Vitamin D in the ICU: More sun for critically ill adult patients?

Critical illness in patients is characterized by systemic inflammation and oxidative stress. Vitamin D has a myriad of biological functions relevant to this population, including immunomodulation by the alteration of cytokine production and nuclear factor loop amplification. Low serum levels have consistently been found in observational studies conducted on critically ill patients, but the causality with mortality and worse outcomes has not been confirmed. The current focus is on interventional trials, whereas the pharmacokinetic profile of vitamin D administration remains sparse and the optimal strategy has not been confirmed. So far, high-dose oral or enteral supplementation is the most studied strategy. The largest randomized controlled trial published so far, the VITdAL-ICU (Effect of High-dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients with Vitamin D Deficiency) trial, showed no benefits on mortality in its primary analysis. However, secondary analysis suggested improvement in those patients with severe deficiency (i.e., 25-dihydroxyvitaminD <12 ng/mL). Smaller trials investigated intramuscular and intravenous administration and found interesting intermediate biochemical findings, including increased cathelicidins, but were not powered to investigate relevant clinical outcomes in the critically ill. The latest meta-analysis, which was recently published, does not support benefits of vitamin D supplementation in the heterogeneous population of critically ill patients. The European guidelines, published in the last year, suggest supplementing severely deficient patients with levels <12.5 ng/mL within the first week after ICU admission. However, other societies do not support such supplementation in their older recommendations. Large trials are currently recruiting ICU patients and could elucidate potential clinical benefits of vitamin D therapy in the critically ill.

Omega-3 polyunsaturated fatty acids in critically ill patients with acute respiratory distress syndrome: A systematic review and meta-analysis.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is characterized by an acute inflammatory response in the lung parenchyma leading to severe hypoxemia. Because of its anti-inflammatory and immunomodulatory properties, omega-3 polyunsaturated fatty acids (ω-3 PUFA) have been administered to ARDS patients, mostly by the enteral route, as immune-enhancing diets with eicosapentaenoic acid, γ-linolenic acid, and antioxidants. However, clinical benefits of ω-3 PUFAs in ARDS patients remain unclear because clinical trials have found conflicting results. Considering the most recent randomized controlled trials (RCTs) and recent change in administration strategies, the aim of this updated systematic review and meta-analysis was to evaluate clinical benefits of ω-3 PUFA administration on gas exchange and clinical outcomes in ARDS patients. METHODS: We searched for RCTs conducted in intensive care unit (ICU) patients with ARDS comparing the administration of ω-3 PUFAs to placebo. The outcomes assessed were PaO2-to-FiO2 ratio evaluated early (3-4 d) and later (7-8 d), mortality, ICU and hospital length of stay (LOS), length of mechanical ventilation (MV), and infectious complications. Two independent reviewers assessed eligibility, risk of bias, and abstracted data. Data were pooled using a random effect model to estimate the relative risk or weighted mean difference (WMD). RESULTS: Twelve RCTs (n = 1280 patients) met our inclusion criteria. Omega-3 PUFAs administration was associated with a significant improvement in early PaO2-to-FiO2 ratio (WMD = 49.33; 95% confidence interval [CI] 20.88-77.78; P = 0.0007; I2 = 69%), which persisted at days 7 to 8 (WMD = 27.87; 95% CI 0.75-54.99; P = 0.04; I2 = 57%). There was a trend in those receiving ω-3 PUFA toward reduced ICU LOS (P = 0.08) and duration of MV (P = 0.06), whereas mortality, hospital LOS, and infectious complications remained unchanged. Continuous enteral infusion was associated with reduced mortality (P = 0.02), whereas analysis restricted to enteral administration either with or without bolus found improved early PaO2 and FiO2 (P = 0.001) and MV duration (P = 0.03). Trials at higher risk of bias had a significant reduction in mortality (P = 0.04), and improvement in late PaO2-to-FiO2 ratio (P = 0.003). CONCLUSIONS: In critically ill patients with ARDS, ω-3 PUFAs in enteral immunomodulatory diets may be associated with an improvement in early and late PaO2-to-FiO2 ratio, and statistical trends exist for an improved ICU LOS and MV duration. Considering these results, administering ω-3 PUFAs appears a reasonable strategy in ARDS.

Vitamin C Administration to the Critically Ill: A Systematic Review and Meta-Analysis.

