Potential preventive and therapeutic effect of Chinese herb rhubarb (da huang) for intensive care unit/pediatric intensive care unit gastrointestinal failure patients: A protocol for systematic review.

INTRODUCTION: The Chinese herb da huang (DH) (Rhubarb) is commonly used for GIF intensive care unit (ICU)/pediatric intensive care unit (PICU) gastrointestinal failure (GIF) patients in China. However, the potential preventive and therapeutic effect of DH in these patients has not yet been studied systematically. OBJECTIVES: The aim of this study was to evaluate the preventive and therapeutic effects of DH in treating ICU/PICU GIF patients with the most recent evidence. METHODS: We systematically searched 7 databases from inception to March 30, 2018. RevMan 5.3 software was used to perform a meta-analysis. GRADE methodology was applied to evaluate the quality of evidence for each outcome. The review protocol was registered on PROSPERO (CRD42018092710) in advance. RESULTS: Seven studies comprising 788 pediatric or adult participants were included in this analysis. Three indicators, including GIF occurrence rates (gastrointestinal mucosal hemorrhage, enteroplegia), multiple organ dysfunction syndrome (MODS)-related items (occurrence rates of MODS, mortality rates of MODS) and duration in the ICU was analyzed. The GIF occurrence rate meta-analysis result was (RR 0.47, CI 95% 0.37-0.60; P = .95); MODS related items indicator result was (RR 0.44, CI 95% 0.33-0.59; P = .41); ICU duration ICU result was (RR -2.87, CI 95% -3.53--2.21; P = .40). The safety of Chinese herb DH (Rhubarb) remains unclear. CONCLUSION: Current evidence suggests that the Chinese herb rhubarb (DH) powder combined with Western medicine was inferior to Western medicine alone in terms of preventive and therapeutic effects in ICU/PICU patients in terms of decreasing GIF occurrence rates (gastrointestinal mucosal hemorrhage and enteroplegia), occurrence rates of MODS, mortality from MODS, and shortened duration time in the ICU/PICU. However, larger sample sizes and rigorously-designed studies are necessary to conclusively determine the association between DH powder and outcomes in ICU/PICU GIF patients.

The Impact of Acute Organ Dysfunction on Long-Term Survival in Sepsis.

OBJECTIVES: To estimate the impact of each of six types of acute organ dysfunction (hepatic, renal, coagulation, neurologic, cardiac, and respiratory) on long-term mortality after surviving sepsis hospitalization. DESIGN: Multicenter, retrospective study. SETTINGS: Twenty-one hospitals within an integrated healthcare delivery system in Northern California. PATIENTS: Thirty thousand one hundred sixty-three sepsis patients admitted through the emergency department between 2010 and 2013, with mortality follow-up through April 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute organ dysfunction was quantified using modified Sequential Organ Failure Assessment scores. The main outcome was long-term mortality among sepsis patients who survived hospitalization. The estimates of the impact of each type of acute organ dysfunction on long-term mortality were based on adjusted Cox proportional hazards models. Sensitivity analyses were conducted based on propensity score-matching and adjusted logistic regression. Hospital mortality was 9.4% and mortality was 31.7% at 1 year. Median follow-up time among sepsis survivors was 797 days (interquartile range: 384-1,219 d). Acute neurologic (odds ratio, 1.86; p < 0.001), respiratory (odds ratio, 1.43; p < 0.001), and cardiac (odds ratio, 1.31; p < 0.001) dysfunction were most strongly associated with short-term hospital mortality, compared with sepsis patients without these organ dysfunctions. Evaluating only patients surviving their sepsis hospitalization, acute neurologic dysfunction was also most strongly associated with long-term mortality (odds ratio, 1.52; p < 0.001) corresponding to a marginal increase in predicted 1-year mortality of 6.0% for the presence of any neurologic dysfunction (p < 0.001). Liver dysfunction was also associated with long-term mortality in all models, whereas the association for other organ dysfunction subtypes was inconsistent between models. CONCLUSIONS: Acute sepsis-related neurologic dysfunction was the organ dysfunction most strongly associated with short- and long-term mortality and represents a key mediator of long-term adverse outcomes following sepsis.

Low serum selenium is associated with the severity of organ failure in critically ill children.

