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Clinical Outcomes Related to the Gastrointestinal Trophic Effects of Erythropoietin in Preterm Neonates: A Systematic Review and Meta-Analysis.
Ananthan, A, Balasubramanian, H, Rao, S, Patole, S
Advances in nutrition (Bethesda, Md.). 2018;(3):238-246
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Abstract
Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.
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Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation.
Moskowitz, A, Andersen, LW, Huang, DT, Berg, KM, Grossestreuer, AV, Marik, PE, Sherwin, RL, Hou, PC, Becker, LB, Cocchi, MN, et al
Critical care (London, England). 2018;(1):283
Abstract
The combination of thiamine, ascorbic acid, and hydrocortisone has recently emerged as a potential adjunctive therapy to antibiotics, infectious source control, and supportive care for patients with sepsis and septic shock. In the present manuscript, we provide a comprehensive review of the pathophysiologic basis and supporting research for each element of the thiamine, ascorbic acid, and hydrocortisone drug combination in sepsis. In addition, we describe potential areas of synergy between these therapies and discuss the strengths/weaknesses of the two studies to date which have evaluated the drug combination in patients with severe infection. Finally, we describe the current state of current clinical practice as it relates to the thiamine, ascorbic acid, and hydrocortisone combination and present an overview of the randomized, placebo-controlled, multi-center Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) trial and other planned/ongoing randomized clinical trials.
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Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: A PRISMA-compliant systematic review and meta-analysis.
He, Y, Cao, L, Yu, J
Medicine. 2018;(35):e11976
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Abstract
BACKGROUND Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial. METHODS Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). RESULTS A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics. CONCLUSION Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.
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Applications of vitamin D in sepsis prevention.
Takeuti, FAC, Guimaraes, FSF, Guimaraes, PSF
Discovery medicine. 2018;(140):291-297
Abstract
Vitamin D (VD) is a steroid prohormone that regulates the body's calcium and phosphate levels in bone mineralization. It is also well described as a fat-soluble vitamin playing an important role in immunomodulation, regulation of cytokines, and cell proliferation. Thus, VD is a powerful hormone with pleiotropic effects, which acts to maintain optimal health. Recent studies demonstrate that VD deficiency is associated with the development of cardiovascular diseases, autoimmune disorders, and various types of cancer, each associated with increased mortality rates. VD deficiency is commonly seen in the intensive care unit (ICU); it aggravates the incidence and outcome of infectious complications in critically ill patients. In particular, VD deficiency is associated with an increased risk of sepsis and more severe clinical outcomes in patients with sepsis. These patients have dysregulated VD metabolism and frequently present insufficient plasma VD levels, which contribute to the deterioration of their clinical state. In this review, we summarize the role of VD in the immune system, the consequences of its deficiency and we discuss potential perspectives on VD supplementation in preventing sepsis and enhancing patient recovery. Although the relevance of the applications of VD in sepsis is stated, further studies are required to elucidate the optimal VD plasma levels and the recommended daily intake.
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A Population-Based Cohort Study on the Drug-Specific Effect of Statins on Sepsis Outcome.
Lee, CC, Lee, MG, Hsu, TC, Porta, L, Chang, SS, Yo, CH, Tsai, KC, Lee, M
Chest. 2018;(4):805-815
Abstract
BACKGROUND Whether statin treatment, proved by recent experimental studies to have an antimicrobial activity, exerts a drug- or a class-specific effect in sepsis remains unknown. METHODS Short-term mortality in patients with sepsis was analyzed using data from the National Health Insurance Research Database. Use of statins was defined as the cumulative use of a specific statin (atorvastatin, simvastatin, or rosuvastatin) for > 30 days prior to the index sepsis admission. We determined the association between statin and sepsis outcome by multivariate-adjusted Cox models and propensity score (PS)-matched analysis, using a 1:1:1 PS matching technique. RESULTS A total of 52,737 patients with sepsis fulfilled the inclusion criteria, of which 1,855 were prescribed atorvastatin, 916 were prescribed simvastatin, and 732 were prescribed rosuvastatin. Compared with nonusers, simvastatin (hazard ratio [HR], 0.72; 95% CI, 0.58-0.90) and atorvastatin (HR, 0.78; 95% CI, 0.68-0.90) were associated with an improved 30-day survival, whereas rosuvastatin was not (HR, 0.87; 95% CI, 0.73-1.04). Using rosuvastatin as the reference, atorvastatin (HR, 0.79; 95% CI, 0.64-0.99) and simvastatin (HR, 0.77; 95% CI, 0.59-0.99) had superior effectiveness in preventing mortality. CONCLUSIONS Compatible with in vitro experimental findings, our results suggest that the drug-specific effect of statins on sepsis is not correlated to their lipid-lowering potency.
