Lactate Monitoring in Critically Ill Patients

The resident internal medicine called from the Emergency Department (ED). “Can you please come and see my patient, I think he is becoming septic and needs admission to the intensive care”. In the ED we found a confused older patient with an oxygen mask who was clearly dyspnoeic, the urinary catheter was filled with a dark brown fluid, the collecting bag was empty. The resident reported that he admitted the patient 4 hours earlier as he suspected pneumonia. On admission the patient was hypoxic but this clearly improved with the supplemental oxygen. The resident was still waiting for all the laboratory results and the chest X-ray. However, now that the patient had developed hypotension he thought the patient was clearly at risk and intensive care admission was required. When we asked why he had not called us earlier, he replied that he intended to admit the patient to the general ward as he was haemodynamically stable and oxygenation had improved on supplemental oxygen so intensive care admission was not required. When reviewing the blood sample that was drawn 30 min following presentation, besides hypoxaemia, an increased lactate level of 4.6 mmol/l was present. The resident pointed out that hyperlactataemia in sepsis is not related to tissue hypoxia but rather is a marker of increased aerobic metabolism. Therefore he thought there was no need to react to this hyperlactataemia. In this case presentation the presence of hyperlactataemia did not result in treatment consequences. When having read this thesis the reader should be able to indicate whether the resident was right or wrong in this decision. The general aim of this thesis is to evaluate the clinical value of blood lactate monitoring by assessing various aspects of lactate monitoring, including aetiology, the prognostic value and the impact on clinical outcome when incorporating lactate measurement in a treatment algorithm at the bedside. As the process of obtaining informed consent for participation in research is challenging in intensive care patients due to the emergency nature of critical illness, the secondary aim of this thesis is to evaluate consent procedures in emergency critical care research

Clinical use of lactate monitoring in critically ill patients

Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients

Background: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. Methods: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). Results: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8+ and PD-L1+ cells than NB tumors. B cells (CD20+) and macrophages (CD163+) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. Conclusion: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe