Sepsis Serum Research Articles

Case 3: Neonate with Sudden Onset of Hypotonia on the Second Day After Birth

A 2-day-old 3-kg female term neonate is born in a normal vaginal delivery with Apgar scores of 8, 8, and 9 at 1, 5, and 10 minutes, respectively. During morning rounds, she is noted to have a weak cry. Antenatal and natal history findings are normal. Detailed neurologic examination shows a fully conscious neonate with decreased shoulder tone and head lag. Neonatal reflexes are also diminished, with a weak cry, poor swallowing, and poor sucking reflex. There are no clinical features of respiratory distress or respiratory failure, shock, seizure, or altered sensorium. The neonate is evaluated with a sepsis screen, serum glucose, serum calcium, serum electrolytes, and serum magnesium for neonatal sepsis or metabolic derangements. Laboratory investigation shows normal sepsis screen and metabolic evaluation (total white blood cell count of 13,000/μL [13×109/L], C-reactive protein level of 0.01 mg/L [0.10 nmol/L], serum glucose of 89 mg/dL [4.9 mmol/L], total serum calcium of 8.4 mg/dL [2.1 mmol/L], ionized calcium of 4.6 mg/dL [1.1 mmol/L], serum magnesium of 1.3 mEq/L [0.65 mmol/L], serum sodium of 138 mEq/L [138 mmol/L], and serum potassium of 4.6 mEq/L [4.6 mmol/L]). Head neurosonography to rule out any bleeding or malformations has normal findings but neonatal hypotonia persists. At this time, one investigation clinches the diagnosis. In a neonate with sudden onset of hypotonia, the initial differential diagnosis includes neonatal sepsis; metabolic derangements such as hypermagnesemia, hypocalcemia, and hypokalemia; antibiotic toxicity due to aminoglycosides; botulism; and cerebral malformations or bleeding. The neonate was evaluated for metabolic causes and neonatal sepsis, and the investigation showed normal sepsis screen and metabolic profile, thus ruling out these causes. The infant had no history of receiving antibiotics and she was exclusively breastfed, thus ruling out elevated levels of aminoglycosides or …

Sustained high serum caspase-3 concentrations and mortality in septic patients.

Caspase-3 is the main executor of the apoptotic process. Higher serum caspase-3 concentrations in non-survivor compared to survivor septic patients have been found. The objectives of this work (with the increase of sample size to 308 patients, and the determination of serum caspase-3 concentrations also on days 4 and 8 of diagnosis of severe sepsis) were to know whether an association between serum caspase-3 concentrationss during the first week, degree of apoptosis, sepsis severity, and sepsis mortality exists. We collected serum samples of 308 patients with severe sepsis from eight intensive care units on days 1, 4 and 8 to measure concentrations of caspase-3 and caspase-cleaved cytokeratin (CCCK)-18 (to assess degree of apoptosis). End point was 30-day mortality. We found higher serum concentrations of caspase-3 and CCCK-18 in non-survivors compared to survivors on days 1 (p<0.001), 4 (p<0.001), and 8 (p<0.001). We found an association between serum caspase-3 concentrations on days 1, 4 and 8 of severe sepsis diagnosis and serum CCCK-18 concentrations (p<0.001), SOFA (p<0.001), serum acid lactic concentrations (p<0.001), and 30-day sepsis mortality (p<0.001). The new findings of this work were that an association between serum caspase-3 concentrations during the first week, apoptosis degree, sepsis severity, and sepsis mortality exists.

The pancreas responds to remote damage and systemic stress by secretion of the pancreatic secretory proteins PSP/regI and PAP/regIII.

IntroductionIn patients with infection and sepsis serum levels of Pancreatic Stone protein/regenerating protein I (PSP) are highly elevated. The origin of PSP during these conditions is presumably the pancreas, however, an intestinal origin cannot be excluded. Similarly, pancreatitis-associated protein (PAP) was identified in the pancreas. These proteins were also localized in intestinal organs. Here we aim to elucidate the bio-distribution of PSP and PAP in animal models of sepsis and in healthy humans.ResultsPSP and PAP responded to remote lesions in rats although the pancreatic response was much more pronounced than the intestinal. Tissue distribution of PSP demonstrated a 100-fold higher content in the pancreas compared to any other organ while PAP was most abundant in the small intestine. Both proteins responded to CLP or sham operation in the pancreas. PSP also increased in the intestine during CLP. The distribution of PSP and PAP in human tissue mirrored the distribution in the murine models.Materials and methodsDistribution of PSP and PAP was visualized by immunohistochemistry. Rats and mice underwent midline laparotomies followed by mobilization of tissue and incision of the pancreatic duct or duodenum. Standard cecum-ligation-puncture (CLP) procedures or sham laparotomies were performed. Human tissue extracts were analyzed for PSP and PAP.ConclusionsThe pancreas reacts to remote lesions and septic insults in mice and rats with increased PSP synthesis, while PAP is selectively responsive to septic events. Furthermore, our results suggest that serum PSP in septic patients is predominantly derived through an acute phase response of the pancreas.

Inhibitory effects of serum from sepsis patients on epithelial cell migration in vitro: a case control study

BackgroundSepsis delays wound re-epithelialization. In this study we explored the effect of human sepsis sera as well as the effects of cytokines, growth factors and exosomes of sepsis sera treated normal fibroblasts (NF) on keratinocyte migration and proliferation in vitro.MethodsSerum samples were taken on days 1, 4, and 9 from 44 patients diagnosed with severe sepsis, and from 14 matching healthy controls. We evaluated the effects of sepsis serum with or without TNF-α, EGF, EGF receptor inhibitor or exosomes of sepsis sera treated NF on human keratinocyte (HaCaT) proliferation (BrdU assay), viability (MTT assay), and migration (horizontal wound healing model). Cytokine levels of sepsis and healthy sera were measured by multiplex assay. Comparisons between groups were carried out using SPSS statistics and P < 0.05 was considered significant.ResultsSevere-sepsis sera collected on days 1, 4, and 9 reduced keratinocyte proliferation by 6% (P = 0.005), 20% (P = 0.001), and 18% (P = 0.002), respectively, compared to control sera. Cell viability in cultures exposed to sepsis sera from days 4 and 9 was reduced by 38% (P = 0.01) and 58% (P < 0.001), respectively. Open-surface wounds exposed to sepsis sera from days 1 and 4 were larger than those exposed to sera from healthy controls (60 vs. 31%, P = 0.034 and 66 vs. 31%, P = 0.023, respectively). Exosomes of sepsis or healthy sera treated NF inhibited keratinocyte migration. We detected higher serum levels of cytokines TNF-α (5.7 vs. 0.7 pg/ml, P < 0.001), IL-6 (24.8 vs. 3.8 pg/ml, P < 0.001), IL-10 (30.0 vs. 11.9 pg/ml, P = 0.040), and VEGF (177.9 vs. 48.1 pg/ml, P = 0.018) in sepsis sera. Levels of EGF were significantly lower in sepsis sera than in that of healthy controls (6.5 vs. 115.6 pg/ml, P < 0.001). Sepsis serum supplemented with EGF 5 ng/ml and TNF-α in all concentrations improved keratinocyte migration.ConclusionsKeratinocyte viability, proliferation and migration were reduced in severe sepsis in vitro. Exosomes from NF added in healthy or sepsis serum media inhibited keratinocyte migration. Decreased levels of EGF in sepsis sera may partially explain the delay of wound healing with severe-sepsis patients. Increased levels of TNF-α in sepsis sera do not explain diminished keratinocyte migration.

Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients.

