The impact of "early" versus "late" initiation of renal replacement therapy in critical care patients with acute kidney injury: a systematic review and evidence synthesis.

BACKGROUND: The optimal timing of initiating renal replacement therapy (RRT) in critical illness complicated by acute kidney injury (AKI) is not clearly established. Trials completed on this topic have been marked by contradictory findings as well as quality and heterogeneity issues. Our goal was to perform a synthesis of the evidence regarding the impact of "early" versus "late" RRT in critically ill patients with AKI, focusing on the highest-quality research on this topic. METHODS: A literature search using the PubMed and Embase databases was completed to identify studies involving critically ill adult patients with AKI who received hemodialysis according to "early" versus "late"/"standard" criteria. The highest-quality studies were selected for meta-analysis. The primary outcome of interest was mortality at 1 month (composite of 28- and 30-day mortality). Secondary outcomes evaluated included intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: Thirty-six studies (seven randomized controlled trials, ten prospective cohorts, and nineteen retrospective cohorts) were identified for detailed evaluation. Nine studies involving 1042 patients were considered to be of high quality and were included for quantitative analysis. No survival advantage was found with "early" RRT among high-quality studies with an OR of 0.665 (95 % CI 0.384-1.153, p = 0.146). Subgroup analysis by reason for ICU admission (surgical/medical) or definition of "early" (time/biochemical) showed no evidence of survival advantage. No significant differences were observed in ICU or hospital LOS among high-quality studies. CONCLUSIONS: Our conclusion based on this evidence synthesis is that "early" initiation of RRT in critical illness complicated by AKI does not improve patient survival or confer reductions in ICU or hospital LOS.

Diagnosis of Febrile Illnesses Other Than Ebola Virus Disease at an Ebola Treatment Unit in Sierra Leone.

Patients with febrile illnesses presenting to an Ebola treatment unit in Sierra Leone had a wide range of diagnoses other than Ebola virus disease. Rapid diagnostic tests were useful in confirming these diagnoses, reducing the length of patient stay with valuable consequences. These alternative diagnoses should assist in future planning.

Erythropoietin improves skeletal muscle microcirculation through the activation of eNOS in a mouse sepsis model.

BACKGROUND: Sepsis and septic shock remain the major causes of morbidity and mortality in intensive care units. One mechanism that leads to organ failure is microcirculatory dysfunction. Erythropoietin (EPO) is a glycoprotein produced by the kidney that primarily regulates erythropoiesis, but it also can exert hemodynamic, anti-inflammatory, and tissue protective effects. We previously reported that administration of EPO to septic mice improves mouse skeletal muscle capillary perfusion and tissue bioenergetics. The objective of this study was to explore the potential mechanism(s) involved. METHODS: Sepsis was induced by intraperitoneal (i.p.) injection of a fecal suspension (12.5 g in 0.5 saline/mouse) in mice. At 18 hours after sepsis induction, a single dose of rHuEPO (400 U/kg) was given to the mice. Mouse capillary perfusion density and nicotinamide adenine dinucleotide (NADH) fluorescence in skeletal muscle were observed using intravital microscopy. Endothelial cells derived from the skeletal muscle were treated with rHuEPO (5 U/mL) and endothelial nitric oxide synthase (eNOS) activation and activity were assessed. RESULTS: Septic mice had decreased capillary perfusion density and increased tissue NADH fluorescence indicating impaired tissue bioenergetics, whereas animals treated with rHuEPO demonstrated an improvement in capillary perfusion density and decreased skeletal muscle NADH fluorescence. The beneficial effect of rHuEPO did not occur in septic mice treated with l-NAME (an NOS inhibitor, 20 mg/kg) or mice genetically deficient in eNOS. Treatment of endothelial cells with rHuEPO resulted in activation of eNOS as indicated by increased eNOS phosphorylation and NO production. CONCLUSIONS: Our results suggest that eNOS plays an important role in mediating the beneficial effect of rHuEPO on microcirculation in this septic mouse model.

The effect of erythropoietin on microcirculation perfusion and tissue bioenergetics of the small intestine in a hemorrhagic shock and resuscitation rat model.

