Early high-dose vitamin C in post-cardiac arrest syndrome (VITaCCA): study protocol for a randomized, double-blind, multi-center, placebo-controlled trial.

BACKGROUND: High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients. METHODS: This is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations. DISCUSSION: Vitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest. TRIAL REGISTRATION: ClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662 European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL.

Vitamin C: should we supplement?

PURPOSE OF REVIEW: Hypovitaminosis C and vitamin C deficiency are very common in critically ill patients due to increased needs and decreased intake. Because vitamin C has pleiotropic functions, deficiency can aggravate the severity of illness and hamper recovery. RECENT FINDINGS: Vitamin C is a key circulating antioxidant with anti-inflammatory and immune-supporting effects, and a cofactor for important mono and dioxygenase enzymes. An increasing number of preclinical studies in trauma, ischemia/reperfusion, and sepsis models show that vitamin C administered at pharmacological doses attenuates oxidative stress and inflammation, and restores endothelial and organ function. Older studies showed less organ dysfunction when vitamin C was administered in repletion dose (2-3 g intravenous vitamin C/day). Recent small controlled studies using pharmacological doses (6-16 g/day) suggest that vitamin C reduces vasopressor support and organ dysfunction, and may even decrease mortality. SUMMARY: A short course of intravenous vitamin C in pharmacological dose seems a promising, well tolerated, and cheap adjuvant therapy to modulate the overwhelming oxidative stress in severe sepsis, trauma, and reperfusion after ischemia. Large randomized controlled trials are necessary to provide more evidence before wide-scale implementation can be recommended.

Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens.

BACKGROUND: Early high-dose IV vitamin C is being investigated as adjuvant therapy in patients who are critically ill, but the optimal dose and infusion method are unclear. The primary aim of this study was to describe the dose-plasma concentration relationship and safety of four different dosing regimens. METHODS: This was a four-group randomized pharmacokinetic trial. Patients who were critically ill with multiple organ dysfunction were randomized to receive 2 or 10 g/d vitamin C as a twice daily bolus infusion or continuous infusion for 48 h. End points were plasma vitamin C concentrations during 96 h, 12-h urine excretion of vitamin C, and oxalate excretion and base excess. A population pharmacokinetic model was developed using NONMEM. RESULTS: Twenty patients were included. A two-compartment pharmacokinetic model with creatinine clearance and weight as independent covariates described all four regimens best. With 2 g/d bolus, plasma vitamin C concentrations at 1 h were 29 to 50 mg/L and trough concentrations were 5.6 to 16 mg/L. With 2 g/d continuous, steady-state concentrations were 7 to 37 mg/L at 48 h. With 10 g/d bolus, 1-h concentrations were 186 to 244 mg/L and trough concentrations were 14 to 55 mg/L. With 10 g/d continuous, steady-state concentrations were 40 to 295 mg/L at 48 h. Oxalate excretion and base excess were increased in the 10 g/d dose. Forty-eight hours after discontinuation, plasma concentrations declined to hypovitaminosis levels in 15% of patients. CONCLUSIONS: The 2 g/d dose was associated with normal plasma concentrations, and the 10 g/d dose was associated with supranormal plasma concentrations, increased oxalate excretion, and metabolic alkalosis. Sustained therapy is needed to prevent hypovitaminosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02455180; URL: www.clinicaltrials.gov.

Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Vitamin C supplementation in the critically ill patient.

PURPOSE OF REVIEW: Vitamin C is not only an essential nutrient involved in many anabolic pathways, but also an important player of the endogenous antioxidant defense. Low plasma levels are very common in critical care patients and may reflect severe deficiency states. RECENT FINDINGS: Vitamin C scavenges reactive oxygen species such as superoxide and peroxynitrite in plasma and cells (preventing damage to proteins, lipids and DNA), prevents occludin dephosphorylation and loosening of the tight junctions. Ascorbate improves microcirculatory flow impairment by inhibiting tumor-necrosis-factor-induced intracellular adhesion molecule expression, which triggers leukocyte stickiness and slugging. Clinical trials in sepsis, trauma and major burns testing high-dose vitamin C show clinical benefit. Restoration of normal plasma levels in inflammatory patients requires the administration of 3 g/day for several days, which is 30 times the daily recommended dose. SUMMARY: The recent research on the modulation of oxidative stress and endothelial protection offer interesting therapeutic perspectives, based on the biochemical evidence, with limited or even absent side-effects.

