Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial.

Critically ill children requiring intensive care suffer from impaired physical/neurocognitive development 2 y later, partially preventable by omitting early use of parenteral nutrition (early-PN) in the paediatric intensive-care-unit (PICU). Altered methylation of DNA from peripheral blood during PICU-stay provided a molecular basis hereof. Whether DNA-methylation of former PICU patients, assessed 2 y after critical illness, is different from that of healthy children remained unknown. In a pre-planned secondary analysis of the PEPaNIC-RCT (clinicaltrials.gov-NCT01536275) 2-year follow-up, we assessed buccal-mucosal DNA-methylation (Infinium-HumanMethylation-EPIC-BeadChip) of former PICU-patients (N = 406 early-PN; N = 414 late-PN) and matched healthy children (N = 392). CpG-sites differentially methylated between groups were identified with multivariable linear regression and differentially methylated DNA-regions via clustering of differentially methylated CpG-sites using kernel-estimates. Analyses were adjusted for technical variation and baseline risk factors, and corrected for multiple testing (false-discovery-rate <0.05). Differentially methylated genes were functionally annotated (KEGG-pathway database), and allocated to three classes depending on involvement in physical/neurocognitive development, critical illness and intensive medical care, or pre-PICU-admission disorders. As compared with matched healthy children, former PICU-patients showed significantly different DNA-methylation at 4047 CpG-sites (2186 genes) and 494 DNA-regions (468 genes), with most CpG-sites being hypomethylated (90.3%) and with an average absolute 2% effect-size, irrespective of timing of PN initiation. Of the differentially methylated KEGG-pathways, 41.2% were related to physical/neurocognitive development, 32.8% to critical illness and intensive medical care and 26.0% to pre-PICU-admission disorders. Two years after critical illness in children, buccal-mucosal DNA showed abnormal methylation of CpG-sites and DNA-regions located in pathways known to be important for physical/neurocognitive development.

Continuous Assessment of Gastric Motility and Its Relation to Gastric Emptying in Adult Critically Ill Patients.

BACKGROUND: Critically ill patients frequently develop feeding intolerance, which is difficult to predict. In healthy subjects, gastric motility, assessed by nasogastric balloon tube, correlated with gastric emptying. We now investigated this correlation in critically ill patients, as well as the feasibility and safety of such application in a pilot study. METHODS: Endotracheally intubated adults scheduled to receive enteral nutrition (EN) were included. After insertion of a double-lumen nasogastric balloon tube and radiographic confirmation of position, balloon pressure was recorded for 10 hours after inflation (4 hours fasted, 2 hours during administration of 13 C-labeled EN, and 4 hours postprandially). Gastric motility was expressed as Gastric Balloon Motility Index (GBMI), reflecting the fraction of time in which phasic gastric contractions occurred. Gastric emptying was assessed by 13 C-octanoate breath test and expressed as gastric half-emptying time (GET½). Correlation between GBMI (assessed in different time intervals) and GET½ was investigated by Pearson/Spearman correlation. Feasibility was defined as the success of tube placement and pressure recording. Safety was assessed based on adverse device effects. RESULTS: Thirty patients were enrolled, of whom 19 had paired GBMI and GET½ data. There was no correlation between GBMI and GET½. The tube was successfully placed in 28/30 (93.3%) patients. In 3/28 (10.7%) patients, balloon leakage precluded analysis. Two safety events were directly linked to the device. CONCLUSION: This pilot study showed no significant correlation between balloon-assessed gastric motility and emptying in critically ill patients. The feasibility/safety profile of the balloon tube appears similar to that of standard nasogastric tubes.

Cost-effectiveness study of early versus late parenteral nutrition in critically ill children (PEPaNIC): preplanned secondary analysis of a multicentre randomised controlled trial.