BackgroundAcute kidney injury and hyperchloremia are commonly present in critically ill septic patients. Our study goal was to evaluate the association of hyperchloremia and acute kidney injury in severe sepsis and septic shock patients.MethodsIn this retrospective cohort study in a provincial tertiary care hospital, adult patients with severe sepsis or septic shock and serum chloride measurements were included. Serum chloride was measured on a daily basis for 48 hours. Primary outcome was development of acute kidney injury (AKI) and association of AKI and serum chloride parameters was analyzed.ResultsA total of 240 patients were included in the study, 98 patients (40.8 %) had hyperchloremia. The incidence of acute kidney injury (AKI) was significantly higher in the hyperchloremia group (85.7 % vs 47.9 %; p < 0.001). Maximal chloride concentration in the first 48 hours ([Cl-]max) was significantly associated with AKI. In multivariate analysis, [Cl-]max was independently associated with AKI [adjusted odds ratio (OR) for AKI = 1.28 (1.02–1.62); p = 0.037]. The increase in serum chloride (Δ[Cl-] = [Cl-]max – initial chloride concentration) demonstrated a dose-dependent relationship with severity of AKI. The mean Δ[Cl-] in patients without AKI was 2.1 mmol/L while in the patients with AKI stage 1, 2 and 3 the mean Δ[Cl-] was 5.1, 5.9 and 6.7 mmol/L, respectively. A moderate increase in serum chloride (Δ[Cl-] ≥ 5 mmol/L) was associated with AKI [OR = 5.70 (3.00–10.82); p < 0.001], even in patients without hyperchloremia [OR = 8.25 (3.44–19.78); p < 0.001].ConclusionsHyperchloremia is common in severe sepsis and septic shock and independently associated with AKI. A moderate increase in serum chloride (Δ[Cl-] ≥5 mmol/L) is associated with AKI even in patients without hyperchloremia.

Cumulative Fluid Balance and Mortality in Septic Patients With or Without Acute Kidney Injury and Chronic Kidney Disease.

Incident acute kidney injury and prevalent chronic kidney disease are commonly encountered in septic patients. We examined the differential effect of acute kidney injury and chronic kidney disease on the association between cumulative fluid balance and hospital mortality in critically ill septic patients. Retrospective cohort study. Urban academic medical center ICU. ICU adult patients with severe sepsis or septic shock and serum creatinine measured within 3 months prior to and 72 hours of ICU admission. Patients with estimated glomerular filtration rate less than 15 mL/min/1.73 m or receiving chronic dialysis were excluded. None. A total of 2,632 patients, 1,211 with chronic kidney disease, were followed up until hospital death or discharge. Acute kidney injury occurred in 1,525 patients (57.9%), of whom 679 (44.5%) had chronic kidney disease. Hospital mortality occurred in 603 patients (22.9%). Every 1-L increase in cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality in all patients (adjusted odds ratio, 1.06 [95% CI] 1.04-1.08; p < 0.001), and in each acute kidney injury/chronic kidney disease subgroup (adjusted odds ratio, 1.06 [1.03-1.09] for acute kidney injury+/chronic kidney disease+; 1.09 [1.05-1.13] for acute kidney injury-/chronic kidney disease+; 1.05 [1.03-1.08] for acute kidney injury+/chronic kidney disease-; and 1.07 [1.02-1.11] for acute kidney injury-/chronic kidney disease-). There was a significant interaction between acute kidney injury and chronic kidney disease on cumulative fluid balance (p =0.005) such that different cumulative fluid balance cut-offs with the best prognostic accuracy for hospital mortality were identified: 5.9 L for acute kidney injury+/chronic kidney disease+; 3.8 L for acute kidney injury-/chronic kidney disease+; 4.3 L for acute kidney injury+/chronic kidney disease-; and 1.5 L for acute kidney injury-/chronic kidney disease-. The addition of cumulative fluid balance to the admission Sequential Organ Failure Assessment score had increased prognostic utility for hospital mortality when compared with Sequential Organ Failure Assessment alone, particularly in patients with acute kidney injury. Higher cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality regardless of acute kidney injury or chronic kidney disease presence. We characterized cumulative fluid balance cut-offs associated with hospital mortality based on acute kidney injury/chronic kidney disease status, underpinning the heterogeneity of fluid regulation in sepsis and kidney disease.

The synthetic antimicrobial peptide 19-2.5 attenuates mitochondrial dysfunction in cardiomyocytes stimulated with human sepsis serum.

