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

Abstract

Background: 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. 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.

Methods: Telomere 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.

Results: Leukocyte 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.

Conclusions: Shorter 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 registration: ClinicalTrials.gov, NCT01536275 . Registered on 16 February 2012.

Keywords: Children; Critical care; Critical illness; Intensive care; Nutrition; PICU; Paediatric; Telomere length; Telomeres.

Fig. 1

Consolidated Standards of Reporting Trials (CONSORT) flow diagram of the study participants

Fig. 2

Daily caloric intake of patients in the early parental nutrition (PN) and late PN groups. The total caloric intake per day of patients in the early and late PN groups was calculated for the first week in the paediatric ICU (PICU) for the total number of patients for whom leukocyte telomere length was determined (N = 1148) (a), and for the subset of patients for whom neutrophil counts were available (N = 644) (b), with N indicating the number of patients for whom these data were available. Data are presented as mean and standard error of the mean (SEM). d, day; kcal, kilocalories

Fig. 3

Illustration of the impact of the randomised nutritional management on the change in leukocyte telomere length. Differences were calculated between telomere length on the last day in the paediatric ICU (PICU) and that upon admission to the PICU (a), and between neutrophil fraction on the last day in PICU and that upon admission to the PICU (b), and the impact of the randomised intervention on these changes was calculated in univariate analysis. Data are presented as mean and standard error of the mean (SEM). Adjusted estimates and corresponding 95% confidence intervals were calculated for the telomere-shortening effect of early versus late PN (c). PN, parenteral nutrition; T/S, telomere/single-copy-gene ratio