BACKGROUND: The multicentre randomised controlled PEPaNIC trial showed that withholding parenteral nutrition (PN) during the first week of critical illness in children was clinically superior to providing early PN. This study describes the cost-effectiveness of this new nutritional strategy. METHODS: Direct medical costs were calculated with use of a micro-costing approach. We compared the costs of late versus early initiation of PN (n = 673 versus n = 670 patients) in the Belgian and Dutch study populations from a hospital perspective, using Student's t test with bootstrapping. Main cost drivers were identified and the impact of new infections on the total costs was assessed. RESULTS: Mean direct medical costs for patients receiving late PN (€26.680, IQR €10.090-28.830 per patient) were 21% lower (-€7.180, p = 0.007) than for patients receiving early PN (€33.860, IQR €11.080-34.720). Since late PN was more effective and less costly, this strategy was superior to early PN. The lower costs for PN only contributed 2.1% to the total cost reduction. The main cost driver was intensive care hospitalisation costs (-€4.120, p = 0.003). The patients who acquired a new infection (14%) were responsible for 41% of the total costs. Sensitivity analyses confirmed consistency across both healthcare systems. CONCLUSIONS: Late initiation of PN decreased the direct medical costs for hospitalisation in critically ill children, beyond the expected lower costs for withholding PN. Avoiding new infections by late initiation of PN yielded a large cost reduction. Hence, late initiation of PN was superior to early initiation of PN largely via its effect on new infections. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01536275 . Registered on 16 February 2012.

Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis.

RATIONALE: Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes. OBJECTIVES: To determine acute outcomes, 1-year mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge. METHODS: Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis. MEASUREMENTS AND MAIN RESULTS: A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio [HR], 0.709 [0.549-0.888]; P = 0.009), live ICU (HR, 0.698 [0.553-0.861]; P = 0.008) and hospital discharge (HR, 0.680 [0.514-0.871]; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001). CONCLUSIONS: After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Early versus late parenteral nutrition in ICU patients: cost analysis of the EPaNIC trial.

INTRODUCTION: The EPaNIC randomized controlled multicentre trial showed that postponing initiation of parenteral nutrition (PN) in ICU-patients to beyond the first week (Late-PN) enhanced recovery, as compared with Early-PN. This was mediated by fewer infections, accelerated recovery from organ failure and reduced duration of hospitalization. Now, the trial's preplanned cost analysis (N = 4640) from the Belgian healthcare payers' perspective is reported. METHODS: Cost data were retrieved from individual patient invoices. Undiscounted total healthcare costs were calculated for the index hospital stay. A cost tree based on acquisition of new infections and on prolonged length-of-stay was constructed. Contribution of 8 cost categories to total hospitalization costs was analyzed. The origin of drug costs was clarified in detail through the Anatomical Therapeutic Chemical (ATC) classification system. The potential impact of Early-PN on total hospitalization costs in other healthcare systems was explored in a sensitivity analysis. RESULTS: ICU-patients developing new infection (24.4%) were responsible for 42.7% of total costs, while ICU-patients staying beyond one week (24.3%) accounted for 43.3% of total costs. Pharmacy-related costs represented 30% of total hospitalization costs and were increased by Early-PN (+608.00 EUR/patient, p = 0.01). Notably, costs for ATC-J (anti-infective agents) (+227.00 EUR/patient, p = 0.02) and ATC-B (comprising PN) (+220.00 EUR/patient, p = 0.006) drugs were increased by Early-PN. Sensitivity analysis revealed a mean total cost increase of 1,210.00 EUR/patient (p = 0.02) by Early-PN, when incorporating the full PN costs. CONCLUSIONS: The increased costs by Early-PN were mainly pharmacy-related and explained by higher expenditures for PN and anti-infective agents. The use of Early-PN in critically ill patients can thus not be recommended for both clinical (no benefit) and cost-related reasons. TRIAL REGISTRATION: ClinicalTrials.gov NCT00512122.

The interobserver agreement of handheld dynamometry for muscle strength assessment in critically ill patients.

