Catherine Ingels

Early versus Late Parenteral Nutrition in Critically Ill Adults

BACKGROUND Controversy exists about the timing of the initiation of parenteral nutrition in critically ill adults in whom caloric targets cannot be met by enteral nutrition alone. METHODS In this randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition. In 2312 patients, parenteral nutrition was initiated within 48 hours after ICU admission (early-initiation group), whereas in 2328 patients, parenteral nutrition was not initiated before day 8 (late-initiation group). A protocol for the early initiation of enteral nutrition was applied to both groups, and insulin was infused to achieve normoglycemia. RESULTS Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P=0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P=0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P=0.008) and a lower incidence of cholestasis (P<0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P=0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P=0.008), and a mean reduction in health care costs of €1,110 (about

Soluble RAGE and the RAGE ligands HMGB1 and S100A12 in critical illness: impact of glycemic control with insulin and relation with clinical outcome

1,600) (P=0.04). CONCLUSIONS Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation. (Funded by the Methusalem program of the Flemish government and others; EPaNIC ClinicalTrials.gov number, NCT00512122.).

Lectin pathway of complement activation and relation with clinical complications in critically ill children

ABSTRACT Systemic inflammation often leads to complications in critically ill patients. Activation of the receptor for advanced glycation end-products (RAGE) generates inflammatory cytokines, proteases, and oxidative stress and may link inflammation to subsequent organ damage. Furthermore, hyperglycemia-induced oxidative stress increases RAGE ligands and RAGE expression. We hypothesized that preventing hyperglycemia during critical illness reduces the risk of excessively enhanced RAGE signaling, which could relate to clinical outcomes and risk of death. In 405 long-stay surgical intensive care unit patients randomized to intensive or conventional insulin treatment, serum concentrations of soluble RAGE (decoy receptor) and the RAGE ligands high-mobility group box 1 (HMGB1) and S100A12 were measured on admission, day 7, and last day. These were compared with levels in 71 matched control subjects and with C-reactive protein (CRP) as a routinely monitored inflammation marker. On admission, soluble RAGE, HMGB1, S100A12, and CRP were higher in patients than in controls. The HMGB1, S100A12, and CRP remained elevated throughout intensive care unit stay, whereas soluble RAGE decreased to levels lower than in controls by day 7. Unexpectedly, insulin treatment did not affect the circulating levels of these markers. In univariable analysis, elevated levels of soluble RAGE on admission were associated with adverse outcome, including circulatory failure, kidney failure, liver dysfunction, and mortality. The associations with circulatory and kidney failure remained significant in multivariable logistic regression analysis corrected for baseline risk factors. Critical illness affects components of RAGE signaling, unaffected by insulin treatment. Elevated on-admission soluble RAGE was associated with adverse outcomes.

Glucose homeostasis, nutrition and infections during critical illness

Background:Critically ill children are susceptible to nosocomial infections, which contribute to adverse outcomes. Deficiencies in the innate immunity lectin pathway of complement activation are implicated in a child’s vulnerability to infections in conditions such as cancer, but the role during critical illness remains unclear. We hypothesized that low on-admission levels of the pathway proteins are, in part, genetically determined and associated with susceptibility to infectious complications and adverse outcomes.Methods:We studied protein levels of mannose-binding lectin (MBL), H-ficolin and M-ficolin, three MBL-associated-serine proteases (MASPs) and MBL-associated protein (MAp44), and relation with functional genetic polymorphisms, in 130 healthy children and upon intensive care unit (ICU) admission in 700 critically ill children of a randomized study on glycemic control.Results:Levels of MASP-1, MASP-2, MASP-3, and MAp-44 were lower and the levels of M-ficolin were higher in ICU patients on admission than those in matched healthy controls. Only a low on-admission MASP-3 level was independently associated with risk of new ICU infections and prolonged ICU stay, after correcting for other risk factors. On-admission MASP-3 varied with age, illness severity, and genetic variation.Conclusion:Low on-admission MASP-3 levels in critically ill children were independently associated with subsequent acquisition of infection and prolonged ICU stay. The biological explanation needs further investigation.

Endocrine and Metabolic Alterations in Sepsis and Implications for Treatment

Critical illness is a complex life-threatening disease characterized by profound endocrine and metabolic alterations and by a dysregulated immune response, together contributing to the susceptibility for nosocomial infections and sepsis. Hitherto, two metabolic strategies have been shown to reduce nosocomial infections in the critically ill, namely tight blood glucose control and early macronutrient restriction. Hyperglycaemia, as part of the endocrine-metabolic responses to stress, is present in virtually all critically ill patients and is associated with poor outcome. Maintaining normoglycaemia with intensive insulin therapy has been shown to reduce morbidity and mortality, by prevention of vital organ dysfunction and prevention of new severe infections. The favourable effects of this intervention were attributed to the avoidance of glucose toxicity and mitochondrial damage in cells of vital organs and in immune cells. Hyperglycaemia was shown to impair macrophage phagocytosis and oxidative burst capacity, which could be restored by targeting normoglycaemia. An anti-inflammatory effect of insulin may have contributed to prevention of collateral damage to host tissues. Not using parenteral nutrition during the first week in intensive care units, and so accepting a large macronutrient deficit, also resulted in fewer secondary infections, less weakness and accelerated recovery. This was at least partially explained by a suppressive effect of early parenteral nutrition on autophagic processes, which may have jeopardized crucial antimicrobial defences and cell damage removal. The beneficial impact of these two metabolic strategies has opened a new field of research that will allow us to improve the understanding of the determinants of nosocomial infections, sepsis and organ failure in the critically ill.

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

Sepsis induces profound neuroendocrine and metabolic alterations. During the acute phase, the neuroendocrine changes are directed toward restoration of homeostasis, and also limit unnecessary energy consumption in the setting of restricted nutrient availability. Such changes are probably adaptive. In patients not recovering quickly, a prolonged critically ill phase may ensue, with different neuroendocrine changes, which may represent a maladaptive response. Whether stress hyperglycemia should be aggressively treated or tolerated remains a matter of debate. Until new evidence from randomized controlled trials becomes available, preventing severe hyperglycemia is recommended. Evidence supports withholding parenteral nutrition in the acute phase of sepsis.

The pattern recognition molecule collectin-L1 in critically ill children

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.

Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study.

Background:Critically ill children are prone to nosocomial infections, which may lead to adverse outcome. Low serum concentrations upon admission to the pediatric intensive care unit (PICU) of the mannan-binding lectin (MBL)-associated serine protease (MASP)-3 protein of the lectin pathway of complement activation have been associated with risk of infection and prolonged need for intensive care. We hypothesized that also a low upon-admission concentration of collectin-L1 (CL-L1), a novel member of this pathway, is independently associated with these adverse outcomes.Methods:We quantified the serum concentrations of CL-L1 in 81 healthy children and in 700 critically ill children upon PICU admission.Results:CL-L1 concentrations were significantly lower in the critically ill children as compared with the healthy children. However, corrected for baseline characteristics, risk factors and several lectin pathway proteins, a higher CL-L1 concentration upon PICU admission was independently associated with an increased risk of acquiring a new infection and with a prolonged time to PICU discharge. In contrast, a low MASP-3 concentration remained independently associated with these adverse outcomes.Conclusion:A high serum CL-L1 concentration in critically ill children upon PICU admission is associated with an increased risk of infection and prolonged need of intensive care, and counteracts the protective effect of having a high MASP-3 concentration.