BACKGROUND & AIMS: Low concentration of serum selenium is associated with the inflammatory response and multiple organ failure in adult ICU-patients. Critically ill children are less well characterized. In this study, serum selenium concentration and its possible relation to multiple organ failure as well as glutathione status was investigated in pediatric intensive care (PICU) patients. METHODS: A prospective consecutive cohort of critically ill children (n = 100) admitted to the PICU of a tertiary university hospital, and in addition an age stratified reference group of healthy children (n = 60) were studied. The concentrations of serum selenium and reduced and total glutathione were determined at admission and at day 5 for patients still in the PICU. RESULTS: Low concentration of serum selenium as well as a high-reduced fraction of glutathione (GSH/tGSH) was associated with multiple organ failure (p < 0.001 and p < 0.01) respectively. A correlation between low serum selenium concentration and high-reduced fraction of glutathione (GSH/tGSH) was also seen (r = -0.19 and p = 0.03). The serum selenium concentrations in the pediatric reference group in a selenium poor area were age dependent with lower concentrations in infants as compared to older children (p < 0.001). CONCLUSIONS: Both low serum selenium concentration and high reduced fraction of glutathione (GSH/tGSH) were associated with the development of multiple organ failure. The association between low serum selenium concentration and high fraction of reduced glutathione in whole blood favour the hypothesis that selenium is of critical importance for the scavenge capacity of glutathione peroxidase (GPX).

Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis.

Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick­end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1 expression. Furthermore, YY1 and Fas expression in PBMCs may be used to as prognostic markers.

Trace Element Concentrations in Human Tissues of Death Cases Associated With Secondary Infection and MOF After Severe Trauma.

Proper trace element level is crucial for the organs in maintaining normal physiological functions. Multiple organ failure (MOF) might be added to critically ill patients due to a lack of trace elements. Alterations of trace element levels in brain, heart, liver, and kidney after severe trauma, however, have been little studied so far. In this study, tissue samples of the frontal cortex of the brain, interventricular septum of the heart, right lobe of the liver, and upper pole of the kidney were obtained from forensic autopsies, of which 120 cases died during the 5th to 15th day of hospitalization, whereas the trauma death group and 43 cases immediately died due to severe craniocerebral trauma as the control group. Copper (Cu), iron (Fe), zinc (Zn), and selenium (Se) were quantified by inductively coupled plasma atomic emission spectrophotometry (ICP-AES). Cu, Fe, Zn, and Se concentrations in the brain, heart, liver, and kidney in the trauma group decreased dramatically (p<0.05) compared to the control group. The incidence of secondary infection and multiple organ failure (MOF) in the trauma death group were 78.33 and 29.17%, respectively. The concentrations of all elements exhibited a significant correlation with secondary infection and MOF (p<0.01). Our data suggest that low concentrations of Cu, Fe, Zn, and Se in pivotal organs may contribute to the incidence of secondary infection and MOF after severe trauma, which to some extent results in death.

Polydatin: a new therapeutic agent against multiorgan dysfunction.

BACKGROUND: Polydatin (PD), a monocrystalline and polyphenolic drug isolated from a traditional Chinese herb (Polygonum cuspidatum), is protective against mitochondrial dysfunction and has been approved for clinical trials in the treatment of shock. However, whether the administration of PD has a therapeutic effect on multiple-organ dysfunction syndrome (MODS) requires investigation. MATERIAL AND METHODS: MODS was induced in Sprague-Dawley rats via hemorrhage and ligation and puncture of cecum-induced sepsis. The rats were divided into three groups as follows: MODS + PD, MODS + normal saline, and a control group (no treatment). Survival time, blood biochemical indexes, and histopathologic changes in various organs were evaluated; serum oxidative stress (advanced oxidative protein products [AOPPs]) and proinflammatory cytokines (tumor necrosis factor-α, interleukin 1ß, and interleukin 6) were assayed using enzyme-linked immunosorbent assay. Apoptosis-related protein expression (B-cell lymphoma-2 [Bcl-2] and Bax) was assayed by immunohistochemical and Western blotting methods, whereas caspase-3 activity was assayed by spectrophotometry. RESULTS: PD improved organ function, prolonged survival time, and reduced MODS incidence and serum levels of AOPPs and proinflammatory cytokines. It also decreased Bax levels and caspase-3 activity and increased Bcl-2 levels in the kidney and liver. CONCLUSIONS: PD may serve as a potential therapeutic for MODS, as it suppresses oxidative stress, inhibits inflammatory response, attenuates apoptosis, and protects against mitochondrial dysfunction.

A randomized controlled trial investigating the effects of parenteral fish oil on survival outcomes in critically ill patients with sepsis: a pilot study.