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Changes in lipid metabolism in pediatric patients with severe sepsis and septic shock.
Bermudes, ACG, de Carvalho, WB, Zamberlan, P, Muramoto, G, Maranhão, RC, Delgado, AF
Nutrition (Burbank, Los Angeles County, Calif.). 2018;:104-109
Abstract
OBJECTIVES Limited knowledge exists regarding the lipid profiles of critically ill pediatric patients with systemic inflammatory response syndrome. The aim of this study was to evaluate the relationship between the intensity of the inflammatory response and changes in the lipid profiles of critically ill pediatric patients admitted to a pediatric intensive care unit (PICU) with severe sepsis/septic shock. METHODS This was a prospective and observational study at a 15-bed PICU at a public university hospital. We analyzed the lipid profiles of 40 patients with severe sepsis/septic shock admitted to the PICU on the first and seventh days of hospitalization. C-reactive protein was used as a marker for systemic inflammation. Forty-two pediatric patients seen in the emergency department and without systemic inflammatory response syndrome were used to provide control values. RESULTS On day 1 of admission to the PICU, the patients had significantly lower levels of total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) as well as higher concentrations of triacylglycerols compared with the control group. There was a significant increase in the TC, HDL, LDL, and apolipoprotein levels from day 1 to day 7 of the study. CONCLUSIONS During severe sepsis/septic shock, we found lower serum levels of lipoproteins and apolipoproteins, and these were negatively correlated with C-reactive protein. As the inflammatory response improved, the levels of TC, HDL, LDL, and apolipoproteins increased, suggesting a direct relationship between changes in the lipid profiles and inflammation.
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Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid.
Marik, PE
Nutrients. 2018;(11)
Abstract
Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host's response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C.
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Electroacupuncture Improves Intestinal Dysfunction in Septic Patients: A Randomised Controlled Trial.
Meng, JB, Jiao, YN, Zhang, G, Xu, XJ, Ji, CL, Hu, MH, Lai, ZZ, Zhang, M
BioMed research international. 2018;:8293594
Abstract
OBJECTIVE To investigate the effects of electroacupuncture (EA) at "Zusanli" (ST36) and "Shangjuxu"(ST37) on reducing inflammatory reaction and improving intestinal dysfunction in patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi. METHODS A total of 71 patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi were randomly assigned to control group (n=36) and treatment group (n=35). Patients in control group were given conventional therapies including fluid resuscitation, anti-infection, vasoactive agents, mechanical ventilation, supply of enteral nutrition, and glutamine as soon as possible. In addition to conventional therapies, patients in treatment group underwent 20 minutes of EA at ST36-ST37 twice a day for five days. At baseline, day 1, day 3, and day 7 after treatment, the plasma levels of procalcitonin (PCT), tumor necrosis factor-α (TNF-α), intestinal fatty acid-binding proteins (I-FABP), D-lactate, citrulline, and TCM quantitative score of intestinal dysfunction were measured and recorded, respectively. And days on mechanical ventilation (MV), length of stay in intensive care unit (ICU), and 28d mortality were recorded. RESULTS During treatment, the plasma levels of PCT, TNF-α, I-FABP, D-lactate, and TCM quantitative score of intestinal dysfunction were declining in both groups, while the treatment group showed a significant decline (P<0.05). Plasma levels of citrulline were increasing in both groups, while the treatment group showed a significant increase (P<0.05). However, there were no significant differences in the days on MV, length of stay in ICU, and 28d mortality between two groups (P>0.05). CONCLUSIONS EA at ST36-ST37 can reduce inflammatory reaction and has protective effects on intestinal function in patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi. TRIAL REGISTRATION This trial was registered at http://www.chictr.org.cn/(ChiCTR-IOR-17010910).