Septic cardiomyopathy affects up to 70% of patients with septic shock and the derangement of cardiac mitochondrial function contributes to the likelihood of death. However, at present, there is no specific therapeutic drug available. The peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α) and coactivator-1β (PGC-1β) modulate members of the PPARs, which regulate mitochondrial energy metabolism and the production of mitochondrial reactive oxygen species in the heart. This study investigated the potential of the newly developed synthetic antimicrobial peptide 19-2.5 (Pep2.5) to attenuate mitochondrial dysfunction in murine cardiomyocytes stimulated with serum from septic shock patients. Pep2.5 treatment attenuated the suppression of PPAR-α, PPAR-γ ( P = 0.0004 and P = 0.0001, respectively) and PGC-1α/β ( P = 0.0008 and P = 0.0147, respectively) in cardiomyocytes stimulated with serum from septic shock patients compared with untreated cells. Pep2.5 treatment enhanced the mitochondrial maximum respiration ( P < 0.0001), increased cellular ATP levels ( P < 0.0001) and reduced the production of mitochondrial reactive oxygen species. Thus, the administration of Pep2.5 may have the potential as a promising therapeutic approach in septic cardiomyopathy by attenuating mitochondrial dysfunction in the septic heart.

Case 1: Recurrent Apnea in a Preterm Neonate

A preterm male infant is born at 29-2/7 weeks of gestation to a 25-year-old primigravida Asian Indian mother who conceived after infertility treatment. She is admitted for preterm labor pains and receives 1 dose of betamethasone 12 mg intramuscularly at admission. ### Birth Details The neonate is delivered vaginally and has a birthweight of 1,050 g. He does not require resuscitation at birth and his Apgar scores are 7 and 8 at 1 and 5 minutes, respectively. ### Nursery Admission Course The neonate is transferred to the nursery in view of prematurity, very low birthweight, and respiratory distress. At admission, he has a respiratory distress score of 2/10 (Silverman score) for which continuous positive airway pressure (CPAP) is initiated at 5 cm H2O and fraction of inspired oxygen of 50%. The neonate is weaned off CPAP 72 hours after birth. He has an episode of apnea (requiring bag and mask ventilation) 6 hours after weaning off CPAP. CPAP is reinitiated and complete evaluation for an underlying cause of apnea is conducted (sepsis evaluation, serum calcium, serum electrolytes, blood dextrose, head ultrasonography, echocardiography, and chest radiography), all of which are normal. Oral caffeine is initiated after a loading dose. CPAP is continued and a weaning trial is started on day 10 after birth, which the infant tolerates, and he is weaned to room air on day 12. He has …

Artemisinin protects mice against burn sepsis through inhibiting NLRP3 inflammasome activation

BackgroundNLRP3 inflammasome activation is recently reported to be linked to the pathogenesis of sepsis. Artemisinin is shown to play beneficial effects in sepsis. However, the impacts of artemisinin on burn sepsis have not been investigated. This study is designed to investigate the role of artemisinin in burn sepsis and the involvement of NLRP3 inflammasome activation. MethodsMale BALB/c mice were randomly divided into sham burn, burn, burn sepsis, and artemisinin treated groups. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Adhesion molecules and neutrophil infiltration in lung and heart were detected by real-time polymerase chain reaction. Mortality rates were monitored. Artemisinin was added to Raw 264.7 cells that were stimulated with burn sepsis serum in the presence/absence of an inhibitor of NLRP3 inflammasome, 3, 4-methylenedioxy-β-nitrostyrene. Interleukin (IL) 1β and IL-18 messenger RNA expression as well as NLRP3 and caspase 1 protein were measured. ResultsProduction of inflammatory cytokines in serum, levels of adhesion molecules and neutrophil infiltration in lung and heart, and mortality rate of burn septic mice were significantly higher than those of control. These effects were attenuated by artemisinin. Artemisinin down-regulated protein levels of NLRP3 and caspase 1 and inhibited the increases of IL-1β and IL-18 messenger RNA expression from Raw 264.7 cells that were stimulated with burn sepsis serum. These effects of artemisinin were not further strengthened in the presence of 4-methylenedioxy-β-nitrostyrene. ConclusionArtemisinin protects mice from burn sepsis by attenuating the inflammatory response and alleviating inflammatory infiltration in vital organs, likely through inhibiting the activation of NLRP3 inflammasome.