INTRODUCTION: Death from sepsis in the intensive care unit (ITU) is frequently preceded by the development of multiple organ failure as a result of uncontrolled inflammation. Treatment with ω-3 has been demonstrated to attenuate the effects of uncontrolled inflammation and may be clinically beneficial. METHOD: A randomized control trial investigating the effects of parenteral ω-3 was carried out. Consecutive patients diagnosed with sepsis were entered into the study and randomized to receive either parenteral ω-3 or standard medical care only. The primary outcome measure was a reduction in organ dysfunction using the Sequential Organ Failure Assessment (SOFA) score as a surrogate marker. The secondary outcome measures were mortality, length of stay, mean C-reactive protein (CRP), and days free of organ dysfunction/failure. RESULTS: Sixty patients were included in the study. The baseline demographics were matched for the two cohorts. Patients treated with parenteral ω-3 were associated with a significant reduction in new organ dysfunction (Δ-SOFA 2.2 ± 2.2 vs. 1.0 ± 1.5, P = .005 and maximum-SOFA 10.1 ± 4.2 vs. 8.1 ± 3.2, P = .041) and maximum CRP (186.7 ± 78 vs. 141.5 ± 62.6, P = .019). There was no significant reduction in the length of stay between cohorts. Patients treated with ω-3 in the strata of less severe sepsis had a significant reduction in mortality (P = .042). CONCLUSION: The treatment of critically ill septic patients with parenteral ω-3 is safe. It is associated with a significant reduction in organ dysfunction. It may be associated with a reduction in mortality in patients with less severe sepsis.

Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.

BACKGROUND: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. MATERIALS AND METHODS: This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). RESULTS: The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. CONCLUSIONS: After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.

SodiUm SeleniTe Adminstration IN Cardiac Surgery (SUSTAIN CSX-trial): study design of an international multicenter randomized double-blinded controlled trial of high dose sodium-selenite administration in high-risk cardiac surgical patients.

BACKGROUND: Cardiac surgery has been shown to result in a significant decrease of the antioxidant selenium, which is associated with the development of multiorgan dysfunction and increased mortality. Thus, a large-scale study is needed to investigate the effect of perioperative selenium supplementation on the occurrence of postoperative organ dysfunction. METHODS/DESIGN: We plan a prospective, randomized double-blind, multicenter controlled trial, which will be conducted in North and South America and in Europe. In this trial we will include 1,400 high-risk patients, who are most likely to benefit from selenium supplementation. This includes patients scheduled for non-emergent combined and/or complex procedures, or with a predicted operative mortality of ≥ 5% according to the EuroSCORE II. Eligible patients will be randomly assigned to either the treatment group (bolus infusion of 2,000 µg sodium selenite immediately prior to surgery, followed by an additional dosage of 2,000 µg at ICU admission, and a further daily supplementation of 1,000 µg up to 10 days or ICU discharge) or to the control group (placebo administration at the same time points).The primary endpoint of this study is a composite of 'persistent organ dysfunction' (POD) and/or death within 30 days from surgery (POD + death). POD is defined as any need for life-sustaining therapies (mechanical ventilation, vasopressor therapy, mechanical circulatory support, continuous renal replacement therapy, or new intermittent hemodialysis) at any time within 30 days from surgery. DISCUSSION: The SUSTAIN-CSX™ study is a multicenter trial to investigate the effect of a perioperative high dosage sodium selenite supplementation in high-risk cardiac surgical patients. TRIAL REGISTRATION: This trial was registered at Clinicaltrials.gov (identifier: NCT02002247) on 28 November 2013.

Calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase kinase signaling.