Vitamin C revisited.

This narrative review summarizes the role of vitamin C in mitigating oxidative injury-induced microcirculatory impairment and associated organ failure in ischemia/reperfusion or sepsis. Preclinical studies show that high-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting activation of nicotinamide adenine dinucleotide phosphate-oxidase and inducible nitric oxide synthase, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, and decreasing the formation of superoxide and peroxynitrite, and by directly scavenging superoxide. Vitamin C can additionally restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier by maintaining cyclic guanylate phosphatase and occludin phosphorylation and preventing apoptosis. Finally, high-dose vitamin C can augment antibacterial defense. These protective effects against overwhelming oxidative stress due to ischemia/reperfusion, sepsis or burn seems to mitigate organ injury and dysfunction, and promote recovery after cardiac revascularization and in critically ill patients, in the latter partially in combination with other antioxidants. Of note, several questions remain to be solved, including optimal dose, timing and combination of vitamin C with other antioxidants. The combination obviously offers a synergistic effect and seems reasonable during sustained critical illness. High-dose vitamin C, however, provides a cheap, strong and multifaceted antioxidant, especially robust for resuscitation of the circulation. Vitamin C given as early as possible after the injurious event, or before if feasible, seems most effective. The latter could be considered at the start of cardiac surgery, organ transplant or major gastrointestinal surgery. Preoperative supplementation should consider the inhibiting effect of vitamin C on ischemic preconditioning. In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.

Glutamine supplementation in the critically ill: friend or foe?

In the previous issue of Critical Care, Mori and colleagues demonstrate that glutamine supplementation in mechanically ventilated patients as part of parenteral nutrition increases plasma glutamine concentration and glutamine utilization, but does not mitigate protein degradation and even increases de novo glutamine production. Studies suggest that protein degradation is regulated by the degree of inflammation. Immune cells utilize large amounts of glutamine and derive their glutamine requirements from muscle protein degradation. We hypothesize that the effects of glutamine supplementation depend on the degree of inflammation. Infusing large amounts of exogenous glutamine into patients with inflammatory conditions like sepsis and multiple organ failure may not only enhance immune competence, but may potentially augment the inflammatory response and thereby negatively influence outcome.

Bioenergetic gain of citrate anticoagulated continuous hemodiafiltration--a comparison between 2 citrate modalities and unfractionated heparin.

PURPOSE: To determine bioenergetic gain of 2 different citrate anticoagulated continuous hemodiafiltration (CVVHDF) modalities and a heparin modality. MATERIALS AND METHODS: We compared the bio-energetic gain of citrate, glucose and lactate between 29 patients receiving 2.2% acid-citrate-dextrose with calcium-containing lactate-buffered solutions (ACD/Ca(plus)/lactate), 34 on 4% trisodium citrate with calcium-free low-bicarbonate buffered fluids (TSC/Ca(min)/bicarbonate), and 18 on heparin with lactate buffering (Hep/lactate). RESULTS: While delivered CVVHDF dose was about 2000 mL/h, total bioenergetic gain was 262 kJ/h (IQR 230-284) with ACD/Ca(plus)/lactate, 20 kJ/h (8-25) with TSC/Ca(min)/bicarbonate (P < .01) and 60 kJ/h (52-76) with Hep/lactate. Median patient delivery of citrate was 31.2 mmol/h (25-34.7) in ACD/Ca(plus)/lactate versus 14.8 mmol/h (12.4-19.1) in TSC/Ca(min)/bicarbonate groups (P < .01). Median delivery of glucose was 36.8 mmol/h (29.9-43) in ACD/Ca(plus)/lactate, and of lactate 52.5 mmol/h (49.2-59.1) in ACD/Ca(plus)/lactate and 56.1 mmol/h (49.6-64.2) in Hep/lactate groups. The higher energy delivery with ACD/Ca(plus)/lactate was partially due to the higher blood flow used in this modality and the calcium-containing dialysate. CONCLUSIONS: The bioenergetic gain of CVVHDF comes from glucose (in ACD), lactate and citrate. The amount substantially differs between modalities despite a similar CVVHDF dose and is unacceptably high when using ACD with calcium-containing lactate-buffered solutions and a higher blood flow. When calculating nutritional needs, we should account for the energy delivered by CVVHDF.

Prevention of acute kidney injury and protection of renal function in the intensive care unit. Expert opinion of the Working Group for Nephrology, ESICM.