Vitamin C, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation, oxidative stress, and microvascular dysfunction. While observational studies have demonstrated that critical illness is associated with low levels of vitamin C, randomized controlled trials (RCTs) of vitamin C, alone or in combination with other antioxidants, have yielded contradicting results. We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials (inception to December 2017) for RCTs comparing vitamin C, by enteral or parenteral routes, with placebo or none, in intensive care unit (ICU) patients. Two independent reviewers assessed study eligibility without language restrictions and abstracted data. Overall mortality was the primary outcome; secondary outcomes were incident infections, ICU length of stay (LOS), hospital LOS, and duration of mechanical ventilation (MV). We prespecified 5 subgroups hypothesized to benefit more from vitamin C. Eleven randomized trials were included. When 9 RCTs (n = 1322) reporting mortality were pooled, vitamin C was not associated with reduced risk of mortality (risk ratio [RR] 0.72, 95% confidence interval [CI]: 0.43-1.20, P = .21). No effect was found on infections, ICU or hospital LOS, or duration of MV. In multiple subgroup comparison, no statistically significant subgroup effects were observed. However, we did observe a tendency towards a mortality reduction (RR 0.21; 95% CI: 0.04-1.05; P = .06) when intravenous high-dose vitamin C monotherapy was administered. Current evidence does not support supplementing critically ill patients with vitamin C. A moderately large treatment effect may exist, but further studies, particularly of monotherapy administration, are warranted.

Vitamin D supplementation in the critically ill: A systematic review and meta-analysis.

INTRODUCTION: Vitamin D insufficiency is reported in up to 50% of the critically ill patients and is associated with increased mortality, length of stay (LOS) in intensive care unit (ICU) and hospital, and respiratory disorders with prolonged ventilation. Benefits of vitamin D supplementation remain unclear. The aim of this systematic review was to evaluate the clinical benefits of vitamin D administration in critically ill patients. METHODS: We searched Medline, Embase, CINAHL and Cochrane database for randomized controlled trials (RCT) conducted on heterogeneous ICU patients comparing vitamin D administration to placebo. Evaluated outcomes included mortality, infectious complications, hospital/ICU LOS and length of mechanical ventilation. Two independent reviewers assessed eligibility, risk of bias and abstracted data. Data was pooled using a random effect model to estimate the risk ratio (RR) or weighted mean difference. Pre-defined subgroup analysis included oral-enteral vs. parenteral administration, high vs. low dose, vitamin d deficient patient, high vs. low quality trials. RESULTS: Six RCTs (695 patients) met study inclusion. No reduction in mortality was found (P = 0.14). No differences in ICU and hospital LOS, infection rate and ventilation days existed. In the subgroup analysis, the oral-enteral group, there was no improvement in mortality (P = 0.12) or hospital LOS (P = 0.16). Daily doses >300,000 IU did not improve mortality (P = 0.12) and ICU LOS (P = 0.12). CONCLUSIONS: In critically ill patients, Vitamin D administration does not improve clinical outcomes. The statistical imprecision could be explained by the sparse number of trials.

Omega-3 polyunsaturated fatty acids in cardiac surgery patients: An updated systematic review and meta-analysis.

BACKGROUND: Omega-3 polyunsaturated fatty acids (ω-3 PUFA) supplementation is an attractive therapeutic option for patients undergoing open-heart surgery due to their anti-inflammatory and anti-arrhythmic properties. Several randomized controlled trials (RCT) have found contradictory results for perioperative ω-3 PUFA administration. Therefore, we conducted an updated systematic review and meta-analysis evaluating the effects of perioperative ω-3 PUFA on some clinically important outcomes for cardiac surgery. METHODS: A systematic literature search was conducted to find RCT evaluating clinical outcomes after ω-3 PUFA therapy in adult patients undergoing cardiac surgery. Intensive care unit (ICU) length of stay (LOS) was the primary outcome; secondary outcomes were hospital LOS, postoperative atrial fibrillation (POAF), mortality and duration of mechanical ventilation (MV). Predefined subgroup analysis and sensibility analysis were performed. RESULTS: A total of 19 RCT including 4335 patients met inclusion criteria. No effect of ω-3 PUFA on ICU LOS was found (weighted mean difference WMD -2.95, 95% confidence interval, CI -10.28 to 4.39, P = 0.43). However, ω-3 PUFA reduced hospital LOS (WMD -1.37, 95% CI -2.41 to -0.33; P = 0.010) and POAF incidence (Odds Ratio OR = 0.78, 95% CI 0.68 to 0.90; P = 0.004). No effects were found on mortality or MV duration. Heterogeneity remained in subgroup analysis and we found a significant POAF reduction when ω-3 PUFA doses were administered to patients exposed to extra-corporeal circulation. Oral/enteral administration seemed to further reduce POAF. CONCLUSIONS: In patients undergoing cardiac surgery, ω-3 PUFA supplementation by oral/enteral and parenteral route reduces hospital LOS and POAF. Nonetheless considerable clinical and statistical heterogeneity weaken our findings.

