Sepsis Abstracts 2

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Selenium Supplementation for Prevention of Late-Onset Sepsis in Very Low Birth Weight Preterm Neonates.
            (Aggarwal et al., 2016) Download
BACKGROUND:  Neonatal mortality continues to be a significant problem in the Indian setting, especially in very low birth weight (VLBW) neonates. Selenium (Se) has been shown to possess antioxidant properties, and some recent studies have shown a reduction in the sepsis-attributable neonatal mortality with its use. India is a Se-deficient country. Blood Se concentrations in newborns are lower than those of their mothers and lower still in preterm infants. OBJECTIVE:  To evaluate the efficacy of Se in preventing the first episode of late-onset sepsis in VLBW preterm neonates. METHODS:  Ninety neonates weighing <1500 g and period of gestation <32 weeks, asymptomatic at birth and admitted to the neonatal intensive-care unit (NICU) in the first 12 h of birth with no maternal risk factors for sepsis were analyzed in the study. Se or placebo was supplemented orally once daily from 1st to 28th day of life to the test (n = 45) or control (n = 45) groups, respectively, followed by daily clinical assessment for signs or symptoms of sepsis in the hospital and weekly after discharge. RESULTS:  Preterm VLBW neonates (mean birth weight 1464.22 ± 50.14 g and mean gestational age 221.75 ± 4 days) are Se deficient at birth, with mean (SD) Se levels 31.1 ± 14.8 µg/l. Se supplementation at 10 µg/day increased serum Se levels significantly (63.9 ± 13.9 µg/l on Day 28 in Se vs. 40.9 ± 17.3 on Day 28 in placebo; p < 0.01). The incidence of the first episode of culture-proven late-onset sepsis was significantly lower in the Se than in the placebo group. [0/45 (0%) in Se vs. 6/45 (13.3%) in placebo; p = 0.033]. The incidence of probable sepsis was found to be significantly lower in the Se group [7/45 (15.55%)] than in the placebo [16/45 (35.55%)]; p = 0.02. The total incidence of any late-onset sepsis (i.e. culture-proven plus probable sepsis) was also significantly reduced by Se supplementation. [7/45 (15.55%) in Se vs. 22/45 (48.88%) in placebo; p = 0.001]. CONCLUSION:  Preterm VLBW neonates are Se deficient at birth. Se supplementation at 10 µg/day resulted in getting the Se levels into the acceptable normal level and reduced the incidence of the first episode of late-onset sepsis in these neonates.


 

Antioxidative system in the erythrocytes of preterm neonates with sepsis: the effects of vitamin E supplementation.
            (Bajčetić et al., 2014) Download
BACKGROUND:  Vitamin E is routinely supplemented to preterm babies, including those with neonatal sepsis. Our aim was to examine the effects of neonatal sepsis and vitamin E on antioxidative system (AOS) in the blood. METHODS:  A prospective, randomized, open label study involved 65 preterm neonates (control/sepsis - 34/31), which were divided into two subgroups - non-supplemented and supplemented with vitamin E (25 IU/day for 60 days). The activities of superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) were determined in erythrocytes at days 0, 30, and 60, following sepsis diagnosis. RESULTS:  There was no difference in the activity of AOS between controls and neonates with ongoing sepsis. At 60 days, septic neonates showed higher CAT activity compared to controls (P = 0.027), and lower GPx activity compared to 0 days (P = 0.022). The later was mitigated by vitamin E, which on the other hand provoked lower GPx activity at 30 days, compared to untreated septic neonates (P = 0.014). In addition, vitamin E suppressed GR activity in septic neonates (P = 0.025 and P = 0.017 at 30 and 60 days). Finally, vitamin E supplementation in control neonates provoked a significant increase of GPx activity (P = 0.015 at 60 days). CONCLUSIONS:  The absence of altered redox settings in the blood of neonates during sepsis episode, and vitamin E-provoked decrease in the activity of some components of AOS, suggest that the supplementation of vitamin E in these patients might not be rational.

