the first 7 days in the PICU,6 we can surmise that there is a large difference in protein provision between the two groups (early vs late parenteral nutrition). The early parenteral nutrition group was exposed to high doses of aminoacids (some patients were given close to 100% of requirements) in the first 3 days of PICU stay. Many care providers in the PICU might not aim for such high protein intakes in the first few days of critical illness. Perhaps a more appropriate message from the data is that early and significant provision of aminoacids is not warranted based on available evidence. The authors examined the effect of each macronutrient individually in their multivariate analysis but did not include interaction terms in their model. This approach of including interaction terms between the 3 macronutrients, perhaps in the sensitivity analysis, could shed some light on how the provision of one macronutrient could modulate the effect of another. The results of this analysis open more questions for paediatric critical care teams in an area that lacks robust data. The results suggest that high provision of aminoacids in the first few days of critical illness is potentially harmful, but is the effect the same throughout the course of paediatric critical illness? A stratified analysis of the PEPaNIC data according to early and late parenteral nutrition group could potentially address this issue. The authors did perform
www.thelancet.com/respiratory Published online May 15, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30175-3
Burger/Phanie/Science Photo Library
Protein provision in the critically ill child: is less more?
Lancet Respir Med 2017 Published Online May 15, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30175-3 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30186-8
1
Comment
such an analysis and reported that provision of aminoacid did not reveal any benefit. Optimal timing of protein supplementation remains an important area on which to focus research efforts. Many considerations remain with regard to optimal nutrition support in the critically ill child, including optimal route and doses of macronutrient supplementation, timing of such supplementation, and to whom this supplementation should be provided. This study reminds us of the complexity of nutrient metabolism and requirements in the critically ill child, and how much we still do not know. Further high-quality randomised controlled trials, supplemented with newer study approaches such as comparative effectiveness research strategies and adaptive trial designs are needed to inform nutritional practice recommendations in the PICU. *Chengsi Ong, Jan Hau Lee Department of Nutrition and Dietetics, KK Women’s and Children’s Hospital, Singapore 229899 (CO); Children’s Intensive Care Unit, KK Women’s and Children’s Hospital, Singapore (JHL); and Duke-NUS School of Medicine, Singapore (JHL) [email protected]
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Mehta NM, Compher C. A.S.P.E.N. Clinical Guidelines: nutrition support of the critically ill child. J Parenter Enteral Nut 2009; 33: 260–76. Coss-Bu JA, Hamilton-Reeves J, Patel JJ, Morris CR, Hurt RT. Protein requirements of the critically ill pediatric patient. Nut Clin Pract 2017; 32 (suppl): 128s–41s. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nut 2016; 40: 159–211. Weijs PJ, Dickerson RN, Heyland DK, Moore FA, Rugeles SJ, McClave SA. Experimental and outcome-based approaches to protein requirements in the intensive care unit. Nut Clin Pract 2017; 32 (suppl): 77s–85s. Vanhorebeek I, Verbruggen S, Casaer MP, et al. Effect of early supplemental parenteral nutrition in the paediatric ICU: an observational study of postrandomisation treatments in the PEPaNIC trial. Lancet Respir Med 2017; published online May 15. http://dx.doi.org/10.1016/S22132600(17)30186-8. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med 2016; 374: 1111–22. Bechard LJ, Parrott JS, Mehta NM. Systematic review of the influence of energy and protein intake on protein balance in critically ill children. J Pediatr 2012; 161: 333–39.e1. Wong JJ, Han WM, Sultana R, Loh TF, Lee JH. Nutrition delivery affects outcomes in pediatric acute respiratory distress syndrome. J Parenter Enteral Nut 2016; published online March 9. DOI:10.1177/0148607116637937 Mehta NM, Bechard LJ, Zurakowski D, Duggan CP, Heyland DK. Adequate enteral protein intake is inversely associated with 60-d mortality in critically ill children: a multicenter, prospective, cohort study. Am J Clin Nut 2015; 102: 199–206.
We declare no competing interests.
