A. Raffaele De Gaudio

Glycocalyx and sepsis-induced alterations in vascular permeability

Endothelial cells line the inner portion of the heart, blood vessels, and lymphatic vessels; a basal membrane of extracellular matrix lines the extraluminal side of endothelial cells. The apical side of endothelial cells is the site for the glycocalyx, which is a complex network of macromolecules, including cell-bound proteoglycans and sialoproteins. Sepsis-associated alterations of this structure may compromise endothelial permeability with associated interstitial fluid shift and generalized edema. Indeed, in sepsis, the glycocalyx acts as a target for inflammatory mediators and leukocytes, and its ubiquitous nature explains the damage of tissues that occurs distant from the original site of infection. Inflammatory-mediated injury to glycocalyx can be responsible for a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and hepatic dysfunction. Moreover, some markers of glycocalyx degradation, such as circulating levels of syndecan or selectins, may be used as markers of endothelial dysfunction and sepsis severity. Although a great deal of experimental evidence shows that alteration of glycocalyx is widely involved in endothelial damage caused by sepsis, therapeutic strategies aiming at preserving its integrity did not significantly improve the outcome of these patients.

Low-dose hydrocortisone during severe sepsis: effects on microalbuminuria.

Objective:The aim of this study was to investigate the effect of low-dose hydrocortisone on glomerular permeability measured by the microalbuminuria to creatinine ratio (MACR) and on other markers of sepsis in severe septic patients. Design:Randomized prospective study. Setting:University intensive care unit. Patients:The study involved 40 patients with severe sepsis randomized into the hydrocortisone group (n = 20) and the standard therapy group (n = 20). Interventions:The hydrocortisone group received standard therapy plus a continuous infusion of hydrocortisone for 6 days, whereas the standard therapy group received only standard therapy. Measurements and Main Results:MACR, serum C-reactive protein, and procalcitonin concentrations were recorded every day from the day before the steroid therapy (T0) until the 6 days after (T1, T2, T3, T4, T5, and T6). Concentrations in the hydrocortisone group and the standard therapy group were compared using Mann-Whitney test at each time. We also compared with Wilcoxon signed rank test the values determined in each group at T0 with those at each subsequent time. Median MACR decreased from T0 to T6 in both patient groups; however, values were significantly lower in the hydrocortisone group from T3 through to T6. Median serum C-reactive protein also decreased from T0 in both patient groups, with significantly lower values in the hydrocortisone group from T3 through to T6. There were no significant differences in procalcitonin between groups compared with baseline values or at any individual time point. Conclusions:Low-dose hydrocortisone seems to reduce MACR and serum C-reactive protein but not procalcitonin in patients with severe sepsis. Further studies are needed to confirm these results and to understand the underlying molecular mechanisms.

Selenium supplementation in critically ill patients: A systematic review and meta-analysis

PURPOSE The oxidative stress is recognized as a constant feature in critical illness. Nevertheless, the use of antioxidant therapy remains controversial. We tried to demonstrate that intravenous selenium supplementation could promote antioxidant status and help protect against infection and organ failure, improving outcome in critically ill patients. MATERIALS AND METHODS We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the exogenous supplementation of selenium versus standard therapy without any adjuvant in critically ill adults. RESULTS Nine RCTs met inclusion criteria. Selenium supplementation was associated with a reduction in 28-day mortality of borderline statistical significance (risk ratio = 0.84, 95% confidence interval 0.71-0.99, P = .04). The analysis of pre-defined subgroups detected no significant effects regarding the supplementation with doses of selenium ≤ 500 μg/d, administration of a load dose with a bolus and duration of treatment. Only 2 studies analyzed 6-month mortality and could not show a difference. No effects could be demonstrated on hospital length of stay, pulmonary infections, or renal failure. CONCLUSIONS The use of high-dose selenium might be associated with a beneficial effect on 28-day mortality in critically ill patients. Nevertheless, the use of selenium as adjuvant therapy needs further evaluations.

Cytokine removal with high cut-off membrane: review of literature.

During the last decade, blood purification therapies have been proposed as an effective therapy to control the cytokines dysregulation in systemic inflammatory syndromes. Among them, the treatment with high cut-off membranes is characterized by larger pore size and more effective clearance for middle molecular weight molecules (cytokines). In this paper, we performed a thoughtful review of the literature on HCO being used for blood purification indications in all systemic inflammation syndromes. Clinical and experimental studies show that the use of high effluent flows in a pure diffusive treatment effectively removes serum cytokines with a safe profile in albumin clearance. In clinical studies, the removal of these inflammatory mediators is associated with a significant improvement in hemodynamic condition, oxygenation indices, and organ dysfunction.

