Pascal L. Langlois

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

IntroductionIntravenous 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.MethodsWe 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.ResultsA 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 I2 = 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 I2 =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).ConclusionFO-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.

Update on antioxidant micronutrients in the critically ill.

Purpose of reviewTo evaluate recent evidence on pharmaconutrition with antioxidant micronutrients, for different populations of adult critically ill patients. Recent findingsOver the last few years, different studies have shown that high-dose trace elements and vitamins, especially parenteral selenium and zinc, may be able to improve relevant clinical outcomes in the most seriously ill patients. High-dose selenite monotherapy reduces mortality, particularly when a pharmacological loading dose is given in the early stage of severe sepsis and septic shock. Notwithstanding, the recently published REducing Deaths due to OXidative Stress study using an antioxidant cocktail and parenteral selenite, in addition to standard enteral nutrition, was unable to show any benefits for patients with multiple organ failure. SummaryThere is evidence supporting the concept of pharmaconutrition with high-dose micronutrients. Selenium therapy may be able to decrease infections and reduce mortality in sepsis, but more research is needed to better understand pharmacokinetics, optimal composition, timing, duration, and dose of antioxidant cocktails for the critically ill.

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.

Selenium pharmaconutrition in sepsis: To give or not to give? Is this still the question?

The Surviving Sepsis Campaign (SSC) International Guidelines for Management of Severe Sepsis and Septic Shock [1] were recently updated to assist critical care practitioners in managing the proliferation of emerging evidence for the treatment of sepsis syndromes and improving the prognosis of sepsis. Regarding pharmaconutrition with high-dose intravenous (IV) selenium, we find it surprising that these new SSC guidelines suggest, “not using intravenous selenium for the treatment of severe sepsis (grade 2C)” [1]. We respectfully disagree with this recommendation and question the rationale for this conclusion. In our opinion, the SSC may not have considered much of the published clinical evidence. In fairness, the author’s recommendation does not exclude the use of low-dose selenium in parenteral nutrition (PN) but no reference is made to the American Society for Parenteral and Enteral Nutrition (ASPEN) position paper on micronutrients [2] indicating that, although controversial, “patients who are deficient in selenium or who are critically ill, septic, or have severe burns may benefit from short termvery high daily doses [of selenium] administered separately from the PN” [2]. In fact, several observational studies have demonstrated that: low selenium status is associated with severity of illness; septic shock patients exhibit the lowest plasma selenium levels; and serum selenium shows a relatively good predictive value for mortality in the intensive care unit (ICU) [3–5]. Therefore, it seems logical that selenium supplementation is not only able to correct a nutritional deficiency but can help to improve outcome for septic patients. One of the most relevant selenium pharmaconutrition trials, quoted by the SSC was the SIC (Selenium in Intensive Care) study [6]. The SIC protocol incorporated an initial selenite loading dose by IV bolus to optimize selenium levels and extracellular glutathione peroxidase activity, followed by continuous infusion for 14 d. Although the reduction in 28-d mortality for supplemented patients failed to reach statistical significance in the intentionto-treat analysis, mortality was significantly lower in the perprotocol group (56.7% versus 42.6%; P 1⁄4 0.049). Additionally, mortality was significantly reduced in those septic patients with

Fish Oil-Containing Emulsions: When Fat Seems to Improve Clinical Outcomes in the Critically Ill.

Third generation lipid emulsions were developed as a soybean oil sparing strategy with the aim to provide ω-3 polyunsaturated fatty acids (ω-3-PUFAs) derived from fish oil (FO), such as eicosapentanoic acid (EPA) and decosahexanoic acid (DHA), and reduce the amount of ω-6 polyunsaturated fatty acids (ω-6-PUFAs), which have been associated with negative effects on immune function and inflammatory response [1,2]. Over the last decade, several relatively small phase II randomized controlled trials (RCTs) have evaluated clinical and mechanistic effects of intravenous (I.V.) FO containing emulsions in intensive care unit (ICU) patients.

Intravenous lipid emulsions in the critically ill: an update.

Purpose of reviewPurpose of the review is to summarize recent research addressing the role of intravenous lipid emulsions (IVLEs) in the critically ill. Recent findingsSoybean 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. SummaryThere 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.

The role of alternative lipid emulsions in critically ill patients: what the evidence shows.