Metallothionein ameliorates burn sepsis partly via activation of Akt signaling pathway in mice: a randomized animal study.

IntroductionMetallothioneins (MTs) are a family of cysteine-rich and low molecular-weight proteins that can regulate metal metabolism and act as antioxidants. Recent studies showed that MTs played a protective role in excessive inflammation and sepsis. However, the role of MTs in burn sepsis remains unclear. This study is designed to investigate the role of MTs in burn sepsis in an experimental mouse model.MethodsMT-I/II knockout (−/−) mice on a C57BL/6 background and their wild-type (WT) littermates were randomly divided into sham burn, burn, burn sepsis, Zn treated and Zn-MT-2 treated groups. Levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Myeloperoxidase (MPO) activity was detected by spectrophotometry. In in vitro study, exogenous MT was added to macrophages that stimulated with serum from burn sepsis mice with or without Akt inhibitor LY294002. The IL-1 β and IL-6 mRNA expression were detected by quantitative real-time polymerase chain reaction. The levels of Akt expression were determined by western blot.ResultsBurn sepsis induced significantly elevated levels of inflammatory cytokines in serum and increased inflammatory infiltration in the liver and lung. These effects were more prominent in MT (−/−) mice than in WT mice. Furthermore, exogenous MT-2 inhibited these elevated inflammatory response in both WT and MT (−/−) mice. MT-2 up-regulated Akt phosphorylation and abrogated the increase of IL-1β and IL-6 mRNA expression from macrophages that stimulated with burn sepsis serum. These effects of MT-2 were abolished in the presence of LY294002.ConclusionMT-2 ameliorates burn sepsis by attenuating inflammatory response and diminishing inflammatory organ damage, which is at least partly mediated by activation of Akt signaling pathway.

Predictors of 30-day morbidity and mortality in transnasal microscopic pituitary tumor excision.

There is a lack of population-based, multi-institutional analyses of factors associated with morbidity and mortality following pituitary tumor excision. The American College of Surgeons National Surgical Quality Improvement Project files were used to compile information on patients that had undergone transnasal microscopic pituitary tumor resection from 2006 to 2012. Patient demographics, comorbidities, operative characteristics, and morbidity and mortality in the 30 days following surgery were included. Multivariate logistic regression was used for categorical variables and multivariate linear regression was used for continuous variables to evaluate factors leading to adverse events. A total of 658 patients were included, of which 58 (8.81%) experienced a complication, reoperation or death in the 30 days following surgery. The most common complications were reoperation (3.37%), followed by unplanned reintubation (1.99%), urinary tract infection (1.68%), and transfusion (1.68%). Predictors of any complication, reoperation, or death include preoperative sepsis (odds ratio [OR] = 7.596) and lower preoperative serum albumin (OR = 6.667). Younger age predicted surgical complications (OR = 1.105). Predictors of medical complications include higher body mass index (OR = 1.112), chronic steroid use (OR = 6.568), preoperative sepsis (OR = 15.297), and lower preoperative serum hematocrit (OR = 1.225). Predictors of increased total length of hospital stay were older age (β = 0.146), higher body mass index (β = 0.188), chronic steroid use (β = 0.142), preoperative sepsis (β = 0.489), and lower preoperative serum albumin (β = -0.213). Although adverse events following pituitary tumor excision are low, awareness of factors associated with morbidity and mortality in the early postoperative period may allow for improved patient monitoring and outcomes.