BACKGROUND: Calcium plays an essential role in nearly all cellular processes. As such, cellular and systemic calcium concentrations are tightly regulated. During sepsis, derangements in such tight regulation frequently occur, and treating hypocalcemia with parenteral calcium administration remains the current practice guideline. OBJECTIVE: We investigated whether calcium administration worsens mortality and organ dysfunction using an experimental murine model of sepsis and explored the mechanistic role of the family of calcium/calmodulin-dependent protein kinases in mediating these physiological effects. To highlight the biological relevance of these observations, we conducted a translational study of the association between calcium administration, organ dysfunction, and mortality among a cohort of critically ill septic ICU patients. DESIGN: Prospective, randomized controlled experimental murine study and observational clinical cohort analysis. SETTING: University research laboratory and eight ICUs at a tertiary care center. PATIENTS: A cohort of 870 septic ICU patients. SUBJECTS: C57Bl/6 and CaMKK mice. INTERVENTIONS: Mice underwent cecal ligation and puncture polymicrobial sepsis and were administered with calcium chloride (0.25 or 0.25 mg/kg) or normal saline. MEASUREMENTS AND MAIN RESULTS: Administering calcium chloride to septic C57Bl/6 mice heightened systemic inflammation and vascular leak, exacerbated hepatic and renal dysfunction, and increased mortality. These events were significantly attenuated in CaMKK mice. In a risk-adjusted analysis of septic patients, calcium administration was associated with an increased risk of death, odds ratio 1.92 (95% CI, 1.00-3.68; p = 0.049), a significant increase in the risk of renal dysfunction, odds ratio 4.74 (95% CI, 2.48-9.08; p < 0.001), and a significant reduction in ventilator-free days, mean decrease 3.29 days (0.50-6.08 days; p = 0.02). CONCLUSIONS: Derangements in calcium homeostasis occur during sepsis that is sensitive to calcium administration. This altered calcium signaling, transduced by the calmodulin-dependent protein kinase kinase cascade, mediates heightened inflammation and vascular leak that culminates in elevated organ dysfunction and mortality. In the clinical management of septic patients, calcium supplementation provides no benefit and may impose harm.

A randomized trial of glutamine and antioxidants in critically ill patients.

BACKGROUND: Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting. METHODS: In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance. RESULTS: There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83). CONCLUSIONS: Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00133978.).

Acute respiratory distress syndrome: evaluation and management.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition that affects patients admitted in the Intensive Care Units (ICUs) under mechanical ventilation. ARDS is a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of conditions, resulting in a direct (e.g., pneumonia) or indirect (e.g., sepsis) lung injury and is associated with a significant morbidity and mortality. A large body of clinical and basic research has focused in ventilatory strategies and novel pharmacological therapies but, nowadays, treatment is mainly supportive. Mechanical ventilation is the hallmark of the management of these patients. In the last decades, the recognition that mechanical ventilation can contribute to harming the lung has changed the goals of this therapy and has driven research to focus in ventilatory strategies that mitigate lung injury. This review emphasizes clinical aspects in the evaluation and management of ARDS in the ICUs and updates the latest advances in these therapies.

Glutamine and glutathione at ICU admission in relation to outcome.

Glutamine depletion is demonstrated to be an independent predictor of hospital mortality in ICU (intensive care unit) patients. Today glutamine supplementation is recommended to ICU patients on parenteral nutrition. In addition to glutamine, glutathione may be a limiting factor in ICU patients with MOF (multiple organ failure). To study the prevalence of glutamine and glutathione depletion an observational study was performed. The results were analysed in relation to mortality and the conventional predictors of mortality outcome, APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment). Consecutive patients admitted to the ICU at Karolinska University Hospital Huddinge were studied. Patient admission scoring of APACHE II and SOFA were registered as well as mortality up to 6 months. Plasma glutamine concentration and whole blood glutathione status at admittance were analysed. The admission plasma glutamine concentrations were totally independent of the conventional risk scoring at admittance, and a subnormal concentration was an independent predictor of mortality. In addition, glutathione redox status was also an independent mortality predictor, but here a normal ratio was the risk factor. In both cases the mortality risk was mainly confined to the post-ICU period. A low plasma concentration of glutamine at ICU admission is an independent risk factor for post-ICU mortality. The possible benefit of extending glutamine supplementation post-ICU should be evaluated prospectively.

The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients.

