Theis Skovsgaard Itenov

High Levels of Methylarginines Were Associated With Increased Mortality in Patients With Severe Sepsis

Introduction: Nitric oxide (NO) likely plays a pivotal role in the pathogenesis of sepsis. Arginine is a substrate for NO, whereas the methylated arginines—asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA)—are endogenous by-products of proteolysis that inhibit NO production. We investigated if high-plasma levels of ADMA, SDMA, and arginine/ADMA ratio were associated with 90-day mortality in patients with severe sepsis or septic shock. Methods: We included 267 adult patients admitted to intensive care unit with severe sepsis or septic shock. The patients had previously been included in the randomized controlled trial “Scandinavian Starch for Severe Sepsis and Septic Shock (6S).” ADMA, SDMA, and arginine/ADMA ratio were measured in plasma. The risk of death within 90 days was estimated in multivariate Cox regression analyses adjusted for gender, age ≥65 years, major cardiovascular disease, diabetes, hypertension, respiratory failure, vasopressor treatment, highest quartile of creatinine and bilirubin, and lowest quartile of platelet count. In the regression analyses missing values were estimated using multiple imputation. Results: Twenty-five patients had missing data in one or more of the baseline variables and 44 patients had missing methylarginine values. Both ADMA and SDMA were independently associated with 90-day mortality (ADMA: hazard ratio 1.54; 95% CI, 1.00–2.38; P = 0.046, and SDMA: hazard ratio 1.78; 95% CI, 1.14–2.72; P = 0.011). Arginine/ADMA ratio was not associated with 90-day mortality neither in univariate nor in multivariate analyses. The difference in mortality between patients with high and low ADMA was most pronounced in the first week after inclusion. Conclusions: High levels of ADMA and SDMA in plasma were associated with increased 90-day mortality in patients with severe sepsis or septic shock. Interfering with the methylarginine-NO systems may be a novel target in these patients.

Endothelial Damage Signals Refractory Acute Kidney Injury in Critically Ill Patients

ABSTRACT Critically ill patients with acute kidney injury (AKI) are heterogeneous on pathophysiology and prognosis. The role of endothelial damage in the pathogenesis of refractory AKI has not been clarified. The aim was to determine if biomarkers of endothelial damage, independently of the inflammatory insult on the kidney, can predict recovery of acute kidney injury. Methods: From the “Procalcitonin And Survival Study” multicenter intensive care unit cohort, followed for 28 days after admission, we included patients without chronic kidney disease, who survived >24 h after admission and with plasma samples at admission available for biomarker analysis. We defined AKI by the “Kidney Disease: Improving Global Outcomes” guidelines and recovery of prior kidney function as alive for five consecutive days after admission with no need for renal replacement therapy and creatinine levels consistently below ×1.5 the level before admission. We adjusted models for age, gender, vasopressor treatment, mechanical ventilation and levels of creatinine, procalcitonin, platelets, and bilirubin at admission. Results: Of a total 213 with AKI at admission, 99 recovered prior kidney function during follow-up. Endothelial damage on admission, measured by Soluble Thrombomodulin (sTM), was the strongest predictor of a reduced chance of recovery of prior kidney function (sTM in the highest vs. three lower quartiles hazard ratio 0.39; 95% confidence interval 0.21–0.73, P = 0.003). In contrast, the degree of the initial inflammatory insult on the kidney, measured by neutrophil gelatinase-associated lipocalin (NGAL), failed to predict this outcome (NGAL in highest vs. three lower quartiles hazard ratio = 1.20; 95% CI 0.72–2.00; P = 0.48). Procalcitonin, a specific marker of bacterial infection, was also associated with the rate of recovery (PCT in highest vs. three lower quartiles hazard ratio = 0.59; 95% CI 0.36–0.98; P = 0.04). Conclusion: AKI patients with high levels of sTM had a reduced chance of recovering prior renal function. Our findings support disintegration of the endothelium as a critical point in the pathogenesis of AKI that is refractory to treatment.

Serum and plasma neutrophil gelatinase associated lipocalin (NGAL) levels are not equivalent in patients admitted to intensive care.

Neutrophil gelatinase associated lipocalin (NGAL) is proposed as a biomarker of acute kidney injury (AKI). NGAL has been studied in a range of body fluids including serum and EDTA plasma. The aim of the present study was to establish relationship between serum NGAL concentrations and EDTA plasma NGAL concentrations in patients admitted to intensive care units (ICUs) and whether these determinations are directly comparable in this setting.

