Leukocyte telomere length in paediatric critical illness: effect of early parenteral nutrition

Abstract

BackgroundChildren who have suffered from critical illnesses that required treatment in a paediatric intensive care unit (PICU) have long-term physical and neurodevelopmental impairments. The mechanisms underlying this legacy remain largely unknown. In patients suffering from chronic diseases hallmarked by inflammation and oxidative stress, poor long-term outcome has been associated with shorter telomeres. Shortened telomeres have also been reported to result from excessive food consumption and/or unhealthy nutrition. We investigated whether critically ill children admitted to the PICU have shorter-than-normal telomeres, and whether early parenteral nutrition (PN) independently affects telomere length when adjusting for known determinants of telomere length.MethodsTelomere length was quantified in leukocyte DNA from 342 healthy children and from 1148 patients who had been enrolled in the multicenter, randomised controlled trial (RCT), PEPaNIC. These patients were randomly allocated to initiation of PN within 24 h (early PN) or to withholding PN for one week in PICU (late PN). The impact of early PN versus late PN on the change in telomere length from the first to last PICU-day was investigated with multivariable linear regression analyses.ResultsLeukocyte telomeres were 6% shorter than normal upon PICU admission (median 1.625 (IQR 1.446–1.825) telomere/single-copy-gene ratio (T/S) units vs. 1.727 (1.547–1.915) T/S-units in healthy children (P < 0.0001)). Adjusted for potential baseline determinants and leukocyte composition, early PN was associated with telomere shortening during PICU stay as compared with late PN (estimate early versus late PN –0.021 T/S-units, 95% CI −0.038; 0.004, P = 0.01). Other independent determinants of telomere length identified in this model were age, gender, baseline telomere length and fraction of neutrophils in the sample from which the DNA was extracted. Telomere shortening with early PN was independent of post-randomisation factors affected by early PN, including longer length of PICU stay, larger amounts of insulin and higher risk of infection.ConclusionsShorter than normal leukocyte telomeres are present in critically ill children admitted to the PICU. Early initiation of PN further shortened telomeres, an effect that was independent of other determinants. Whether such telomere-shortening predisposes to long-term consequences of paediatric critical illness should be further investigated in a prospective follow-up study.Trial registrationClinicalTrials.gov, NCT01536275. Registered on 16 February 2012.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-1972-6) contains supplementary material, which is available to authorized users.

Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial

“…23 Also the potential involvement of telomere shortening, which has shown to be accelerated by early initiation of PN during paediatric critical illness, should be further investigated. 32 This study has limitations to highlight. First, the young age of post-PICU patients precluded complete and reliable results for certain neurocognitive tests.…”

Telomere Length Changes during Critical Illness: A Prospective, Observational Study

“…We used a cutoff of 15%, which has been used by others [20]. This is higher than what was used in the largest study to date by Van den Berghe et al, who used a cutoff of 6% to describe significant attrition [18]. Further studies are required to provide a possible optimal cutoff of significant changes in telomere length.…”

“…In this regard, chronic stress has been demonstrated to be an important factor contributing to telomere attrition in both animal models and cell cultures [17]. Another large study by Van den Berghe et al [18] was performed with a critically ill pediatric population. This study included many patients ( n = 644) and showed a correlation between telomere attrition of 6% and early parenteral nutrition administration.…”

International survey of De-implementation of initiating parenteral nutrition early in Paediatric intensive care units

“…All these new findings were supportive for de-implementation of early-PN. Additionally, underlying mechanisms are currently explored [32]. Finally, since many clinical practices depend on the international opinion, de-implementation might be accelerated if the international guidelines would be revised more frequently in order to cover the most up-to-date evidence.…”