Included studies

As limited RCT evidence was available, we also included observational studies. Two studies were identified for inclusion in this review, one randomised controlled trial (RCT) (Richards 1993), and one observational study (Peters 1997).

The RCT (n=59) compared a standard chloride-based PN regimen to an acetate-based PN regimen, which restricted the provision of chloride up to 3mmol/kg/day (Richards 1993). The observational study (n=58) compared a standard chloride-based PN regimen to a acetate-based PN regimen (Peters 1997)

The included studies are 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.

Included studies

A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question. 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 this review question.

Clinical evidence statements

Economic evidence statements

No economic evidence was identified which was applicable to this review question.

The outcomes that matter most

The committee identified hyperchloraemia, metabolic acidosis and metabolic alkalosis as critical outcomes. These outcomes are likely to be directly influenced by the addition of acetate in PN, as acetate is used as an alternative binding agent for cations such as sodium, thereby reducing the chloride load. However, no evidence was identified for metabolic acidosis and metabolic alkalosis. In addition, mortality, body composition, and growth measures, such as weight gain, linear growth, and head circumference were identified as important outcomes. Although chloride and acetate levels may not directly contribute to these outcomes, prolonged metabolic acidosis is of concern. Due to this, the outcomes of pH (a measure of the acidity or alkalinity of a fluid) and base excess were included where available. Base excess (and base deficit) are indicators of the overall non-respiratory acid-base blood level. It is measured in values which are usually (+) in alkalosis and (–) in acidosis and are typically defined as the amount of acid or base that would restore one litre of blood to normal acid-base composition at a Pco₂ of 40 mmHg. It is therefore a marker of acidosis or alkalosis.

The quality of the evidence

The quality of evidence was assessed using GRADE methodology. The evidence for hyperchloraemia and mean difference in base excess was considered of moderate quality; all other evidence was very low or low quality, indicating high uncertainty in the reliability of effect. The evidence drawn from the randomised controlled trial was downgraded for unclear detection and attrition bias. The evidence drawn from the observational study was downgraded for bias regarding the selection of participants, classification of interventions and missing data. Data were downgraded due to serious or very serious risk of imprecision across the outcomes as the 95% confidence intervals crossed either one or both default MID.

Benefits and harms

The evidence in this review showed that acetate was beneficial in decreasing the risk of hyperchloraemia, increasing the pH and the base excess in infants receiving PN in the first 10 days of life; however, the evidence did not provide data to determine the optimal dosages of acetate which should be provided in PN. The committee considered the evidence presented, but acknowledged it was limited and agreed it was not sufficient to make a recommendation on the use of acetate.

Data from the RCT showed that participants in the acetate-based PN regimen group had a higher mortality risk compared to the participants assigned to the chloride-based PN regimen. However, the committee agreed that this was likely not directly associated to the intervention since two out of four deaths in the acetate group occurred before, or during, the initiation of the intervention.

Data from one study (Peters, 1997) showed that participants assigned to an acetate-based PN regimen were less likely to develop hyperchloraemia and had higher levels of pH and base excess compared to those assigned to a PN regimen with no acetate. The differences regarding the risk of hyperchloraemia between the participants were clinically meaningful, favouring the acetate-based PN regimen group. The committee acknowledged that these findings are consistent with their knowledge and experience, that adding acetate helps to balance the PN solution if there is an excess of chloride.

The committee discussed the use of acetate and agreed that generally there should be no need to add acetate to PN. However, they noted that acetate may be needed to reduce the risk of acidosis, and if hyperchloraemia occurs. The committee agreed that preventing too much chloride in the PN initially should be the priority. The committee discussed how chloride intake should be reduced as a priority over the routine provision of acetate to treat acidosis. Chloride is provided alongside sodium and phosphate as these are delivered as chloride salts. In addition, other non-PN sources of chloride may increase a baby’s chloride levels, for example some trace elements are in the form of chloride salts and arterial line infusions can contain sodium chloride, or sodium chloride is used to flush intravenous lines after drug administration. The committee agreed, that chloride intake should be monitored and limited where possible by carefully controlling the intake of chloride from PN and non-PN sources. The evidence included in this review did not clearly show how chloride was given, making it difficult to determine the true benefits of acetate as a standard component in PN. The committee discussed how acetate should be given to decreases the risk of hyperchloraemia and disturbances occurring in pH and the base excess only if hyperchloraemia occurs despite minimising chloride from parenteral and non-PN sources. The committee agreed there were reasons for both giving and not giving acetate; due to the limited evidence they did not think they should make a recommendation on the use of acetate.

The committee, based on informal consensus and their experience and knowledge, emphasised that these findings support the standardisation of the PN bags (see section 1.5 of the guideline). For example, standardised bags should be developed with limited chloride content, which would include a balanced solution to avoid the need for acetate. This would also decrease the risk of metabolic acidosis and improve neonatal care.

Cost effectiveness and resource use

No economic studies were identified which were applicable to this review question. The committee discussed the acetate and the avoidance of an excessive chloride intake in the administration of neonatal PN may result in potentially avoiding additional costs associated with adverse effects to the NHS given that PN associated biochemical abnormalities may require more resource-intensive management, i.e. the risk of hyperchloraemia, hypochloraemia, metabolic acidosis and metabolic alkalosis are likely directly influenced by the addition of acetate in PN. However, the evidence was not strong enough and the committee did not make any recommendations about acetate.

Economic studies

No economic evidence was identified for this review. See supplementary material D for further information.