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Glucose
Evidence review D1
NICE Guideline, No. 154
National Guideline Alliance (UK).
Optimal target dose and approach for carbohydrates
Review questions
This evidence report contains information on two questions conducted as one review relating to the individual constituents (carbohydrates) in parenteral nutrition for preterm and term babies.
- D1a. What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- D1b. What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?
Introduction
Carbohydrate, in the form of glucose, is an essential constituent in parenteral nutrition (PN). It provides an important source of energy, and is essential for normal metabolism.
Hyperglycaemia is associated with increased mortality and increased morbidity in very preterm infants. Balancing the need for optimal energy intake against the potential risks of hyperglycaemia and/or its treatment is a key and area of nutritional strategy in very preterm infants. Determining a safe minimum and maintenance total intravenous glucose intake and a regimen to achieve this dose is therefore the objective of this review. An incremental rather than a sudden increase in glucose intake could be beneficial by reducing the risk of very early hyperglycaemia. Unlike other nutrients, glucose is the base constituent of most other (non-PN) fluids. This means total fluid intake and other infusions (e.g. drugs) will also affect total intravenous glucose intake. It is important to recognise this when determining an appropriate intravenous glucose (carbohydrate) dosage to aim for in preterm and term infants.
Summary of the protocol
Please see Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.
Table 1
Summary of the protocol (PICO table).
For full details see the review protocol in appendix A.
Clinical evidence
Included studies
As limited RCT evidence was available, we also included observational studies. Three studies were identified for this review (Forsyth 1995, Morgan 2014, Pineault 1988).
Optimal target dose
One randomised controlled trial ((RCT); Morgan 2014), one cross-over RCT (Forsyth 1995) and one observational study (Pineault 1988) compared higher versus lower glucose intake.
How to achieve target dose
All of the included studies kept glucose intake consistent across the study periods. No studies were identified that compared different starting doses or rates of increase.
The included study is summarised in Table 2.
Table 2
Summary of included studies.
See the literature search strategy in appendix B, study selection flow chart in appendix C, study evidence tables in appendix D, and GRADE tables in appendix F.
Excluded studies
Studies not included in this review are listed, and reasons for their exclusions are provided, in appendix K.
Summary of clinical studies included in the evidence review
Summaries of the studies that were included in this review are presented in Table 2.
See appendix D for full evidence tables.
Quality assessment of clinical outcomes included in the evidence review
GRADE was conducted to assess the quality of outcomes. Evidence was identified for critical and important outcomes. The clinical evidence profiles can be found in appendix F.
Economic evidence
Included studies
A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to these review questions. A single economic search was undertaken for all topics included in the scope of this guideline. Please see supplementary material D for details.
Excluded studies
No studies were identified which were applicable to these review questions.
Summary of studies included in the economic evidence review
No economic evaluations were identified which were applicable to these review questions.
Economic model
No economic modelling was undertaken for these reviews because the committee agreed that other topics were higher priorities for economic evaluation.
Evidence statements
Clinical evidence statements
Higher versus lower glucose intake
Infection (including sepsis) at 28 days and 36 weeks’ corrected gestational age (CGA)
- Moderate quality evidence from 1 RCT (n=150) showed a clinically important difference in rate of infection at 28 days in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake, with more babies with infection associated with lower glucose intake. However, there was uncertainty around the effect: Relative risk (RR) 0.74 (95% CI 0.47 to 1.18).
- Low quality evidence from 1 RCT (n=127) showed no clinically important difference in rate of infection at 36 weeks’ CGA in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake. However, there was high uncertainty around the effect: RR 0.94 (95% CI 0.63 to 1.41).
Mortality at 28 days and 36 weeks’ CGA
- Low quality evidence from 1 RCT showed no clinically important difference in rate of mortality at 28 days (RR 1.17 [95% CI 0.45 to 3.07]; n=150) or 36 weeks’ CGA (RR 0.93 [95% CI 0.44 to 1.95]; n=127) in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake. However, there was high uncertainty around the effects.