Early enteral supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: outcome of a randomized, controlled, double-blind trial.
            (Beale et al., 2008) Download
OBJECTIVE:  To assess the safety and efficacy of an early enteral pharmaconutrition supplement containing glutamine dipeptides, antioxidative vitamins and trace elements, and butyrate in critically ill, septic patients. DESIGN:  A prospective, randomized, controlled, double-blind clinical trial. SETTING:  Adult intensive care unit in a university hospital. PATIENTS:  Fifty-five critically ill, septic patients requiring enteral feeding. INTERVENTIONS:  Patients received either an enteral supplement (500 mL of Intestamin, Fresenius Kabi) containing conditionally essential nutrients or a control solution via the nasogastric route for up to 10 days. Inclusion occurred within 24 hrs of intensive care unit admission. Additionally, patients received enteral feeding with an immunonutrition formula (experimental group) or standard formula (control group) initiated within 48 hrs after enrollment. MEASUREMENTS AND MAIN RESULTS:  Organ dysfunction was assessed by daily total Sequential Organ Failure Assessment (SOFA) score over the 10-day study period in both patient groups. Patients receiving the experimental supplement showed a significantly faster decline in the regression slopes of delta daily total SOFA score over time compared with control. The difference between the regression coefficients of the two slopes was significant irrespective of the level of analysis: intent to treat -0.32 vs. -0.14, p < .0001; per protocol -0.34 vs. -0.14, p < .0001; and completers (patients receiving > or = 80% of the calculated caloric target over a period of 6 days), -0.26 vs. -0.16, p = .0005. Vitamin C, as a marker of supplement absorption, increased from 10.6 (1.9-159.4) micromol/L (normal range 20-50 micromol/L) on day 1 to 58.7 (5.4-189.9) micromol/L by day 3 (p = .002) in the intervention group but remained below the normal range in the control group 17.0 (2.8-78.5) on day 1 and 14.3 (2.4-179.6) on day 3. Serum levels of glycine, serine, arginine, ornithine, vitamin E, and beta-carotene all increased significantly with treatment in the supplementation group. CONCLUSIONS:  In medical patients with sepsis, early enteral pharmaconutrition with glutamine dipeptides, vitamin C and E, beta-carotene, selenium, zinc, and butyrate in combination with an immunonutrition formula results in significantly faster recovery of organ function compared with control.

Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial.
            (Bertolini et al., 2003) Download
OBJECTIVE:  To compare the mortality of critically ill patients given either enteral feeding with an immune-enhancing formula or parenteral nutrition (PN). We report the results of a planned interim analysis on patients with severe sepsis which was undertaken earlier than planned once a meta-analysis suggested excess mortality in patients with severe sepsis given enteral immunonutrition. DESIGN:  Randomised multicentre unblinded controlled clinical trial. SETTING:  Thirty-three General Intensive Care Units in Italy. PATIENTS AND PARTICIPANTS:  Among the 237 recruited patients, 39 had severe sepsis or septic shock; 21 of them received PN. INTERVENTIONS:  Eligible patients received either total PN or enteral nutrition, the latter containing extra L-arginine, omega-3 fatty acids, vitamin E, beta carotene, zinc, and selenium. MEASUREMENTS AND RESULTS:  The primary endpoint for the subgroup analysis on patients with severe sepsis was mortality on Intensive Care Unit (ICU). The ICU mortality of patients with severe sepsis given enteral nutrition (EN) was higher than for those given PN (44.4% vs 14.3%; p=0.039). More patients given EN than patients given PN still had severe sepsis when they died (38.9% vs 9.5%, p=0.055). Recruitment of patients with severe sepsis was subsequently stopped. CONCLUSIONS:  Our results show that enteral immunonutrition, compared to PN, may be associated with excess mortality in patients with severe sepsis.