OBJECTIVE: The trace elements selenium, copper, and zinc are essential for maintaining the oxidative balance. A depletion of antioxidative trace elements has been observed in critically ill patients and is associated with the development of multiorgan dysfunction and an increased mortality. Cardiac surgery using cardiopulmonary bypass provokes ischemia-reperfusion-mediated oxidative stress. We hypothesized that an intraoperative decrease of circulating trace elements may be involved in this response. DESIGN: Prospective observational clinical study. SETTING: University hospital cardiothoracic operation theater and intensive care unit. PATIENTS: Sixty patients (age 65 ± 14 yrs) undergoing cardiac surgery with the use of cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Whole blood concentrations of selenium, copper, and zinc were measured after induction of anesthesia and 1 hr after admission to the intensive care unit. All patients were separated in a priori defined subgroups according to the development of no organ failure, single organ failure, and ≥ 2 organ failures in the postoperative period. RESULTS: Fifty patients exhibited a significant selenium deficiency already before surgery, whereas copper and zinc concentrations were within the reference range. In all patients, blood levels of selenium, copper, and zinc were significantly reduced after end of surgery when compared to preoperative values (selenium: 89.05 ± 12.65 to 70.84 ± 10.46 µg/L; zinc: 5.15 ± 0.68 to 4.19 ± 0.73 mg/L; copper: 0.86 ± 0.15 to 0.65 ± 0.14 mg/L; p < .001). During their intensive care unit stay, 17 patients were free from any organ failure, while 31 patients developed single-organ failure and 12 patients multiple organ failure. Multilogistic regression analysis showed that selenium concentrations at end of surgery were independently associated with the postoperative occurrence of multiorgan failure (p = .0026, odds ratio 0.8479, 95% confidence interval 0.7617 to 0.9440). CONCLUSIONS: Cardiac surgery using cardiopulmonary bypass resulted in a profound intraoperative decrease of whole blood levels of antioxidant trace elements. Low selenium concentrations at end of surgery were an independent predictor for the postoperative development of multiorgan failure.

[Urosepsis and treatment]. / Urosepsis und Therapie.

Urosepsis is one of the most frequent sepsis entities. Mortality from urosepsis is nowadays mostly lower than from other entities. Sepsis syndrome is pathophysiologically characterized by a generalized infection and immune dysregulation. Exogenous microbiological and active or passive endogenous factors released from body cells initiate and accompany the immune dysregulation. Diagnosis and therapy of urosepsis need to be instigated as early as possible (within the first hour), in order to prevent cell and tissue damage in the early phase. For this reason a series of measures is started, aimed at achieving early control of the focus of infection, providing antibiotic treatment, and stabilizing respiratory and cardiovascular function in order to optimize tissue oxygenation. A significant clinical problem ensues due to increasing antibiotic resistance mainly of enterobacteria. The choice of antibiotic therefore is made on the basis of local antibiotic resistance statistics. Dosage is determined on an individual basis, as well as according to current pharmacokinetic/pharmacodynamic knowledge. The intensive care of the septic patient needs to be started as early as on patient admission and, where necessary, continued on the intensive care ward.

Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis.

OBJECTIVE: Zinc deficiency is common among populations at high risk for sepsis mortality, including elderly, alcoholic, and hospitalized patients. Zinc deficiency causes exaggerated inflammatory responses to endotoxin but has not been evaluated during bacterial sepsis. We hypothesized that subacute zinc deficiency would amplify immune responses and oxidant stress during bacterial sepsis {lsqb;i.e., cecal ligation and puncture (CLP){rsqb; resulting in increased mortality and that acute nutritional repletion of zinc would be beneficial. DESIGN: Prospective, randomized, controlled animal study. SETTING: University medical center research laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Ten-week-old, male, C57BL/6 mice were randomized into three dietary groups: 1) control diet, 2) zinc-deficient diet for 3 weeks, and 3) zinc-deficient diet for 3 weeks followed by oral zinc supplementation for 3 days (n = 35 per diet). Mice were then assigned to receive either CLP or sham operation (n = 15 each per diet). CLP and sham-operated treatment groups were further assigned to a 7-day survival study (n = 10 per treatment per diet) or were evaluated at 24 hours (n = 5 per treatment per diet) for signs of vital organ damage. MEASUREMENTS AND MAIN RESULTS: Sepsis mortality was significantly increased with zinc deficiency (90% vs. 30% on control diet). Zinc-deficient animals subject to CLP had higher plasma cytokines, more severe organ injury, including increased oxidative tissue damage and cell death, particularly in the lungs and spleen. None of the sham-operated animals died or developed signs of organ damage. Zinc supplementation normalized the inflammatory response, greatly diminished tissue damage, and significantly reduced mortality. CONCLUSIONS: Subacute zinc deficiency significantly increases systemic inflammation, organ damage, and mortality in a murine polymicrobial sepsis model. Short-term zinc repletion provides significant, but incomplete protection despite normalization of inflammatory and organ damage indices.

Pathological changes in multiple organs of rats with severe acute pancreatitis treated by baicalin and octreotide.