Lipid emulsions (LEs) are a component of parenteral nutrition (PN) providing a dense source of energy and essential fatty acids. In critically ill patients, commonly used LEs have been rich in long-chain triglycerides (LCTs) providing a high percentage of linoleic acid (ω-6 polyunsaturated fatty acids [ω-6 PUFA] 18:2 ω-6). The current literature suggests that intravenous (IV) soybean-oil (SO) and safflower-based LEs are able to promote production of pro-inflammatory prostanoids and leukotrienes and therefore increase oxidative stress and systemic inflammation in the critically ill. In 2006, it was suggested that inclusion of ω-6-based LEs might be detrimental, which is more probable in the most seriously ill patients. Withholding lipid emulsion high in SO has been recommended in patients who tolerate some EN and who require short term PN (< 10 days).

Vitamin C for the critically ills: is the evidence strong enough?

Vitamin C exhibits interesting properties in the context of critical illness, with benefits described in neurologic, cardiovascular, renal, and hematologic systems, both in in vitro and in animal models. Through direct effects on bacterial replication, immunomodulation, and antioxidant reserve of the organism, vitamin C directly affects the pathophysiological process of sepsis, trauma, burn, and systemic inflammation. Even if several observational trials have linked vitamin C deficiency to worse outcomes, the evidence is not such as to provide us with a distinction between causality effects or simple epiphenomenon, and the current focus is on interventional trials. Pharmacokinetic data suggest that a minimal supplementation of 3 g/d intravenously is required to restore normal serum values in critically ill patients with known deficiency. According to these data, only five trials, including a retrospective analysis, studied pharmacologic dose: three as an antioxidant cocktail and two as monotherapy. The largest trial, conducted in 2002, reported reduced incidence of multiorgan failure and duration of mechanical ventilation. Recently a retrospective analysis reported impressive results after administration of vitamin C, thiamine, and hydrocortisone. The two most recent trials reported improved clinical outcomes, including improved mortality, but contained significant methodological limitations. A recent systematic review did not find clinical benefits with the most-studied low-dose oral supplementation, potentially because of suboptimal or insufficient repletion. Current guidelines do not support the administration of high-dose vitamin C in critically ill patients. Future larger trials are required to support any therapy, but the low cost and safety profile can justify supplementation in the meantime. Metabolomics study will further help understand biological effect.

Vitamin C to Improve Organ Dysfunction in Cardiac Surgery Patients—Review and Pragmatic Approach

The pleiotropic biochemical and antioxidant functions of vitamin C have sparked recent interest in its application in intensive care. Vitamin C protects important organ systems (cardiovascular, neurologic and renal systems) during inflammation and oxidative stress. It also influences coagulation and inflammation; its application might prevent organ damage. The current evidence of vitamin C’s effect on pathophysiological reactions during various acute stress events (such as sepsis, shock, trauma, burn and ischemia-reperfusion injury) questions whether the application of vitamin C might be especially beneficial for cardiac surgery patients who are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of vitamin C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between vitamin C and clinical health outcomes are reviewed with special emphasis on its application in cardiac surgery. Additionally, this review pragmatically discusses evidence on the administration of vitamin C in every day clinical practice, tackling the issues of safety, monitoring, dosage, and appropriate application strategy.

Thérapie par sélénite de sodium chez le patient aux soins intensifs: supplémentation ou intervention pharmacologique ?

Sepsis-related organ dysfunction remains a major cause of death in the intensive care unit (ICU). So far, different adjunct therapies including antioxidant micronutrients have been developed to improve survival in septic patients.According to current evidence, selenium therapy should be considered as the cornerstone antioxidant strategy and not only as an antioxidant supplementation in ICU patients. The selenocompounds including selenious acid (H2SeO3) and sodium selenite (Na2SeO3) provided as pentahydrate sodium selenite (5H2O-Na2SeO3) should be considered as drugs with oxidant and cytotoxic effects when a loading dose is administered as intravenous bolus. Teratogenic and carcinogenic risks should also be taken into consideration. Animal studies are still required to define Na2SeO3 mechanisms of action and toxicity. A better understanding of its pharmacokinetic profile, duration of therapy, and long-term toxicity data is required. Additionally, the effect of selenium therapy in sepsis should be assessed in large, well-designed phase III clinical trials. Our purpose is to review selenium therapy in ICU adult patients, investigating whether its effects are related to a simple supplementation or a pharmacological intervention.