High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis.

BACKGROUND: Selenium (Se) is an essential trace element with antioxidant, anti-inflammatory, and immunomodulatory effects. So far, several randomized clinical trials (RCTs) have demonstrated that parenteral Se may improve clinical outcomes in intensive care unit (ICU) patients. Since publication of our previous systematic review and meta-analysis on antioxidants in the ICU, reports of several trials have been published, including the largest RCT on Se therapy. The purpose of the present systematic review was to update our previous data on intravenous (IV) Se in the critically ill. METHODS: We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. We included RCTs with parallel groups comparing parenteral Se as single or combined therapy with placebo. Potential trials were evaluated according to specific eligibility criteria, and two reviewers abstracted data from original trials in duplicate independently. Overall mortality was the primary outcome; secondary outcomes were infections, ICU length of stay (LOS), hospital LOS, ventilator days, and new renal dysfunction. RESULTS: A total of 21 RCTs met our inclusion criteria. When the data from these trials were aggregated, IV Se had no effect on mortality (risk ratio [RR] 0.98, 95 % CI 0.90-1.08, P = 0.72, heterogeneity I 2 = 0 %). In addition, when the results of ten trials in which researchers reported on infections were statistically aggregated, there was no significant treatment effect of parenteral Se (RR 0.95, 95 % CI 0.88-1.02, P = 0.15, I 2 = 0 %). There was no positive or negative effect of Se therapy on ICU and hospital LOS, renal function, or ventilator days. CONCLUSIONS: In critically ill patients, IV Se as monotherapy does not improve clinical outcomes.

Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis.

BACKGROUND: Critical illness is characterized by a loss of commensal flora and an overgrowth of potentially pathogenic bacteria, leading to a high susceptibility to nosocomial infections. Probiotics are living non-pathogenic microorganisms, which may protect the gut barrier, attenuate pathogen overgrowth, decrease bacterial translocation and prevent infection. The purpose of this updated systematic review is to evaluate the overall efficacy of probiotics and synbiotic mixtures on clinical outcomes in critical illness. METHODS: Computerized databases from 1980 to 2016 were searched. Randomized controlled trials (RCT) evaluating clinical outcomes associated with probiotic therapy as a single strategy or in combination with prebiotic fiber (synbiotics). Overall number of new infections was the primary outcome; secondary outcomes included mortality, ICU and hospital length of stay (LOS), and diarrhea. Subgroup analyses were performed to elucidate the role of other key factors such as probiotic type and patient mortality risk on the effect of probiotics on outcomes. RESULTS: Thirty trials that enrolled 2972 patients were identified for analysis. Probiotics were associated with a significant reduction in infections (risk ratio 0.80, 95 % confidence interval (CI) 0.68, 0.95, P = 0.009; heterogeneity I (2) = 36 %, P = 0.09). Further, a significant reduction in the incidence of ventilator-associated pneumonia (VAP) was found (risk ratio 0.74, 95 % CI 0.61, 0. 90, P = 0.002; I (2) = 19 %). No effect on mortality, LOS or diarrhea was observed. Subgroup analysis indicated that the greatest improvement in the outcome of infections was in critically ill patients receiving probiotics alone versus synbiotic mixtures, although limited synbiotic trial data currently exists. CONCLUSION: Probiotics show promise in reducing infections, including VAP in critical illness. Currently, clinical heterogeneity and potential publication bias reduce strong clinical recommendations and indicate further high quality clinical trials are needed to conclusively prove these benefits.

Intravenous lipid emulsions in the critically ill: an update.