Vpliv vrste povzročitelja na porast koncentracije prokalcitonina pri bolnikih s sepso

AbstractTheoretical background: Procalcitonin (PCT) is diagnostic and prognostic biomarker of sepsis. The objective of this study was to evaluate the correlation between sepsis causative agent and serum PCT concentration, since it would influence the initial empirical antimicrobial therapy selection.Methods: This retrospective study included 96 patients with sepsis who were admitted to Intensive Care Unit of Department of Infectious Diseases and Febrile Illnesses of University Clinical Center Ljubljana from September of 2011 through March of 2013. Sepsis was established clinically and defined aetiologically by haemoculture growth. Statistical evaluation was conducted in 76 patients who had not received proper antimicrobial therapy prior to blood collection. ForPCT determination imunoluminometric method was used and concentrations above 5 mg/L were considered elevated. Results: Serum PCT concentration was significantly higher in Gram-negative sepsis (PCT median was 26,3 μg/L) compared to Gram-positive sepsis (PCT median was 11,2 μg/L) (p = 0,016). Differences in PCT concentrations between Gram-positive pathogens were not statistically significant (p = 0,09), however, S. aureus sepsis is linked to higher serum PCT concentration (median PCT 12,8 μg/L) than all other Gram-positive agents put together (median PCT of 5,9 μg/L) (p = 0,016). Difference in PCT concentration in E. coli sepsis (median PCT of 38,2 μg/L) compared to other enterobacteria (median PCT of 26,3 μg/L) is not statistically significant (p = 0,902). Conclusions: Causative agent has a significant effect on serum PCT concentration in patients with sepsis. Higher values were present in Gram-negative than in Gram-positive sepsis. Amongst Gram-positive pathogens, S. aureus caused greater rise in PCT than other Gram-positive bacteria put together.

Risk factor analysis for bone marrow histiocytic hyperplasia with hemophagocytosis: an autopsy study.

The excessive release of inflammatory cytokines occasionally induces life-threatening hemophagocytosis referred to as hemophagocytic syndrome (HPS). A similar condition, histiocytic hyperplasia with hemophagocytosis (HHH), is often seen in bone marrow collected during autopsy. Unlike HPS, the pathogenesis of HHH remains unclear. Therefore, we performed a clinicopathological analysis of HHH from 70 autopsy cases at the University of Fukui Hospital. HHH was detected in 29 of 70 autopsies (41.4 %) and was significantly complicated with hematological diseases (p < 0.05) and sepsis (p < 0.05). The percentage of macrophages in bone marrow (BM) nucleated cells was significantly increased in HHH (p < 0.001). Data from medical records indicated no significant changes, except for the minimum values of white blood cell counts (p < 0.05) and platelet counts (p < 0.05) in HHH patients as compared with non-HHH patients. Concentrations of inflammatory mediators including IL-1β, IL-6, and IL-8 were significantly increased in HHH patients. Multivariate risk factor analysis identified hematological diseases (odds ratio (OR), 11.71), ≥15 % BM macrophages (OR, 9.42), sepsis (OR, 7.77), and high serum IL-6 levels (OR, 1.00) as independent risk factors for HHH. HHH with hypocellular BM, the most aggressive form of HHH, was recognized in 8 of 29 HHH patients and was associated with ≥25 % BM macrophages (p < 0.001), leukocytopenia (p < 0.05), and high IL-8 levels (p < 0.05). None of the HHH patients fulfilled the diagnostic criteria of HPS. These findings suggest that HHH is a different entity from HPS and that it preferentially develops under conditions of excessive inflammation and its associated risks, such as hematological diseases and sepsis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00428-014-1592-8) contains supplementary material, which is available to authorized users.

Simvastatin inhibits apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax.

Many studies have showed that apoptosis of endothelial cells plays a curial role in the progress of sepsis. But the role of simvastatin in apoptosis of endothelial cells induced by sepsis is not clear. The present study aimed to investigate the role of simvastatin in apoptosis of endothelial cells induced by sepsis and its mechanism. Human umbilical vein endothelial cells (HUVECs) were randomly divided into three groups: control group, sepsis serum intervention group (sepsis group) and simvastatin+sepsis serum intervention group (simvastatin group). After 24-hour incubation with corresponding culture medium, the relative growth rate of HUVECS in different groups was detected by MTT assay; the apoptosis of HUVECs was detected by Hoechst33258 assay and flow cytometry; and the expression of the Bcl-2 and Bax genes of HUVECs was detected by PCR. Compared with the sepsis group, HUVECs in the simvastatin group had a higher relative growth rate. Apoptotic HUVECs decreased significantly in the simvastatin group in comparison with the sepsis group. Expression of the Bcl-2 gene in HUVECs decreased obviously, but the expression of the Bax gene increased obviously after 24-hour incubation with sepsis serum; however, the expression of the Bcl-2 and Bax genes was just the opposite in the simvastatin group. Our study suggests that simvastatin can inhibit apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. It may be one of the mechanisms for simvastatin to treat sepsis.

