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

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies

Abstract Background Withholding parenteral nutrition (PN) until one week after PICU admission facilitated recovery from critical illness and protected against emotional and behavioral problems 4 years later. However, the intervention increased the risk of hypoglycemia, which may have counteracted part of the benefit. Previously, hypoglycemia occurring under tight glucose control in critically ill children receiving early PN did not associate with long-term harm. We investigated whether hypoglycemia in PICU differentially associates with outcome in the context of withholding early PN, and whether any potential association with outcome may depend on the applied glucose control protocol. Methods In this secondary analysis of the multicenter PEPaNIC RCT, we studied whether hypoglycemia in PICU associated with mortality (N = 1440) and 4-years neurodevelopmental outcome (N = 674) through univariable comparison and multivariable regression analyses adjusting for potential confounders. In patients with available blood samples (N = 556), multivariable models were additionally adjusted for baseline serum NSE and S100B concentrations as biomarkers of neuronal, respectively, astrocytic damage. To study whether an association of hypoglycemia with outcome may be affected by the nutritional strategy or center-specific glucose control protocol, we further adjusted the models for the interaction between hypoglycemia and the randomized nutritional strategy, respectively, treatment center. In sensitivity analyses, we studied whether any association with outcome was different in patients with iatrogenic or spontaneous/recurrent hypoglycemia. Results Hypoglycemia univariably associated with higher mortality in PICU, at 90 days and 4 years after randomization, but not when adjusted for risk factors. After 4 years, critically ill children with hypoglycemia scored significantly worse for certain parent/caregiver-reported executive functions (working memory, planning and organization, metacognition) than patients without hypoglycemia, also when adjusted for risk factors including baseline NSE and S100B. Further adjustment for the interaction of hypoglycemia with the randomized intervention or treatment center revealed a potential interaction, whereby tight glucose control and withholding early PN may be protective. Impaired executive functions were most pronounced in patients with spontaneous or recurrent hypoglycemia. Conclusion Critically ill children exposed to hypoglycemia in PICU were at higher risk of impaired executive functions after 4 years, especially in cases of spontaneous/recurrent hypoglycemia

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 +/- 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Eficacia profiláctica de ondansetrón y dexametasona en náusea y vómito posterior a cesárea con opioides neuroaxiales como coadyuvantes. Ensayo clínico controlado

Background: Subarachnoid anesthesia is the most common technique for cesarean section and coadjuvant opioids such as morphineand fentanyl have adverse events, predominantly nausea and vomit. A randomized, placebo-controlled trial was performed to evaluatethe prophylactic effect of ondansetron and dexamethasone on these events. Objective: To establish the efficacy of ondansetron anddexamethasone in nausea and vomit prophylaxis in patients undergoing cesarean section. Method: A sample of 300 pregnant womenwas randomized in 3 groups: dexamethasone 4 mg, ondansetron 4 mg, and placebo. Standardized dose of 9 mg of bupivacaine at 0,5%100 mcg of morphine and 25 mcg of intratechal fentanyl were administered to all patients. Both dexamethasone and ondansetron werecompared against placebo. Emergency cesarean section, ASA III and allergic patients to any study drugs were excluded. Nausea andvomiting were evaluated intraoperative, 2, 6 and 24 hours after anesthesia, with a significance level α of 0,05. Results: On dexamethasonegroup the RR for vomit was 0,46 (CI 95% 0,28 to 0,76) and 0,79 (CI 95% 0, 64-0,96) for nausea. On the ondansetron group, it was 0.41 (CI95% 0,24- 0,69) for vomit and 0,75 (CI 95% 0,67 a 0,84) for nausea. The severity of nausea was statistically lower on the ondansetron groupIntroducción: la anestesia subaracnoidea es la técnica más empleada para realización de cesáreas usando opioides neuroaxiales, cuyosprincipales eventos adversos son náusea y vómito. Objetivo: establecer la eficacia de ondansetrón y dexametasona en la profilaxis denáuseas y vómitos en pacientes sometidos a cesárea. Materiales y métodos: una muestra de 300 embarazadas llevadas a cesárea noemergente bajo anestesia subaracnoidea fueron asignadas aleatoriamente en tres grupos: DEX (dexametasona 4 mg), OND (ondansetrón4 mg), PLB (placebo 5 mL de solución salina normal). La técnica anestésica se estandarizó con 9 mg de bupivacaína al 0.5%, 100 mcg demorfina y 25 mcg de fentanilo Intratecal. Se evaluó el resultado de interés durante el intraoperatorio, a las 2, 6 y 24 horas post-anestesia,con un nivel de significancia α de 0,05. Resultados: el RR en el grupo DEX para vómito fue 0,46 (IC95%: 0,28-0,76), y para náusea fue 0,79(IC95%: 0,64-0,96). En el grupo OND el RR para vómito fue 0,41 (IC95%: 0,24-0,69) y para náusea 0,75 (IC95%: 0,67-0,84). La severidad dela náusea fue menor y significativa en el grupo OND durante todo el tiempo evaluado (p<0.001). Conclusiones: la dexametasona 4 mg y elondansetrón 4 mg mostraron eficacia para disminuir el riesgo de náusea y vómito postoperatorio en pacientes sometidas a cesárea bajoanestesia subaracnoidea cuando se usan opioides neuroaxiales. Trial registration: (ISRCTN 57227250). MÉD.UIS. 2018;31(1):31-8

Reagent use efficiency with removal of nitrogen from pig slurry via struvite: a study on magnesium oxide and related by-products

Controlled struvite formation has been attracting increasing attention as a near mature technology to recover nutrients from wastewater. However, struvite feasibility is generally limited by the high cost of chemical reagents. With the aim to understand and control reagent use efficiency, experiments and equilibrium model simulations examined inorganic nitrogen (TAN) removal from pig manure via struvite with added magnesium and phosphate reagents. Four industrial magnesium oxide (MgO), a commercial product and three by-products from magnesite calcination, were tested with phosphate added as a highly soluble potassium salt. TAN removal extents with the MgOs ranged from 47 to 72%, with the highest grade MgO providing the greatest extent of TAN removal. However, model analysis showed that all the MgO reagents were poorly soluble (only about 40% of added magnesium actually dissolved). The model results suggested that this poor dissolution was due to kinetic limitations, not solubility constraints. A further set of additional reagents (termed stabilization agents) were prepared by pre-treating the MgO reagents with phosphoric acid, and were tested separately as a source of both magnesium and phosphate. Results showed that acid pre-treatment of moderate to highly reactive MgOs (soft to medium-burnt) primarily formed bobierrite as the stabilizing agent, whereas the pre-treatment of very low reactivity MgOs (dead-burnt) mostly formed newberyite. The newberyite stabilizing agents achieved very high TAN removal extents of about 80%, which is significant, considering that these were formed from dead-burnt/low-grade MgOs. However, the bobierrite stabilizing agents achieved a substantially lower TAN removal extent than their medium-to-high reactivity precursor MgOs. Again, model analysis showed that the bobierrite stabilizing agents were poorly soluble, due to kinetic limitations, not solubility constraints. In contrast, the model suggested that the newberyite stabilizing agents almost completely dissolved to very effectively form struvite. A mechanism was proposed by which conditions near a dissolving reagent particle surface causes unwanted struvite nucleation onto and overgrowth of the reagent particle, inhibiting further dissolution and markedly reducing reagent efficiency. The findings of the study could have implications for reagent efficiency with struvite in general, even when using other solid reagents such as magnesium hydroxide or other MgOs