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.
Highlights
Children who have suffered from critical illnesses that required treatment in a paediatric intensive care unit (PICU) have long-term physical and neurodevelopmental impairments
The propensity-score matched comparison revealed that median (IQR) leukocyte telomere length in critically ill children upon PICU admission (1.625 (1.446–1.825)) was 6% shorter than that in healthy children (1.727 (1.547–1.915)) (P < 0.0001)
We first assessed the impact of the randomised nutritional management on the change in telomere length during PICU stay in a univariate analysis
Summary
Children 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. PICU survivors continue to suffer from an important long-term legacy of critical illness, characterised by impaired physical and neurocognitive development [3] This legacy could be explained by the pre-admission disease [4] or be induced or aggravated by the acute event and/or the intensive medical care. Evidence suggests that macronutrient restriction and/or healthy feeding habits may slow down the progressive shortening of telomeres, which could protect against age-related diseases [14, 15]
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