Erythropoietin Attenuates Post-Traumatic Injury in Organotypic Hippocampal Slices

Recent experimental evidence indicates that erythropoietin (Epo), in addition to its hormonal role in regulating red cell production, operates as a neuroprotective agent. So far, the neuroprotective effect of human recombinant Epo (rhEpo) has been mainly demonstrated in models of cerebral ischemia/hypoxia and in selected in vivo studies of traumatic neuronal injury. To further investigate the potential role of this multifunctional trophic factor in post-traumatic cell death, we examined the protective effects of rhEpo in a newly developed model of mechanical trauma in organotypic hippocampal slices. Organotypic rat hippocampal slices were subjected to traumatic injury by allowing a stylus to impact on the CA1 area with an energy of 6 microJ. Hippocampal damage was identified and measured 24 and 48 h later with the fluorescent dye propidium iodide (PI). In untreated slices, the impact induced a significant increase in the mean hippocampal PI fluorescence, co-localized with the area of impact at 24 h (primary post-traumatic injury) and progressively spread to the whole slice between 24 and 48 h (secondary post-traumatic injury). Addition of rhEpo (1-100 UI/mL) or of the NMDA antagonist MK-801 (30 microM) immediately after the traumatic injury reduced hippocampal damage by approximately 30% when observed 24 h later. At 48 h after trauma, the protective effect of rhEpo was greater (by about 47%) and significantly more pronounced than that of MK-801 (28%). Our results suggest that the neuroprotective activity of rhEpo is particularly effective against delayed, secondary post-traumatic damage. This well tolerated agent could provide a therapeutic benefit in pathologies involving post-traumatic neurodegeneration.

Glomerular permeability after surgical trauma in children: Relationship between microalbuminuria and surgical stress score

ObjectivesTo determine whether there is an increase of urinary albumin during and after surgical trauma and investigate a possible relationship between microalbuminuria and the severity of surgical stress. DesignProspective study. SettingUniversity hospital pediatric intensive care unit. PatientsForty consecutive children scheduled for elective surgery. InterventionsNone. Measurements and Main Results Microalbuminuria/urinary creatinine ratio (MACR) was measured before, during, and after elective moderate or major surgical procedures. The Oxford Surgical Stress Score (SSS) was determined for each patient at the end of the operation, and its relationship with maximum deviation of MACR from baseline values was investigated. MACR showed a progressive increase during surgery and a decrease afterward, reaching preoperative values in most cases within 24 hrs after the end of surgery. There was a significant correlation between the increase in MACR and severity of the surgical trauma as measured by SSS. Two patients showed a rise in MACR after the initial postoperative normalization before clinical appearance of a surgical complication and one patient showed a persistent rise in MACR before clinical appearance of a septic complication. None of the other patients showed any rise in MACR after postoperative normalization, and they all had an uneventful recovery. ConclusionsMACR rises during and after major or moderate elective surgery in children. There is a significant positive correlation between severity of surgical trauma and capillary permeability in pediatric patients. Microalbuminuria, as an index of capillary permeability, may be an early sign of incipient complications and assist in the identification of those patients whose condition will deteriorate. The test is a cheap, blood-sparing, easy-to-perform bedside procedure that may have a useful role in clinical practice for evaluating the effect of surgical trauma on capillary permeability in children.

Nomenclature for renal replacement therapy and blood purification techniques in critically ill patients: practical applications

This article reports the conclusions of the second part of a consensus expert conference on the nomenclature of renal replacement therapy (RRT) techniques currently utilized to manage acute kidney injury and other organ dysfunction syndromes in critically ill patients. A multidisciplinary approach was taken to achieve harmonization of definitions, components, techniques, and operations of the extracorporeal therapies. The article describes the RRT techniques in detail with the relevant technology, procedures, and phases of treatment and key aspects of volume management/fluid balance in critically ill patients. In addition, the article describes recent developments in other extracorporeal therapies, including therapeutic plasma exchange, multiple organ support therapy, liver support, lung support, and blood purification in sepsis. This is a consensus report on nomenclature harmonization in extracorporeal blood purification therapies, such as hemofiltration, plasma exchange, multiple organ support therapies, and blood purification in sepsis.

Organ dysfunction during continuous veno-venous high cut-off hemodialysis in patients with septic acute kidney injury: A prospective observational study