BACKGROUND: Acute renal failure on the intensive care unit is associated with significant mortality and morbidity. OBJECTIVES: To determine recommendations for the prevention of acute kidney injury (AKI), focusing on the role of potential preventative maneuvers including volume expansion, diuretics, use of inotropes, vasopressors/vasodilators, hormonal interventions, nutrition, and extracorporeal techniques. METHOD: A systematic search of the literature was performed for studies using these potential protective agents in adult patients at risk for acute renal failure/kidney injury between 1966 and 2009. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, and use of potentially nephrotoxic drugs and radiocontrast media. Where possible the following endpoints were extracted: creatinine clearance, glomerular filtration rate, increase in serum creatinine, urine output, and markers of tubular injury. Clinical endpoints included the need for renal replacement therapy, length of stay, and mortality. Studies are graded according to the international Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) group system. CONCLUSIONS AND RECOMMENDATIONS: Several measures are recommended, though none carries grade 1A. We recommend prompt resuscitation of the circulation with special attention to providing adequate hydration whilst avoiding high-molecular-weight hydroxy-ethyl starch (HES) preparations, maintaining adequate blood pressure using vasopressors in vasodilatory shock. We suggest specific vasodilators [corrected] under strict hemodynamic control, sodium bicarbonate for emergency procedures administering contrast media, and periprocedural hemofiltration in severe chronic renal insufficiency undergoing coronary intervention. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-009-1678-y) contains supplementary material, which is available to authorized users.

Primum non nocere, safety of continuous renal replacement therapy.

PURPOSE OF REVIEW: To highlight selected adverse effects of continuous renal replacement therapy and to suggest measures for reducing harm. RECENT FINDINGS: Adverse effects of continuous renal replacement therapy are related to bioincompatibility, bleeding, metabolic consequences, loss of heat, vascular access and human error. Bioincompatibility initiates coagulation and inflammation. Use of membranes with high pore size permits direct removal of the locally formed inflammatory mediators. Regional anticoagulation with citrate reduces the risk of bleeding and abolishes polymorphonuclear and platelet degranulation in the filter. Continuous renal replacement therapy is associated with increased losses of amino acids and the water-soluble vitamins carnitine and selenium. Compared to bicarbonate, lactate-buffered fluids may increase energy needs and glucose intolerance. Patients on continuous renal replacement therapy may lose heat. SUMMARY: Several measures can be considered to improve safety of continuous renal replacement therapy. Among these are the use of membranes with high pore size, implementation of citrate to reduce bleeding and bioincompatibility, supplementation of water-soluble vitamins and selenium to increase antioxidant defense, use of bicarbonate-buffered solutions in the most critically ill, and prevention of loss of heat. Last but not least, improvement of safety needs continuous training of staff for better understanding of the method.

Glycine does not add to the beneficial effects of perioperative oral immune-enhancing nutrition supplements in high-risk cardiac surgery patients.

BACKGROUND: Elderly patients and patients with a poor cardiac function have increased morbidity rates when undergoing cardiac surgery. The aim of this study was to determine whether addition of glycine to a standard preoperative oral immune-enhancing nutrition supplement (OIENS) improves outcome. Glycine-enriched OIENS was compared with 2 formulas: standard OIENS and control. METHODS: In this double-blind, 3-armed study, patients scheduled to undergo cardiac surgery with the use of extracorporeal circulation received either the glycine-enriched OIENS (OIENS + glyc, n = 24), standard OIENS (OIENS, n = 25), or control formula (Control, n = 25) for minimally 5 preoperative days. Patients were included if they were aged 70 years or older, had a compromised left ventricular function, or were planned for mitral valve surgery. Main outcome measures were postoperative infectious morbidity, organ function, and postoperative recovery. RESULTS: Infectious morbidity was significantly lower in both treatment groups compared with the control group (p = .02). An infection was diagnosed in 5 and 4 patients in the OIENS + glyc and OIENS groups, respectively, and in 12 control patients. Less supportive therapy was necessary to stabilize circulation in both treatment groups compared with the control group. Median length of hospital stay was 7.0, 6.5, and 8.0 days in the OIENS + glyc, OIENS, and control groups, respectively. Inflammatory responses, as measured by systemic levels of proinflammatory cytokines and surface markers on polymorphonuclear cells, were comparable for all groups. CONCLUSIONS: Preoperative OIENS reduces postoperative infectious morbidity and results in a more stable circulation; the addition of glycine does not result in any beneficial effect over standard OIENS.