Readmission after intensive care: frequent, hazardous, and possibly preventable*.

In this issue of Critical Care Medicine, Hua et al (1) aim to present data describing the frequency of readmission among intensive care patients who survive to discharge and to identify risk factors associated with readmission. The decision to discharge a patient is a daily dilemma to physicians across all specialties. The current evidence to support the decision is sparse and often limited to specific patient populations (2). Early readmissions carry substantial negative impact on the life of patients and their families and remain a burden on resources of healthcare systems (3, 4). This is especially true in the setting of post–intensive care, since readmission is in its essence, an indicator of unsuccessful treatment in these vulnerable patients. It is clearly not satisfactory that our current practice involves readmitting patients within days or weeks. In recognition of this, low readmission rates have been associated with and adopted as marker of good quality in healthcare systems (5, 6). However, little systematic evidence has been available to estimate the magnitude of the problem and to support a specific discharge practice to avoid early readmission. Hua et al (1) present data on nearly half a million of patients admitted to ICUs in the state of New York, United States. Using state-of-the-art statistical analysis, they substantiate that one of six intensive care patients get readmitted to hospital within the first month after discharge and this number rises even more within the next 5 months. Notably, nearly a quarter of these early readmissions require intensive care again during readmission and a substantial part of the readmitted patients die during the readmission. The strongest predictors of readmission are surprisingly found to be the length of the index hospitalization, discharge to a skilled nursing facility, and having metastatic cancer. The main message from the study is that readmission after intensive care is a frequent and hazardous event, which we should be more concerned about preventing. Even though the authors are not able to identify a single well-defined patient population to aim interventions against, they do find other interesting associations. Two of the independent predictors of readmissions observed, long index hospitalization and discharge to skilled nursing facility, can be seen simply as markers of severity and thus confounders of other real causes of a less favorable prognosis. However, they do also leave open a possibility for a more controversial hypothesis: that at least some patients are substantially harmed by (too) long intensive care courses. Critical illness, hospitalization, and intensive care admission in particular is associated with well-known side effect such as muscle wasting, loss of daily living activity, and psychological deprivation (7–9). Perhaps, even though this may seem counterintuitive, we may actually be harming a group of patients by keeping them too long time in the ICU? Additionally, patients discharged to nursing facilities may sometimes be readmitted without a valid indication? Could some of these readmissions be prevented by sufficient and timely follow-up on the cause of admission and specialist evaluation of chronic diseases by consultants, that is, in the patients’ home, reduce the readmission rate in this fragile high-risk population? The data from this study cannot lead to any conclusions on this, and thus, we do need more data to guide us in the design of future intensive care strategies. In conclusion, we are faced with a challenge with regard to reducing the frequency of readmission. The study by Hua et al (1) has substantiated this and draws attention to interesting and new potentially causal relationships between admission and readmission. We encourage further investigations into this largely unchartered territory to find innovative ways of improving in-patient care to increase duration and quality of out-of-hospital life.

Sepsis: Personalized Medicine Utilizing ‘Omic’ Technologies—A Paradigm Shift?

Sepsis has over the years proven a considerable challenge to physicians and researchers. Numerous pharmacological and non-pharmacological interventions have been tested in trials, but have unfortunately failed to improve the general prognosis. This has led to the speculation that the sepsis population may be too heterogeneous to be targeted with the traditional one treatment suits all’ approach. Recent advances in genetic and biochemical analyses now allow genotyping and biochemical characterisation of large groups of patients via the ‘omics’ technologies. These new opportunities could lead to a paradigm shift in the approach to sepsis towards personalised treatments with interventions targeted towards specific pathophysiological mechanisms activated in the patient. In this article, we review the potentials and pitfalls of using new advanced technologies to deepen our understanding of the clinical syndrome of sepsis.

Hypophosphatemia and duration of respiratory failure and mortality in critically ill patients

Hypophosphatemia has been associated with prolonged duration of respiratory failure and increased mortality in critically ill patients, but there is very limited evidence supporting the negative effects of low phosphate. We examined the association between hypophosphatemia at ICU admission and time to successful weaning and 28‐day mortality.

Hyaluronic Acid Assays: Turbidimetric or Enzyme-Based Immune Assay? A Method Comparison Study.

Hyaluronic acid (HA) is proposed as a marker of functional liver capacity. The aim of the present study was to compare a new turbidimetric assay for measuring HA with the current standard method.