Nitrogen accretion
Evidence statements for nitrogen balance and retention are divided into two isocalorific comparisons (babies receiving 60kcal/kg/day containing different dosages of glucose; babies receiving 80kcal/kg/day containing different dosages of glucose)
Nitrogen balance (mg/kg/day)
- Very low quality evidence from 1 observational study (n=8) showed no clinically important difference in nitrogen balance in babies who received 60kcal/kg/day and higher (11g/kg/day) compared with lower (5g/kg/day) glucose intake. However, there was high uncertainty around the effect: Mean difference (MD) −8.00mg/kg/day (95% CI −30.49 to 14.49).
- Very low quality evidence from 1 observational study (n=8) showed a clinically important difference in nitrogen balance in babies who received 80kcal/kg/day and higher (17g/kg/day) compared with lower (11g/kg/day) glucose intake, with greater nitrogen balance associated with the group of babies receiving higher glucose intake. However, there was uncertainty around the effect: MD 5.00mg/kg/day (95% CI −3.87 to 13.87).
Nitrogen retention (%)
- Very low quality evidence from 1 observational study (n=8) showed a clinically important difference in nitrogen retention in babies who received 60kcal/kg/day and higher (11g/kg/day) compared with lower (5g/kg/day) glucose intake. However, there was high uncertainty around the effect, with increased nitrogen retention associated with babies receiving lower glucose intake: MD −2.30% (95% CI −7.26 to 2.66).
- Very low quality evidence from 1 observational study (n=8) showed a clinically important difference in nitrogen retention in babies who received 80kcal/kg/day and higher (17g/kg/day) compared with lower (11g/kg/day) glucose intake, with increased nitrogen retention associated with babies receiving higher glucose intake. However, there was uncertainty around the effect: MD 1.20% (95% CI 0.81 to 3.21).
Weight change at day 7, 14, 21 and 28, and 36 weeks’ CGA
- High quality evidence from 1 RCT (n=135) showed no clinically important difference in weight gain at 7 days in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake: MD 20.00g (95% CI −16.88 to 56.88).
- Moderate quality evidence from 1 RCT showed no clinically important difference in weight gain at 14 days (MD 44.00g [95% CI 5.27 to 82.73]; n=135), 21 days (MD 64.00g [95% CI 20.72 to 107.28]; n=135), 28 days (MD 46.00g [95% CI −5.91 to 97.91]; n=135) or 36 weeks’ CGA (MD 95.00g [95% CI 15.54 to 174.46]; n=124) in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake. However, there was uncertainty around the effects.
Head circumference gain at day 7, 14, 21 and 28, and 36 weeks’ CGA
- High quality evidence from 1 RCT (n=135) showed no clinically important difference in head circumference gain at 7 days in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake: MD 1.00cm (95% CI −2.05 to 4.05).
- Moderate quality evidence from 1 RCT showed no clinically important difference in head circumference gain at 14 days (MD 2.00cm [95% CI −1.05 to 5.05]; n=135), 21 days (MD 4.00cm [95% CI 0.62 to 7.38]; n=135) or 36 weeks’ CGA (MD 5.00cm [95% CI 1.68 to 8.32]; n=126) in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake. However, there was uncertainty around the effects.
- Moderate quality evidence from 1 RCT (n=135) showed a clinically important difference in head circumference gain at 28 days in babies who received higher (15.6g/kg/day) compared with lower (13.5g/kg/day) glucose intake, with greater head circumference in the group of babies receiving higher glucose intake. However, there was uncertainty around the effect: MD 6.00cm (95% CI 2.32 to 9.68).
Nutritional intake (g/kg/day)
- Low quality evidence from 1 observational study (n=8) showed a clinically important difference in glucose intake in babies who received 60kcal/kg/day and higher (11g/kg/day) compared with lower (5g/kg/day) glucose intake, with greater glucose intake associated with babies receiving higher glucose intake: MD 5.50g/kg/day (95% CI 5.25 to 5.75).