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Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial.
Kawazoe, Y, Miyamoto, K, Morimoto, T, Yamamoto, T, Fuke, A, Hashimoto, A, Koami, H, Beppu, S, Katayama, Y, Itoh, M, et al
JAMA. 2017;(13):1321-1328
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IMPORTANCE Dexmedetomidine provides sedation for patients undergoing ventilation; however, its effects on mortality and ventilator-free days have not been well studied among patients with sepsis. OBJECTIVES To examine whether a sedation strategy with dexmedetomidine can improve clinical outcomes in patients with sepsis undergoing ventilation. DESIGN, SETTING, AND PARTICIPANTS Open-label, multicenter randomized clinical trial conducted at 8 intensive care units in Japan from February 2013 until January 2016 among 201 consecutive adult patients with sepsis requiring mechanical ventilation for at least 24 hours. INTERVENTIONS Patients were randomized to receive either sedation with dexmedetomidine (n = 100) or sedation without dexmedetomidine (control group; n = 101). Other agents used in both groups were fentanyl, propofol, and midazolam. MAIN OUTCOMES AND MEASURES The co-primary outcomes were mortality and ventilator-free days (over a 28-day duration). Sequential Organ Failure Assessment score (days 1, 2, 4, 6, 8), sedation control, occurrence of delirium and coma, intensive care unit stay duration, renal function, inflammation, and nutrition state were assessed as secondary outcomes. RESULTS Of the 203 screened patients, 201 were randomized. The mean age was 69 years (SD, 14 years); 63% were male. Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38-1.22; P = .20). Ventilator-free days over 28 days were not significantly different between groups (dexmedetomidine group: median, 20 [interquartile range, 5-24] days; control group: median, 18 [interquartile range, 0.5-23] days; P = .20). The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation (range, 17%-58% vs 20%-39%; P = .01); other outcomes were not significantly different between groups. Adverse events occurred in 8 (8%) and 3 (3%) patients in the dexmedetomidine and control groups, respectively. CONCLUSIONS AND RELEVANCE Among patients requiring mechanical ventilation, the use of dexmedetomidine compared with no dexmedetomidine did not result in statistically significant improvement in mortality or ventilator-free days. However, the study may have been underpowered for mortality, and additional research may be needed to evaluate this further. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01760967.
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New insights into the gut as the driver of critical illness and organ failure.
Meng, M, Klingensmith, NJ, Coopersmith, CM
Current opinion in critical care. 2017;(2):143-148
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PURPOSE OF REVIEW The gut has long been hypothesized to be the 'motor' of multiple organ dysfunction syndrome. This review serves as an update on new data elucidating the role of the gut as the propagator of organ failure in critical illness. RECENT FINDINGS Under basal conditions, the gut absorbs nutrients and serves as a barrier that prevents approximately 40 trillion intraluminal microbes and their products from causing host injury. However, in critical illness, gut integrity is disrupted with hyperpermeability and increased epithelial apoptosis, allowing contamination of extraluminal sites that are ordinarily sterile. These alterations in gut integrity are further exacerbated in the setting of preexisting comorbidities. The normally commensal microflora is also altered in critical illness, with increases in microbial virulence and decreases in diversity, which leads to further pathologic responses within the host. SUMMARY All components of the gut are adversely impacted by critical illness. Gut injury can not only propagate local damage, but can also cause distant injury and organ failure. Understanding how the multifaceted components of the gut interact and how these are perturbed in critical illness may play an important role in turning off the 'motor' of multiple organ dysfunction syndrome in the future.