 

Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized, double-blind, placebo-controlled, pilot trial.
            (Donnino et al., 2015) Download
INTRODUCTION:  We previously found decreased levels of Coenzyme Q10 (CoQ10) in patients with septic shock. The objective of the current study was to assess whether the provision of exogenous ubiquinol (the reduced form of CoQ10) could increase plasma CoQ10 levels and improve mitochondrial function. METHODS:  We performed a randomized, double-blind, pilot trial at a single, tertiary care hospital. Adults (age ≥18 years) with severe sepsis or septic shock between November 2012 and January 2014 were included. Patients received 200 mg enteral ubiquinol or placebo twice a day for up to seven days. Blood draws were obtained at baseline (0 h), 12, 24, 48, and 72 h. The primary outcome of the study was change in plasma CoQ10 parameters (total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10). Secondary outcomes included assessment of: 1) vascular endothelial biomarkers, 2) inflammatory biomarkers, 3) biomarkers related to mitochondrial injury including cytochrome c levels, and 4) clinical outcomes. CoQ10 levels and biomarkers were compared between groups using repeated measures models. RESULTS:  We enrolled 38 patients: 19 in the CoQ10 group and 19 in the placebo group. The mean patient age was 62 ± 16 years and 47% were female. Baseline characteristics and CoQ10 levels were similar for both groups. There was a significant increase in total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10 in the ubiquinol group compared to the placebo group. We found no difference between the two groups in any of the secondary outcomes. CONCLUSIONS:  In this pilot trial we showed that plasma CoQ10 levels could be increased in patients with severe sepsis or septic shock, with the administration of oral ubiquinol. Further research is needed to address whether ubiquinol administration can result in improved clinical outcomes in this patient population. TRIAL REGISTRATION:  Clinicaltrials.gov identifier NCT01948063. Registered on 18 February 2013.

Effects of high doses of selenium, as sodium selenite, in septic shock patients a placebo-controlled, randomized, double-blind, multi-center phase II study--selenium and sepsis.
            (Forceville, 2007) Download
Selenium has a double action. (i) Seleno-compounds, among them sodium selenite have a direct pro-oxidant action leading to acute toxicity but may be also beneficial as drug. (ii) Selenium is an essential anti-oxidant required for anti-oxidant seleno-enzymes. Septic shock is a common severe syndrome leading to endothelium damage and multiple organ failure, with increased data suggesting the principle role of oxidative stress. Selenoprotein P, main selenium constituent of the plasma, may decrease dramatically and specifically in septic shock patients and may be involved in the endothelium protection. A prospective, multi-center placebo-controlled, randomized, double-blind study in severe septic shock patients with documented infection has been preformed. Patients received, for 10 days, selenium as sodium selenite (4000 microg on the first day, 1000 microg/day on the 9 following days) or matching placebo using continuous intravenous infusion. Mortality rates did not significantly differ between groups at any time point. Adverse events rates were similar in the two groups. However, high-dose selenium administration has been associated with a tendency to decrease the mortality in septic shock animal and patients, especially when using a bolus administration, whereas studies using a continuous administration failed to find any benefit on mortality. The interest of the successive use of pro-oxidant action of seleno-compounds, followed by anti-oxidant action need to be the further studied in cellular and animal models, preceding new dose-effect phase II. The interest of the selenoprotein-P as a marker of septic shock and for endothelium protection needs also to be studied further.

Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis.
            (Fowler et al., 2014) Download
BACKGROUND:  Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. METHODS:  Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. RESULTS:  Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. CONCLUSIONS:  Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury. TRIAL REGISTRATION:  ClinicalTrials.gov identifier NCT01434121.


 

Randomized controlled trial of calcitriol in severe sepsis.
            (Leaf et al., 2014) Download
RATIONALE:  Vitamin D and its metabolites have potent immunomodulatory effects in vitro, including up-regulation of cathelicidin, a critical antimicrobial protein. OBJECTIVES:  We investigated whether administration of 1,25-dihydroxyvitamin D (calcitriol) to critically ill patients with sepsis would have beneficial effects on markers of innate immunity, inflammation, and kidney injury. METHODS:  We performed a double-blind, randomized, placebo-controlled, physiologic study among 67 critically ill patients with severe sepsis or septic shock. Patients were randomized to receive a single dose of calcitriol (2 μg intravenously) versus placebo. The primary outcome was plasma cathelicidin protein levels assessed 24 hours after study drug administration. Secondary outcomes included leukocyte cathelicidin mRNA expression, plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2), and urinary kidney injury markers. MEASUREMENTS AND MAIN RESULTS:  Patients randomized to calcitriol (n = 36) versus placebo (n = 31) had similar plasma cathelicidin protein levels at 24 hours (P = 0.16). Calcitriol-treated patients had higher cathelicidin (P = 0.04) and IL-10 (P = 0.03) mRNA expression than placebo-treated patients 24 hours after study drug administration. Plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2) and urinary kidney injury markers were similar in calcitriol- versus placebo-treated patients (P > 0.05 for all comparisons). Calcitriol had no effect on clinical outcomes nor were any adverse effects observed. CONCLUSIONS:  Calcitriol administration did not increase plasma cathelicidin protein levels in critically ill patients with sepsis and had mixed effects on other immunomodulatory markers. Additional phase II trials investigating the dose and timing of calcitriol as a therapeutic agent in specific sepsis phenotypes may be warranted. Clinical trial registered with www.clinicaltrials.gov (NCT 01689441).