PURPOSE OF REVIEW: Purpose of the review is to summarize recent research addressing the role of intravenous lipid emulsions (IVLEs) in the critically ill. RECENT FINDINGS: Soybean oil-based IVLEs, which are high in the omega-6 polyunsaturated fatty acids, have been largely used in parenteral nutrition over the last several decades. However, it is now generally accepted that the higher content of phytosterols and polyunsaturated fatty acids in soybean oil IVLE may adversely affect the immunological and inflammatory status of the critically ill. In the last few years, alternative IVLEs with lower soybean oil content have been associated with important improvements in clinical outcomes, such as mortality, mechanical ventilation days, and ICU length of stay. Olive oil and fish oil IVLEs have been reported to reduce the incidence of infections, with no clear benefits in other clinical outcomes. Despite the promising results with these new parenteral nutrition strategies, the optimum composition, dosage and indication for alternative IVLEs still remain controversial. Nevertheless, according to current knowledge alternative IVLEs may be associated with improved clinical outcomes and should be considered in critically ill patients requiring parenteral nutrition. SUMMARY: There is a growing body of evidence suggesting that improved clinical outcomes can be achieved with selective use of alternative IVLEs in parenteral nutrition regimens for the critically ill. More high quality trials are needed, to better evaluate the efficacy of alternative IVLEs.

Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis.

INTRODUCTION: Intravenous fish oil (FO) lipid emulsions (LEs) are rich in ω-3 polyunsaturated fatty acids, which exhibit anti-inflammatory and immunomodulatory effects. We previously demonstrated that FO-containing LEs may be able to decrease mortality and ventilation days in patients who are critically ill. Since 2014, several additional randomized controlled trials (RCTs) of FO-containing LEs have been published. Therefore, the purpose of this systematic review was to update our previous systematic review with the aim of elucidating the efficacy of FO-containing LEs on clinical outcomes of patients who are critically ill. METHODS: We searched electronic databases from 1980 to 2014. We included four new RCTs conducted in critically ill adult patients in which researchers evaluated FO-containing LEs in parenterally or enterally fed patients. RESULTS: A total of 10 RCTs (n = 733) met inclusion criteria. The mean methodological score was 8 (range, 3 to 12). No effect on overall mortality was found. When we aggregated the results of five RCTs in which infections were reported, we found that FO-containing LEs significantly reduced infections (risk ratio (RR) = 0.64; 95% confidence interval (CI), 0.44 to 0.92; P = 0.02; heterogeneity I (2) = 0%). Subgroup analysis demonstrated that predominantly enteral nutrition-based trials showed a tendency toward a reduction in mortality (RR = 0.69; 95% CI, 0.40 to 1.18; P =0.18; heterogeneity I (2) =35%). High-quality trials showed a significant reduction in hospital length of stay (LOS) (weighted mean difference = -7.42; 95% CI, -11.89 to -2.94; P = 0.001), whereas low-quality trials had no effect (P = 0.45). The results of the test for subgroup differences in hospital LOS was significant (P = 0.001). CONCLUSION: FO-containing LEs may be associated with a reduction in infections and also could be associated with a reduction in duration of ventilation and hospital LOS. Further large-scale RCTs are warranted and should be aimed at consolidating potential positive treatment effects.

Pharmaconutrition with selenium in critically ill patients: what do we know?

Selenium is a component of selenoproteins with antioxidant, anti-inflammatory, and immunomodulatory properties. Systemic inflammatory response syndrome (SIRS), multiorgan dysfunction (MOD), and multiorgan failure (MOF) are associated with an early reduction in plasma selenium and glutathione peroxidase activity (GPx), and both parameters correlate inversely with the severity of illness and outcomes. Several randomized clinical trials (RCTs) evaluated selenium therapy as monotherapy or in antioxidant cocktails in intensive care unit (ICU) patient populations, and more recently several meta-analyses suggested benefits with selenium therapy in the most seriously ill patients. However, the largest RCT on pharmaconutrition with glutamine and antioxidants, the REducing Deaths due to Oxidative Stress (REDOXS) Study, was unable to find any improvement in clinical outcomes with antioxidants provided by the enteral and parenteral route and suggested harm in patients with renal dysfunction. Subsequently, the MetaPlus study demonstrated increased mortality in medical patients when provided extra glutamine and selenium enterally. The treatment effect of selenium may be dependent on the dose, the route of administration, and whether administered with other nutrients and the patient population studied. Currently, there are few small studies evaluating the pharmacokinetic profile of intravenous (IV) selenium in SIRS, and therefore more data are necessary, particularly in patients with MOD, including those with renal dysfunction. According to current knowledge, high-dose pentahydrate sodium selenite could be given as an IV bolus injection (1000-2000 µg), which causes transient pro-oxidant, cytotoxic, and anti-inflammatory effects, and then followed by a continuous infusion of 1000-1600 µg/d for up to 10-14 days. Nonetheless, the optimum dose and efficacy still remain controversial and need to be definitively established.