Autologous Intestinal Reconstructive Surgery to Reduce Bowel Dilatation Improves Intestinal Adaptation in Children With Short Bowel Syndrome

Intestinal failure (IF) is a common consequence of neonatal small bowel pathology. In our experience, bowel dilatation is often responsible for the IF state in patients who fail to adapt despite adequate residual bowel length. The aim of the present study was to investigate the role of surgery to reduce bowel dilatation, and thus favour PN independence, for these children. Data were collected prospectively for all of the patients referred to our unit for a 7-year period (2004-2011). Eight patients (2 congenital atresia, 2 gastroschisis with atresia, 1 simple gastroschisis, 3 necrotising enterocolitis) with gut dilatation who failed adaptation despite a bowel length >40 cm were identified. Preoperatively, all patients were totally dependent on parenteral nutrition (PN). Patients were managed by longitudinal intestinal lengthening and tailoring (n = 3), serial transverse enteroplasty (n = 2), or tapering enteroplasty (n = 3). Median age at time of surgery was 273 days (103-1059). Mean gut length increased from 51 (35-75) to 73 cm (45-120) following surgery (P = 0.02). Incidence of sepsis (P = 0.01) and peak serum bilirubin levels (P = 0.005) were reduced postoperatively. PN was discontinued after a median of 110 days (35-537) for 7 patients; 1 patient remains on PN 497 days after surgery. These data indicate that reconstructive surgery to reduce bowel diameter may be an effective technique for treating IF in patients with short bowel syndrome, without sacrificing intestinal length. We suggest that this technique may reduce the need for bowel transplantation in this group of patients.

The effect of sepsis serum on intercellar adhesion molecule-1 of rat intestinal mucosa microvascular endothelial cells and the intervention of Adrenomedullin

：Objective To observe thelevels of intercellar adhesion molecule-1(ICAM-1)of rat intestinal mucosa microvascularendothelial cells in sepsis rat,and to investigate the possible protective effect ofadrenomedullin on the expression of intercellar adhesion molecule-1(ICAM-1)of ratintestinal mucosa microvascular endothelial cells,and to confirm whether adrenomedullincan decrease released inflammatory factors to slow down or inhibit the occurrence anddevelopment of sepsis.Methods The rat intestinal mucosa microvascular endothelial cellswere isolated and cultured in vitro,and it was divided into sham operated(sham operatedserum),sepsis serum(with addition of sepsis serum)and ADM serum(with 0.lng/kgadrenomedullin 6h after sepsis treatment)groups.The soluble ICAM-1(sICAM-1)content inRIMMVECs culture supernatant was measured by ELISA at the 24th hour after serumstimulation.Results The ICAM-1 content in the supernatant of sepsis group [(0.33 ±0.04)ng/L]was obviously higher than that in sham operated [(0.15 ± 0.02)ng/L] and ADM [(0.17 ±0.04)ng/L] group(P ＜ 0.05),but ADM group was nosignificantly different compared with sham operated group(P ＞0.05).Conclusions ADM could decrease theexpression of ICAM-I in RIMMVECs,and the low level of ICAM-1 could suppress its downstreaminflammation factors and inhibit the occurrence and development of sepsis. Key words: Sepsis/BL/ME/DT; Intercellular adhesion molecule-1/ME; Endothelium,vascular/ME; Adrenomedullin/PD

Alternate Day Calorie Restriction Improves Systemic Inflammation in a Mouse Model of Sepsis Induced by Cecal Ligation and Puncture