 

Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.
            (Marik et al., 2017) Download
BACKGROUND:  The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries. METHODS:  In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome. RESULTS:  There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P < .001). CONCLUSIONS:  Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.

Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial.
            (Quraishi et al., 2015) Download
OBJECTIVES:  To compare changes in vitamin D status and cathelicidin (LL-37) levels in septic ICU patients treated with placebo versus cholecalciferol. DESIGN:  Randomized, placebo-controlled, trial. SETTING:  Medical and surgical ICUs of a single teaching hospital in Boston, MA. PATIENTS:  Thirty adult ICU patients. INTERVENTIONS:  Placebo (n = 10) versus 200,000 IU cholecalciferol (n = 10) versus 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS:  Blood samples were obtained at baseline (day 1) and on days 3, 5, and 7, to assess total 25-hydroxyvitamin D, as well as vitamin D-binding protein and albumin to calculate bioavailable 25-hydroxyvitamin D. Plasma LL-37 and high-sensitivity C-reactive protein levels were also measured. At baseline, median (interquartile range) plasma 25-hydroxyvitamin D was 17 ng/mL (13-22 ng/mL) and peaked by day 5 in both intervention groups. Groups were compared using Kruskal-Wallis tests. Relative to baseline, on day 5, median change in biomarkers for placebo, 200,000 IU cholecalciferol, and 400,000 IU cholecalciferol groups, respectively, were as follows: 1) total 25-hydroxyvitamin D, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25-hydroxyvitamin D, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37: -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity C-reactive protein levels did not differ between groups. A positive correlation was observed between bioavailable 25-hydroxyvitamin D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25-hydroxyvitamin D and LL-37. CONCLUSIONS:  High-dose cholecalciferol supplementation rapidly and safely improves 25-hydroxyvitamin D and bioavailable 25-hydroxyvitamin D levels in patients with severe sepsis or septic shock. Changes in bioavailable 25-hydroxyvitamin D are associated with concomitant increases in circulating LL-37 levels. Larger trials are needed to verify these findings and to assess whether optimizing vitamin D status improves sepsis-related clinical outcomes.

High-dose selenium substitution in sepsis: a prospective randomized clinical trial.
            (Valenta et al., 2011) Download
OBJECTIVE:  Systemic inflammatory response syndrome (SIRS) and sepsis remain the leading cause of death in the critically ill. A reduction in the antioxidant capacity, including selenoenzymes that are dependent on selenium (Se), could be a contributing factor. Se supplementation in septic patients have yielded conflicting results. We hypothesized that a high-dose Se supplementation would (1) improve markers of inflammation, nutrition and antioxidant defence, and (2) decrease mortality. METHODS:  This prospective, randomized, open-label, single-centre clinical trial included 150 patients with SIRS/sepsis and a SOFA score of >5. Patients in the Se+ group (n = 75) received Se for 14 days (1,000 μg on day 1,500 μg/day on days 2-14). Patients in both the control (Se-) group (n = 75) and the Se+ group received a standard Se dose (<75 μg/day). Plasma Se, whole-blood glutathione peroxidase (GPx) activity, C-reactive protein (CRP), procalcitonin (PCT), albumin, prealbumin and cholesterol levels, along with APACHE II and SOFA scores, were determined at baseline and on days 1-7 and day 14. Mortality was assessed at day 28. RESULTS:  Plasma Se and GPx activity were increased in the Se+ group from day 1 onwards. Negative correlations were demonstrated between plasma Se, CRP (P = 0.035), PCT (P = 0.022) and SOFA (P = 0.001) at admission but not on days 7 or 14. Prealbumin and cholesterol increased in the Se+ group versus the respective baselines. Mortality was similar between groups, with no gender differences. CONCLUSION:  High-dose Se substitution in patients with SIRS/sepsis increased plasma Se and GPx levels, but did not reduce mortality. Markers of inflammation were reduced similarly in both groups.