OBJECTIVE: Muscle weakness often complicates critical illness and is associated with increased risk of morbidity, mortality, and limiting functional outcome even years later. To assess the presence of muscle weakness and to examine the effects of interventions, objective and reliable muscle strength measurements are required. The first objective of this study is to determine interobserver reliability of handheld dynamometry. Secondary objectives are to quantify muscle weakness, to evaluate distribution of muscle weakness, and to evaluate gender-related differences in muscle strength. DESIGN: Cross-sectional observational study. SETTING: The surgical and medical intensive care units of a large, tertiary referral, university hospital. PATIENTS: A cross-sectional, randomly selected sample of awake and cooperative critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Handheld dynamometry was performed in critically ill patients who had at least a score of 3 (movement against gravity) on the Medical Research Council scale. Three upper limb and three lower limb muscle groups were tested at the right-hand side. Patients were tested twice daily by two independent raters. Fifty-one test-retests were performed in 39 critically ill patients. Handheld dynamometry demonstrated good interobserver agreement with intraclass correlation coefficients >0.90 in four of the muscle groups tested (range, 0.91-0.96) and somewhat less for hip flexion (intraclass correlation coefficient, 0.80) and ankle dorsiflexion (intraclass correlation coefficient, 0.76). Limb muscle strength was considerably reduced in all muscle groups as shown by the median z-score (range, -1.08 to -3.48 sd units). Elbow flexors, knee extensors, and ankle dorsiflexors were the most affected muscle groups. Loss of muscle strength was comparable between men and women. CONCLUSIONS: Handheld dynamometry is a tool with a very good interobserver reliability to assess limb muscle strength in awake and cooperative critically ill patients. Future studies should focus on the sensitivity of handheld dynamometry in longitudinal studies to evaluate predictive values toward patients' functional outcome.

Assessment of blood glucose control in the pediatric intensive care unit: extension of the glycemic penalty index toward children and infants.

BACKGROUND: The glycemic penalty index (GPI) is a measure to assess blood glucose (BG) control in critically ill adult patients but needs to be adapted for children and infants. METHOD: The squared differences between a clinical expertise penalty function and the corresponding polynomial function are minimized for optimization purposes. The average of all penalties (individually assigned to all BG readings) represents the patient-specific GPI. RESULTS: Penalization in the hypoglycemic range is more severe than in the hyperglycemic range as the developing brains of infants and children may be more vulnerable to hypoglycemia. Similarly, hypoglycemia is also more heavily penalized in infants than in children. CONCLUSIONS: Extending the adult GPI toward the age-specific GPI is an important methodological step. Long-term clinical studies are needed to determine the clinically acceptable GPI cut-off level.

Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients.

OBJECTIVE: To perform an analysis of healthcare resource utilization with intensive insulin therapy, which has recently been shown to reduce morbidity and mortality rates of mechanically ventilated critically ill patients in a surgical intensive care unit. DESIGN: A post hoc cost analysis. SETTING: Surgical intensive care unit. PATIENTS: Patients were 1548 mechanically ventilated patients admitted to a surgical intensive care unit. INTERVENTIONS: A post hoc cost analysis was conducted based on data collected prospectively as part of a large randomized controlled trial. The analysis performed was a healthcare resource utilization analysis in which the cost of hospitalization in the intensive care unit was determined based on length of stay and the frequency of crucial cost-generating morbid events occurring in the intensive and conventional insulin treatment groups. Sensitivity analyses were performed to evaluate the robustness of the findings. Discounting of costs was not performed as treatment was limited to the intensive care stay and follow-up was not continued beyond hospitalization. MEASUREMENTS AND MAIN RESULTS: In the intensive treatment group, total treatment cost was 109,838 Euros (144 Euros per patient). In the conventional treatment group, total treatment cost was 56,359 Euros (72 Euros per patient). The excess cost of intensive insulin therapy was 72 Euros per patient. The total hospitalization cost in the intensive treatment group was 6,067,237 Euros (7931 Euros per patient) compared with 8,275,394 Euros (10,569 Euros per patient) in the conventional treatment group. The excess cost of intensive care unit hospitalization in the conventional vs. intensive treatment group was 2638 Euros per patient. These intensive care unit benefits were not offset by additional costs for care on regular wards. CONCLUSIONS: Intensive insulin therapy, which reduces morbidity and mortality rates of mechanically ventilated patients admitted to a surgical intensive care unit, is associated with substantial cost savings compared with conventional insulin therapy.