- Low quality evidence from 1 observational study (n=8) showed a clinically important difference in glucose intake in babies who received 80kcal/kg/day and higher (17g/kg/day) compared with lower (11g/kg/day) glucose intake, with greater glucose intake associated with babies receiving higher glucose intake: MD 4.40g/kg/day (95% 4.15 to 4.65).
- Moderate quality evidence from 1 RCT (n=20) showed a clinically important difference in glucose intake in babies who receive higher (12g/kg/day) compared with lower (8g/kg/day) glucose intake, with greater glucose intake associated with babies receiving higher glucose intake: MD 3.90g/kg/day (95% CI 3.70 to 4.10).
Economic evidence statements
No economic evidence was identified which was applicable to these review questions.
The committee’s discussion of the evidence
Interpreting the evidence
The outcomes that matter most
The committee prioritised neurodevelopmental outcomes and the following adverse effects of IV carbohydrates as critical outcomes: infection including sepsis, hyperglycaemia, hypoglycaemia and PN associated liver disease as these can be directly linked to glucose load (for example optimal glucose intake has an impact on energy to support growth of all functions including neurodevelopment as well as supporting the immune system to prevent infections).
Mortality, body composition, growth, duration of hospital stay and nutritional intake were selected as important outcomes. Adequate glucose as an energy substrate is pivotal to growth which can impact on duration of hospital stay. However, lean growth should not be compromised; and therefore a balance to achieve good growth and a normal body composition is the aim.
The quality of the evidence
The quality of the evidence for this review was assessed using GRADE methodology. The evidence was considered very low to high quality according to GRADE criteria. Evidence was downgraded due to imprecision around the effect estimate and study design (for example, the observational study with a cross-over component).
The committee noted that it is difficult to disentangle the effects of varying amounts of glucose from other constituents (lipids and amino acids) of PN as more than one constituent varied across study arms for two of the included studies. The committee noted that this confounded the evidence and made it difficult to draw clear conclusions related to amounts of glucose on their own.
Benefits and harms
There was no difference in mortality or weight gain based on glucose intake. The evidence for sepsis, head circumference and nitrogen accretion was inconsistent. There was evidence that actual glucose intake was higher when target intake was higher, demonstrating that it is feasible to achieve a higher glucose intake.
Due to the concurrent variation of dosages in other constituents of PN, the committee noted that the evidence was only indirectly able to support a recommendation for an optimal glucose maintenance dose required in preterm infants. They also noted that it provided no evidence in term infants or how to achieve the maintenance dose. Therefore, the committee decided to make a recommendation based on informal consensus, usingtheir experience and expertise, and decided to make one recommendation applicable to both preterm and term babies.
Starting carbohydrates
In their discussion the committee agreed that a range of starting dosages should be provided to allow some clinical judgement about each babies’ particular circumstances. The committee considered what the minimum recommended starting glucose intake should be. Low intakes of glucose (a main energy source) may impair amino acid utilisation and growth. In the absence of studies designed to investigate this, the committee considered the minimum glucose dosage in a range of other neonatal PN studies. They agreed that a minimum starting dosage of 6 g/kg/day of glucose would be sufficient for a baby that had already larger energy stores (such as late preterm and term babies). Based on their knowledge and experience the committee decided that a maximum starting dosage of 9 g/kg/day would be safe for babies in need of higher energy intakes (such as very preterm babies). Therefore the committee decided to recommend, based on informal consent, a higher dosage of up to 9 g/kg/day to address the energy needs of babies not on enteral feeds.