 

Effect of branched chain amino acid enrichment of total parenteral nutrition on nitrogen sparing and clinical outcome of sepsis and trauma: a prospective randomized double blind trial.
            (von Meyenfeldt et al., 1990) Download
Administration of extra branched chain amino acids (BCAA) has been associated with a nitrogen sparing effect in septic and traumatized patients. Whether nitrogen sparing is associated with decreased morbidity and mortality rates is unknown. We therefore undertook a prospective, randomized, double blind trial investigating the effects of BCAA enrichment of a total parenteral nutrition (TPN) regimen on nitrogen balance, 3-methylhistidine excretion, morbidity as evidenced by disturbances in organ function, severity of sepsis and mortality. One hundred and one patients entered the study; 52 received a standard TPN solution and 49 a BCAA-enriched solution. Both groups received 30 kcal kg-1 body-weight, 15 per cent fat calories and 0.17 g nitrogen kg-1 body-weight. In the BCAA-enriched group, patients received 0.56 g BCAA kg-1 body-weight (50.2 per cent BCAA). Standard group patients received 0.18 g BCAA kg-1 body-weight (15.6 per cent BCAA). Nitrogen balances and 3-methylhistidine excretion were not significantly different between groups. Although morbidity scores tended to decrease during the study no difference was observed between groups. Mortality (early or late), sepsis or stress-related, did not differ significantly between groups. We were not able to confirm the reported beneficial effects of BCAA-enriched TPN solutions for use in septic and traumatized patients.

 


References

Aggarwal, R, et al. (2016), ‘Selenium Supplementation for Prevention of Late-Onset Sepsis in Very Low Birth Weight Preterm Neonates.’, J Trop Pediatr, 62 (3), 185-93. PubMed: 26867560
Bajčetić, M, et al. (2014), ‘Antioxidative system in the erythrocytes of preterm neonates with sepsis: the effects of vitamin E supplementation.’, Ann Clin Biochem, 51 (Pt 5), 550-56. PubMed: 24081186
Beale, RJ, et al. (2008), ‘Early enteral supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: outcome of a randomized, controlled, double-blind trial.’, Crit Care Med, 36 (1), 131-44. PubMed: 18007263
Bertolini, G, et al. (2003), ‘Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial.’, Intensive Care Med, 29 (5), 834-40. PubMed: 12684745
Donnino, MW, et al. (2015), ‘Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized, double-blind, placebo-controlled, pilot trial.’, Crit Care, 19 275. PubMed: 26130237
Forceville, X (2007), ‘Effects of high doses of selenium, as sodium selenite, in septic shock patients a placebo-controlled, randomized, double-blind, multi-center phase II study--selenium and sepsis.’, J Trace Elem Med Biol, 21 Suppl 1 62-65. PubMed: 18039501
Fowler, AA, et al. (2014), ‘Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis.’, J Transl Med, 12 32. PubMed: 24484547
Leaf, DE, et al. (2014), ‘Randomized controlled trial of calcitriol in severe sepsis.’, Am J Respir Crit Care Med, 190 (5), 533-41. PubMed: 25029202
Marik, PE, et al. (2017), ‘Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.’, Chest, 151 (6), 1229-38. PubMed: 27940189
Quraishi, SA, et al. (2015), ‘Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial.’, Crit Care Med, 43 (9), 1928-37. PubMed: 26086941
Valenta, J, et al. (2011), ‘High-dose selenium substitution in sepsis: a prospective randomized clinical trial.’, Intensive Care Med, 37 (5), 808-15. PubMed: 21347869
von Meyenfeldt, MF, et al. (1990), ‘Effect of branched chain amino acid enrichment of total parenteral nutrition on nitrogen sparing and clinical outcome of sepsis and trauma: a prospective randomized double blind trial.’, Br J Surg, 77 (8), 924-29. PubMed: 2118408