BACKGROUND: Severe acute pancreatitis (SAP) features fatal pathogenetic conditions and high mortality rate. The study of SAP complicated with multiple organ injuries is of important significance. In this study, we explored the protective effect of baicalin on multiple organs of SAP rats and compared it with that of octreotide through light and electron microscopic observations of the pathological changes. METHODS: The improved Aho method was used to prepare SAP rat models. These rats were then randomly divided into a sham-operated group (n=45), a model control group (n=45), baicalin-treated group (n=45) and octreotide-treated group (n=45). Based on the difference in time points after operation, these groups were subdivided into 3, 6 and 12 hour subgroups (n=15). At the corresponding time point after operation, the mortality rate of rats was recorded, and then the rats were humanely killed to take samples of multiple organs that were subsequently examined for pathological changes under light and electron microscopy. RESULTS: At 12 hours after operation, the mortality rate of rats in the baicalin- and octreotide-treated groups was lower than that in the model control group (P<0.05). Compared to the model control group, the pathological changes and pathological scores in the baicalin- and octreotide-treated groups were mitigated and relieved to varying degrees. The pathological changes under electron microscopy were also improved. CONCLUSIONS: Both baicalin and octreotide show good protective effects on multiple organs of SAP rats. Baicalin as a new drug has good prospects in the treatment of SAP.

Zinc homeostasis in pediatric critical illness.

OBJECTIVE: We explored the hypothesis that marked decline in plasma zinc concentrations among critically ill children is related to shifts in metallothionein expression and inflammation. DESIGN: Prospective pilot study. SETTING: Intensive care unit of tertiary care children's hospital. PATIENTS: All children (<18 yrs) with unadjusted Pediatric Risk of Mortality III score >5 or at least one organ failure admitted to the pediatric intensive care unit from March through August 2006 were eligible for enrollment. INTERVENTIONS: After consent, blood samples were collected on days 1 and 3 of illness and analyzed for serum chemistries, plasma zinc and copper levels, metallothionein isoform expression, and cytokine levels. MEASUREMENTS AND MAIN RESULTS: Twenty patients were enrolled, with median age of 2.9 yrs (interquartile range, 0.7-10.1). Male to female ratio was 1.2:1. All patients had low zinc levels (mean, 0.43; range, 0.26-0.66 mug/dL) on day 1 of pediatric intensive care unit admission, and remained low (mean, 0.51; range, 0.26-0.81 mug/dL) on day 3, even when corrected for hypoalbuminemia. In comparison, serum copper levels were normal. On day 1, there was a positive correlation between zinc levels and expression of MT-1A (p < 0.01), MT-1G (p = 0.02), and MT-1H (p = 0.03). Plasma zinc levels correlated inversely with C-reactive protein levels (r = -.75, p = 0.01) and interleukin-6 levels (r = -.53, p = 0.04) on day 3. On day 3, patients with two or more organ failures had significantly lower plasma zinc concentrations compared with patients with

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients.

INTRODUCTION: Oxidative stress is involved in the development of secondary tissue damage and organ failure. Micronutrients contributing to the antioxidant (AOX) defense exhibit low plasma levels during critical illness. The aim of this study was to investigate the impact of early AOX micronutrients on clinical outcome in intensive care unit (ICU) patients with conditions characterized by oxidative stress. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, single-center trial in patients admitted to a university hospital ICU with organ failure after complicated cardiac surgery, major trauma, or subarachnoid hemorrhage. Stratification by diagnosis was performed before randomization. The intervention was intravenous supplements for 5 days (selenium 270 microg, zinc 30 mg, vitamin C 1.1 g, and vitamin B1 100 mg) with a double-loading dose on days 1 and 2 or placebo. RESULTS: Two hundred patients were included (102 AOX and 98 placebo). While age and gender did not differ, brain injury was more severe in the AOX trauma group (P = 0.019). Organ function endpoints did not differ: incidence of acute kidney failure and sequential organ failure assessment score decrease were similar (-3.2 +/- 3.2 versus -4.2 +/- 2.3 over the course of 5 days). Plasma concentrations of selenium, zinc, and glutathione peroxidase, low on admission, increased significantly to within normal values in the AOX group. C-reactive protein decreased faster in the AOX group (P = 0.039). Infectious complications did not differ. Length of hospital stay did not differ (16.5 versus 20 days), being shorter only in surviving AOX trauma patients (-10 days; P = 0.045). CONCLUSION: The AOX intervention did not reduce early organ dysfunction but significantly reduced the inflammatory response in cardiac surgery and trauma patients, which may prove beneficial in conditions with an intense inflammation. TRIALS REGISTRATION: Clinical Trials.gov RCT Register: NCT00515736.