Maintaining carbohydrates
The committee also discussed what the appropriate maintenance range of carbohydrates should be. Again the committee agreed that this needs clinical judgement based on each individual baby. Those on a lower starting range are likely to only require the minimum maintenance range (9 g/kg/day) as compared to those who start on a higher dosage. Based on their knowledge, the committee noted that hyperglycaemia (caused by too much glucose) is associated with increased mortality and morbidity in preterm infants although it is possible that this is a marker of organ immaturity. Hyperglycaemia also increases the complexity of acute fluid and electrolyte management. The treatment threshold for hyperglycaemia varies considerably between UK neonatal services. Hyperglycaemia treatment comprises two options: glucose reduction or insulin therapy. Glucose reduction results in large interpatient variations in energy intake and poor growth. Insulin therapy is complex, risks hypoglycaemia and has potentially other long term adverse outcomes. However, this is outside the scope of this guideline, and therefore there are no recommendations on this. Taking these considerations into account the committee agreed by informal consensus that a dosage of 16 g/kg/day would be a safe maximum recommendation.
Other considerations
The committee noted that in practice, glucose is given as a default component in many other intravenous infusions as well as the PN solution. The total glucose intake must take into account all these sources when interpreting the maximum recommended glucose intake. Furthermore, total carbohydrate intake will only be equivalent to glucose intake when infants are receiving no enteral feeds. The committee acknowledged that the maximum recommended glucose intake should be reduced with increasing enteral carbohydrate intake, but due to a lack of evidence did not directly make a recommendation on this. The committee acknowledged that the evidence did not clearly demonstrate how carbohydrates should be increased; based on experience the committee agreed that PN should be increased gradually to reach the maintenance dose, this is to reduce the potential risk of adverse events such as hyperglycaemia. The committee suggested 4 days as an example as this would be in line with both amino acid and lipid increments.
No evidence was found on babies who do not start PN from birth. The committeeagreed by informal consensus, based on their knowledge and experience, that babies starting PN after the first 4 days of life should start PN based on the recommended maintenance range. Babies starting PN after this time point may have already made progress with incrementing up to the maintenance levels of macronutrients required for growth from their enteral nutrition. If that enteral nutrition has to be stopped (for example, due to development of necrotising enterocolitis) and PN started the committee felt that returning to starting doses of macronutrients would likely lead to nutritional deficit. Alternatively, babies may be starting PN after this time point as they have not made sufficient progress with enteral fees within the first 72 hours after birth. However, the committee agreed, based on their expertise, that the quantity of macronutrients that can be tolerated is closely linked to the postnatal age of the baby, with older babies able to tolerate greater nutritional intake. Therefore, the committee agreed starting on the maintenance range would be appropriate even if progress has not been made with enteral feeds. The committee agreed to use the same approach for other constituents whenever there is an absence of evidence.
Cost effectiveness and resource use
No economic studies were identified which were applicable to this review question.
The committee explained that recommendations pertaining to an optimal target dosage of carbohydrate in preterm and term babies who are receiving PN or neonatal care and the optimal way of achieving this target dosage would not incur extra resource implications to the health care system.
The committee noted that getting the optimal amount of carbohydrate for neonatal PN may result in avoiding additional costs associated with adverse effects to the NHS (i.e. incorrect amounts of carbohydrates can result in adverse events which may require resource-intensive management).
The committee explained that recommendations in this area reflect practice across many units and as such cost savings to the NHS, if any, are likely to be negligible.
References
Forsyth 1995
Forsyth, J. S., Murdock, N., Crighton, A., Low birthweight infants and total parenteral nutrition immediately after birth. III. Randomised study of energy substrate utilisation, nitrogen balance, and carbon dioxide production, Archives of Disease in Childhood, Fetal and neonatal edition. 73, F13–6, 1995 [PMC free article: PMC2528376] [PubMed: 7552589]Mesotten 2018
Mesotten, D., Joosten, K., van Kempen, A., Verbruggen, S., ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Carbohydrates, Clinical Nutrition, 37, 2337–2343, 2018 [PubMed: 30037708]Morgan 2014
Morgan, C., McGowan, P., Herwitker, S., Hart, A. E., Turner, M. A., Postnatal head growth in preterm infants: a randomized controlled parenteral nutrition study, Pediatrics, 133, e120–8, 2014 [PubMed: 24379229]Pineault 1988
Pineault, M., Chessex, P., Bisaillon, S., Brisson, G., Total parenteral nutrition in the newborn: impact of the quality of infused energy on nitrogen metabolism, American Journal of Clinical Nutrition, 47, 298–304, 1988 [PubMed: 3124593]
Appendices
Appendix A. Review protocols
Review protocol for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?