2
www.thelancet.com/respiratory Published online May 15, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30175-3
Little is known about the appropriate amounts of fat, protein, and carbohydrate that critically ill patients should be given.1 Protein provision has come into the limelight in recent years, due to growing interest in and awareness of muscle wasting and weakness associated with stays in the intensive care unit (ICU),2,3 but evidence for protein supplementation has been inconsistent.4 In The Lancet Respiratory Medicine, Ilse Vanhorebeek and colleagues report the results of a pre-planned analysis of the PEPaNIC trial.5 By examining the provision of the three main macronutrients in the first 7 days of the paediatric intensive care unit (PICU) stay in great detail, this group of investigators demonstrated that higher provision of parenteral aminoacids, not glucose or lipids, was associated with worse clinical outcomes in the original study.5,6 Early provision of higher daily doses of aminoacid were associated with a higher risk of nosocomial infections (hazard ratio [HR] 1·04–1·13 for days 1–5 of PICU stay) and lower likelihood of weaning from mechanical ventilation (0·95–0·98 for days 3–7 of PICU stay) and lower likelihood of earlier PICU discharge (0·94–0·97 for days 1–7 of PICU stay). The investigators did not find any association of harm with glucose and lipids in these clinical outcomes. Instead, their results suggested some potential benefit of provision of glucose and lipids during the first week of PICU stay. The authors should be congratulated for undertaking this detailed analysis of the PEPaNIC trial. Because there was diversity in the orders in which parenteral and enteral nutrition were administered in the PEPaNIC trial, the investigators were able to conduct the statistical analyses required to examine the association between individual macronutrient provision with the clinical outcomes of interest. The analysis included covariates that potentially had an effect on clinical outcomes, such as age, diagnostic categories, illness severity, malnutrition risk, and clinical trial site. The reported harm associated with parenteral aminoacids might come as a surprise to PICU practitioners. Although it is not universal practice, many PICU practitioners believe that provision of protein is necessary to prevent depletion of body muscle stores.2 Prevention of overfeeding while providing adequate protein has become common practice in nutritional care in the ICU.1,3 However, protein recommendations are
based on the assumption that critically ill children have higher protein requirements due to higher turnover than healthy children,1,7 corroborated by observational studies that demonstrate better outcomes associated with a higher protein intake in the PICU.8,9 Before questioning this commonly accepted belief, albeit one without strong grade of evidence, the findings of this pre-planned analysis of the PEPaNIC trial should be considered in the context of its limitations. The main analysis was conducted using data from the whole cohort of patients regardless of the group to which they were randomly assigned. Although use of the whole cohort allowed for use of a larger dataset, and provided the necessary variability in macronutrients doses, it might not accurately reflect the effect of protein provision across the course of critical illness. From the description of the average macronutrient administration in the first 7 days in the PICU,6 we can surmise that there is a large difference in protein provision between the two groups (early vs late parenteral nutrition). The early parenteral nutrition group was exposed to high doses of aminoacids (some patients were given close to 100% of requirements) in the first 3 days of PICU stay. Many care providers in the PICU might not aim for such high protein intakes in the first few days of critical illness. Perhaps a more appropriate message from the data is that early and significant provision of aminoacids is not warranted based on available evidence. The authors examined the effect of each macronutrient individually in their multivariate analysis but did not include interaction terms in their model. This approach of including interaction terms between the 3 macronutrients, perhaps in the sensitivity analysis, could shed some light on how the provision of one macronutrient could modulate the effect of another. The results of this analysis open more questions for paediatric critical care teams in an area that lacks robust data. The results suggest that high provision of aminoacids in the first few days of critical illness is potentially harmful, but is the effect the same throughout the course of paediatric critical illness? A stratified analysis of the PEPaNIC data according to early and late parenteral nutrition group could potentially address this issue. The authors did perform
www.thelancet.com/respiratory Published online May 15, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30175-3
Burger/Phanie/Science Photo Library
Protein provision in the critically ill child: is less more?
Lancet Respir Med 2017 Published Online May 15, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30175-3 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30186-8
1
Comment
such an analysis and reported that provision of aminoacid did not reveal any benefit. Optimal timing of protein supplementation remains an important area on which to focus research efforts. Many considerations remain with regard to optimal nutrition support in the critically ill child, including optimal route and doses of macronutrient supplementation, timing of such supplementation, and to whom this supplementation should be provided. This study reminds us of the complexity of nutrient metabolism and requirements in the critically ill child, and how much we still do not know. Further high-quality randomised controlled trials, supplemented with newer study approaches such as comparative effectiveness research strategies and adaptive trial designs are needed to inform nutritional practice recommendations in the PICU. *Chengsi Ong, Jan Hau Lee Department of Nutrition and Dietetics, KK Women’s and Children’s Hospital, Singapore 229899 (CO); Children’s Intensive Care Unit, KK Women’s and Children’s Hospital, Singapore (JHL); and Duke-NUS School of Medicine, Singapore (JHL) [email protected]
1 2 3
4 5
6 7 8
9
Mehta NM, Compher C. A.S.P.E.N. Clinical Guidelines: nutrition support of the critically ill child. J Parenter Enteral Nut 2009; 33: 260–76. Coss-Bu JA, Hamilton-Reeves J, Patel JJ, Morris CR, Hurt RT. Protein requirements of the critically ill pediatric patient. Nut Clin Pract 2017; 32 (suppl): 128s–41s. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nut 2016; 40: 159–211. Weijs PJ, Dickerson RN, Heyland DK, Moore FA, Rugeles SJ, McClave SA. Experimental and outcome-based approaches to protein requirements in the intensive care unit. Nut Clin Pract 2017; 32 (suppl): 77s–85s. Vanhorebeek I, Verbruggen S, Casaer MP, et al. Effect of early supplemental parenteral nutrition in the paediatric ICU: an observational study of postrandomisation treatments in the PEPaNIC trial. Lancet Respir Med 2017; published online May 15. http://dx.doi.org/10.1016/S22132600(17)30186-8. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med 2016; 374: 1111–22. Bechard LJ, Parrott JS, Mehta NM. Systematic review of the influence of energy and protein intake on protein balance in critically ill children. J Pediatr 2012; 161: 333–39.e1. Wong JJ, Han WM, Sultana R, Loh TF, Lee JH. Nutrition delivery affects outcomes in pediatric acute respiratory distress syndrome. J Parenter Enteral Nut 2016; published online March 9. DOI:10.1177/0148607116637937 Mehta NM, Bechard LJ, Zurakowski D, Duggan CP, Heyland DK. Adequate enteral protein intake is inversely associated with 60-d mortality in critically ill children: a multicenter, prospective, cohort study. Am J Clin Nut 2015; 102: 199–206.
We declare no competing interests.
2
www.thelancet.com/respiratory Published online May 15, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30175-3