Calorie restriction (CR) exerts cytoprotective effects by up-regulating survival factors, such as mammalian target of rapamycin (mTOR), sirtuin, and peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α). These survival factors havewell-established roles in attenuating the inflammatory response. However, it is unclear whether CR affects sepsis-related inflammation. The purpose of this study was to determine whether CR affects sepsis-induced inflammation in a cecal ligation and puncture (CLP)-induced mouse model of sepsis. Male C57BL/6N mice underwent alternate day calorie restriction or normal feeding for 8 d before CLP-induced sepsis. After induction of sepsis, liver and lung histopathology and serum levels of cytokines and survival factors were assessed. Serum cytokine and high mobility group box protein 1 (HMGB1) levels were lower in animals that underwent alternate day calorie restriction compared with normally-fed mice after CLP. Alternate day calorie restriction also increased levels of sirtuin, PGC-1α, and mTOR. While 80% of mice in the CLP group died within 48 h after undergoing CLP, 50% of mice died in the ACR + CLP group (P < 0.05). Alternate day calorie restriction decreased mortality in a mouse model of sepsis. In addition to attenuated organ injury, a significant reduction in cytokine and HMGB1 levels was observed. These findings suggest that alternative day calorie restriction may reduce excessive inflammation.

Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans

BackgroundAcute respiratory distress syndrome (ARDS) is a devastating complication of numerous underlying conditions, most notably sepsis. Although pathologic vascular leak has been implicated in the pathogenesis of ARDS and sepsis-associated lung injury, the mechanisms promoting leak are incompletely understood. Angiopoietin-2 (Ang-2), a known antagonist of the endothelial Tie-2 receptor, was originally described as a naturally occurring disruptor of normal embryonic vascular development otherwise mediated by the Tie-2 agonist angiopoietin-1 (Ang-1). We hypothesized that Ang-2 contributes to endothelial barrier disruption in sepsis-associated lung injury, a condition involving the mature vasculature.Methods and FindingsWe describe complementary human, murine, and in vitro investigations that implicate Ang-2 as a mediator of this process. We show that circulating Ang-2 is significantly elevated in humans with sepsis who have impaired oxygenation. We then show that serum from these patients disrupts endothelial architecture. This effect of sepsis serum from humans correlates with measured Ang-2, abates with clinical improvement, and is reversed by Ang-1. Next, we found that endothelial barrier disruption can be provoked by Ang-2 alone. This signal is transduced through myosin light chain phosphorylation. Last, we show that excess systemic Ang-2 provokes pulmonary leak and congestion in otherwise healthy adult mice.ConclusionsOur results identify a critical role for Ang-2 in disrupting normal pulmonary endothelial function.

Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels*

To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. One hundred fifty-seven intensive care units in the United States and Canada. Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.

Association between hypophosphatemia and cardiac arrhythmias in the early stages of sepsis

Background: The purpose of this study was to evaluate a possible association between serum phosphate levels and the incidence of cardiac arrhythmias in the early stages of sepsis. Methods: We conducted a prospective, controlled study in the General Intensive Care Unit (GICU) of a university hospital. Sixteen patients with sepsis, but without any previous cardiac disease, were studied during their first 24 h in the GICU. Patients were connected to a continuous ECG recording device. Blood samples for serum phosphate level determinations were drawn during the first 6 h after admission to the unit. Results: Ten of 16 patients had 21 episodes of atrial and ventricular arrhythmias. These patients had higher mean Apache II scores (20.2±6.2) than the six patients without arrhythmias (13.2±1.7; P<0.05) and significantly lower mean phosphate levels (0.73±0.16 vs. 1.02±0.32 mmol/l; P<0.03). No association was found between serum phosphate levels and mortality among patients with arrhythmias, or when all survivors (with and without arrhythmia) were compared to all non-survivors. Conclusions: The results indicate that patients with sepsis and low serum phosphate levels are at a greater risk of developing cardiac arrhythmias. We suggest that phosphate supplementation in the early stages of sepsis may prevent cardiac arrhythmias.