Appendix B. Literature search strategies
Literature search strategies for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?One combined search was conducted for the research questions.
Appendix C. Clinical evidence study selection
Clinical study selection for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?
Appendix D. Clinical evidence tables
Clinical evidence tables for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?
Table 4. Clinical evidence table for included studies (PDF, 151K)
Appendix E. Forest plots
Forest plots for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?No meta-analysis was conducted for this review; therefore there are no forest plots.
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?No meta-analysis was conducted for this review; therefore there are no forest plots.
Appendix F. GRADE tables
GRADE tables for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?
Table 4. Evidence profile for comparison higher versus lower glucose intake
Appendix G. Economic evidence study selection
Economic evidence study selection for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?One global search was conducted for all review questions. See supplementary material D for further information.
Appendix H. Economic evidence tables
Economic evidence tables for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?No evidence was identified which was applicable to these review questions.
Appendix I. Health economic evidence profiles
Economic evidence profiles for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?No evidence was identified which was applicable to these review questions.
Appendix J. Health economic analysis
Economic evidence analysis for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?No economic analysis was conducted for these review questions.
Appendix K. Excluded studies
Excluded clinical and economic studies for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?
Clinical studies
Economic studies
No economic evidence was identified for these reviews. See supplementary material D for further information.
Appendix L. Research recommendations
Research recommendations for review questions
- What is the optimal target dosage for carbohydrates in preterm and term babies who are receiving parenteral nutrition and neonatal care?
- What is the optimal way (starting dose and approach to increment, if employed) to achieve this target dosage for carbohydrates?No research recommendation was made for this review.
Final
Evidence reviews
These evidence reviews were developed by the National Guideline Alliance which is part of the Royal College of Obstetricians and Gynaecologists
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
- Supplementary material A - National Guideline Alliance technical team list (PDF)
- Supplementary material B - Glossary and abbreviations (PDF)
- Supplementary material C - Methods (PDF)
- Supplementary material D - Health economic literature (PDF)
- Equality impact assessment (PDF)
- Membership of Neonatal Parenteral Nutrition Guideline Committee (PDF)
- Declarations of interests register (PDF)
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- Early optimal parenteral nutrition and metabolic acidosis in very preterm infants.[PLoS One. 2017]Early optimal parenteral nutrition and metabolic acidosis in very preterm infants.Bonsante F, Gouyon JB, Robillard PY, Gouyon B, Iacobelli S. PLoS One. 2017; 12(11):e0186936. Epub 2017 Nov 27.
- Optimizing parenteral nutrition to achieve an adequate weight gain according to the current guidelines in preterm infants with birth weight less than 1500 g: a prospective observational study.[BMC Pediatr. 2021]Optimizing parenteral nutrition to achieve an adequate weight gain according to the current guidelines in preterm infants with birth weight less than 1500 g: a prospective observational study.Wang N, Cui L, Liu Z, Wang Y, Zhang Y, Shi C, Cheng Y. BMC Pediatr. 2021 Jul 7; 21(1):303. Epub 2021 Jul 7.
- Review Practice of parenteral nutrition in VLBW and ELBW infants.[World Rev Nutr Diet. 2014]Review Practice of parenteral nutrition in VLBW and ELBW infants.Embleton ND, Simmer K. World Rev Nutr Diet. 2014; 110:177-89. Epub 2014 Apr 11.
- Review Parenteral nutrition for preterm infants: Issues and strategy.[Arch Pediatr. 2018]Review Parenteral nutrition for preterm infants: Issues and strategy.Darmaun D, Lapillonne A, Simeoni U, Picaud JC, Rozé JC, Saliba E, Bocquet A, Chouraqui JP, Dupont C, Feillet F, et al. Arch Pediatr. 2018 May; 25(4):286-294. Epub 2018 Apr 12.