BACKGROUND: Erythropoietin (EPO) can exert acute hemodynamic and anti-inflammatory effects in addition to erythropoiesis. We tested the hypothesis that EPO given at resuscitation with saline will improve capillary perfusion and tissue oxygenation in the gut using a hemorrhagic shock model. METHODS: Sprague-Dawley rats were bled 30 mL/kg to maintain a mean arterial blood pressure of 40 mm Hg for 50 minutes and then randomized to one of four resuscitation groups (n = 6 per group): blood, blood + recombinant human EPO (rHuEPO), saline, and saline + rHuEPO. Intravenous rHuEPO (1,000 U/kg) was given at the start of resuscitation. Intravital microscopy was used to measure perfused capillary density, flow motion of red blood cell (RBC), and tissue NADH fluorescence 60 minutes after resuscitation. Venous oxygenation saturation (Svo2) was also measured in a second experiment. RESULTS: In the blood +/- rHuEPO resuscitation group, the perfused capillary density, RBC flow motion scores, and NADH fluorescence returned to near normal values. The saline + rHuEPO group compared with the saline group demonstrated an increased RBC flow motion score (2.32 vs. 1.60; p < 0.01); however, the perfused capillary density was not significantly increased (23.03 Cap/mm vs. 21.61 Cap/mm; p = 0.40). The saline + rHuEPO group also demonstrated statistically significant lower NADH fluorescence than the saline group after shock following resuscitation (110% +/- 3.64% vs. 122% +/- 4.26%; p < 0.05) suggesting decreased tissue dysoxia. The Svo2 in the saline + rHuEPO group was higher when compared with the saline group (45% vs. 38% by continuous oximetry; 38% vs. 29% by co-oximetry; p < 0.05). CONCLUSION: Our results suggest that the addition of rHuEPO at the time of saline resuscitation may have beneficial effects in hemorrhagic shock by improving tissue perfusion and decreasing dysoxia in the gut.

C-peptide attenuates acute lung inflammation in a murine model of hemorrhagic shock and resuscitation by reducing gut injury.

BACKGROUND: The study aims to evaluate whether C-peptide can reduce gut injury during hemorrhagic shock (HS) and resuscitation (R) therefore attenuate shock-induced inflammation and subsequent acute lung injury. METHODS: Twelve-week-old male mice (C57/BL6) were hemorrhaged (mean arterial blood pressure maintained at 35 mm Hg for 60 minutes) and then resuscitated with Ringer's lactate, followed by red blood cell transfusion with (HS/R) or without C-peptide (HS/R + C-peptide). Mouse gut permeability, bacterial translocation into the circulatory system and intestinal pathology, circulating HMGB1, and acute lung injury were assessed at different times after R. The mice in the control group underwent sham procedures without HS. RESULTS: Compared to the sham group, the mice in the HS/R group showed increased gut permeability (6.07 ± 3.41 µg of FD4/mL) and bacterial translocation into the circulatory system (10.05 ± 4.92, lipopolysaccharide [LPS] of pg/mL), and increased gut damage; conversely, mice in the HS/R + C-peptide group showed significantly reduced gut permeability (1.59 ± 1.39 µg of FD4/mL; p < 0.05) and bacterial translocation (4.53 ± 1.08 pg of LPS/mL; p < 0.05) with reduced intestine damage. In addition, mice in the HS/R group had increased circulating HMGB1 (21.64 ± 14.17 ng/mL), lung myeloperoxidase) activity (34.4 ± 8.91 mU/g of tissue), and pulmonary protein leakage (2.33 ± 1.16 µg Evans blue/g tissue per minute). Mice in the HS/R + C-peptide group showed decreased HMGB1 (7.27 ± 1.93 ng/mL; p < 0.05), lung myeloperoxidase (23.73 ± 8.39 mU/g of tissue; p < 0.05), and pulmonary protein leakage (1.17 ± 0.42 Evans Blue/g tissue per minute; p < 0.05). CONCLUSION: Our results indicate that C-peptide exerts beneficial effects to attenuate gut injury and dysfunction, therefore diminishing lung inflammation and subsequent injury in mice with HS and R.