Background Continuous veno-venous hemodialysis with high cut-off membranes (HCO-CVVHD) removes inflammatory mediators involved in organ dysfunction during sepsis. The aim of the present study was to assess the variations in SOFA score and identify early predictors of short-term mortality in a cohort of patients with septic shock, treated with HCO-CVVHD for acute kidney injury (AKI). Methods An observational prospective multicenter cohort study was conducted in four mixed medical-surgical ICUs. Thirty-eight patients with septic shock and AKI (KDIGO stage≥1) treated with HCO-CVVHD have been included in this study. Patients were divided into Survivors and non-Survivors according to mortality observed at 72nd hr of treatment. The variation of SOFA scores and clinical/biochemical parameters were described over time for the entire population and specifically for Survivors and non-Survivors. Similarly, circulating inflammatory mediators (as IL-6, TNF-a and IL-10) were described over time. A logistic regression analysis was used to identify the baseline clinical and biochemical parameters associated with 72 hrs-ICU mortality. Results Overall, the mean SOFA score was 12±3 at baseline, 10.9±3 at 6hrs, 9.8±3 at 12hrs, 8.9±3.3 at 24 hrs, and 8±3.5 at 48 hrs after HCO-CVVHD initiation; and 6.5±2.7 at 24 hrs and 6.6±3 at 48 hrs after HCO-CVVHD discontinuation. In the multivariate regression analysis, baseline serum lactate levels and AKI stage independently correlated with short-term mortality during HCO-CVVHD. A significant reduction was observed in circulating levels of TNFα and IL-6 among Survivors. Conclusions SOFA score significantly decreased early after initiation of HCO-CVVHD in patients with septic AKI. Baseline lactate levels and the AKI stage resulted to be associated to 72 hrs-ICU-mortality.

The New MIRUS System for Short-Term Sedation in Postsurgical ICU Patients*

Objectives: To evaluate the feasibility and safety of the MIRUS system (Pall International, Sarl, Fribourg, Switzerland) for sedation with sevoflurane for postsurgical ICU patients and to evaluate atmospheric pollution during sedation. Design: Prospective interventional study. Setting: Surgical ICU. February 2016 to December 2016. Patients: Postsurgical patients requiring ICU admission, mechanical ventilation, and sedation. Interventions: Sevoflurane was administered with the MIRUS system targeted to a Richmond Agitation Sedation Scale from –3 to –5 by adaptation of minimum alveolar concentration. Measurements and Main Results: Data collected included Richmond Agitation Sedation Scale, minimum alveolar concentration, inspired and expired sevoflurane fraction, wake-up times, duration of sedation, sevoflurane consumption, respiratory and hemodynamic data, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment, and laboratory data and biomarkers of organ injury. Atmospheric pollution was monitored at different sites: before sevoflurane delivery (baseline) and during sedation with the probe 15 cm up to the MIRUS system (S1) and 15 cm from the filter-Reflector group (S2). Sixty-two patients were enrolled in the study. No technical failure occurred. Median Richmond Agitation Sedation Scale was –4.5 (interquartile range, –5 to –3.6) with sevoflurane delivered at a median minimum alveolar concentration of 0.45% (interquartile range, 0.4–0.53) yielding a mean inspiratory and expiratory concentrations of 0.79% (SD, 0.24) and 0.76% (SD, 0.18), respectively. Median awakening time was 4 minutes (2.2–5 min). Median duration of sevoflurane administration was 3.33 hours (2.33–5.75 hr), range 1–19 hours with a mean consumption of 7.89 mL/hr (SD, 2.99). Hemodynamics remained stable over the study period, and no laboratory data indicated liver or kidney injury or dysfunction. Median sevoflurane room air concentration was 0.10 parts per million (interquartile range, 0.07–0.15), 0.17 parts per million (interquartile range, 0.14–0.27), and 0.15 parts per million (interquartile range, 0.07–0.19) at baseline, S1, and S2, respectively. Conclusions: The MIRUS system is a promising and safe alternative for short-term sedation with sevoflurane of ICU patients. Atmospheric pollution is largely below the recommended thresholds (< 5 parts per million). Studies extended to more heterogeneous population of patients undergoing longer duration of sedation are needed to confirm these observations.

High Cutoff Membrane to Reduce Systemic Inflammation Due to Differentiation Syndrome: A Case Report

Background: Differentiation syndrome is a life-threatening complication of therapy that is carried out with agents used for acute promyelocytic leukemia. Its physiopathology comprehends the production of inflammatory mediators by differentiating granulocytes, endothelial and alveolar cells due to stimulation by all-trans retinoic acid and leading to sustained systemic inflammation. Methods: Treatment with high cut-off continuous veno-venous hemodialysis (HCO-CVVHD) was performed to reduce the circulating mediators of systemic inflammation. Results: After 52 h of treatment, an important reduction was observed in inflammatory mediators (IL-1β: from 10 to 2 pg/ml; IL-8: from 57 to 40 pg/ml; TNF-α: from 200 to 105 pg/ml; IL-6: from 263 to 91 pg/ml), as well as in anti-inflammatory mediators (IL-10: from 349 to 216 pg/ml). Conclusions: HCO-CVVHD should be explored as a part of treatment in systemic inflammation states other than sepsis (e.g., differentiation syndrome). Furthermore, its immunomodulatory effects could be particularly useful in immunocompromised patient treated with corticosteroids.