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The Protective Effects of High-Dose Ascorbic Acid on Myocardium against Reperfusion Injury During and After Cardiopulmonary Bypass
Abstract
Freie Sauerstoffradikale werden vor allem für den Reperfusionsschaden nach Ischämie des Herzmuskels verantwortlich gemacht. Durch Abfangen dieser freien Radikale besteht die Chance, den Reperfusionsschaden zu vermindern.
In der folgenden Arbeit wurden die Serumspiegel von Malonyldialdehyd (MDA), Kreatin, Phosphokinase (CPK), Creatin Phosphokinase Isoenzym (CPK-MB) und Laktatdchydrogenase (LDH) bei 85 Patienten während und nach Bypass gemessen. 45 Patienten erhielten 250 mg/kg Askorbinsäure, während 40 Patienten als Kontrollgruppe dienten. Die MDA-, CPK-, CPKMB- und LAD-Spiegel in der Askorbinsäure-Gruppe waren statistisch signifikant niedriger als in der Kontrollgruppe während und nach Bypass. Die MDA-Spiegel blieben postoperativ zwei Tage hoch, die CPK- und CPKMB-Werte, als die spezifischsten Indikatoren für einen Herzmuskelschaden, erholten sich in der Kontrollgruppe nach der Operation rasch. Spontandefibrillationen wurden bei allen Herzen der Askorbinsäure-Gruppe beobachtet, während in der Kontrollgruppe 5 Herzen (12,5%) defibrilliert werden mußten. Der Herzindex (CI) war in der Askorbinsäure-Gruppe deutlich höher (p < 0,05) als in der Kontrollgruppe. Ebenso war die Verweildauer auf der Intensivstation und im Krankenhaus deutlich kürzer.
Die Ergebnisse dieser Arbeit deuten darauf hin, daß Askorbinsäure als Fänger freier Radikale dient und damit den ischämischen Reperfusionsschaden der Herzen während und nach offener Herzoperation vermindern kann.
... [10][11][12][13] Ascorbic acid (vitamin C) also has an antioxidant action, by protecting the cells from the effects of oxygen free radicals. [14][15][16][17][18][19][20] However, previous studies have shown only partial protection from the action of the highly toxic hydroxyl radical. [21][22][23][24] A possible explanation for these unsatisfactory results lies in the complexity of the process of reperfusion injury. ...
... 15,17,20,32,33 The combination of ascorbic acid and desferrioxamine would be expected to have a synergistic action, because both drugs attenuate the effect of oxygen free radicals, but with a different mode of action. Ascorbic acid (vitamin C) is a potent, water-soluble antioxidant, because it scavenges reactive oxygen radicals, protecting many substrates from oxidative damage, [14][15][16][17][18][19][20] while desferrioxamine may ameliorate oxidative stress by reducing the availability of Fe+ and thus the production of hydroxyl radicals during reperfusion via Fenton reactions. 2,[8][9][10][11] In the present study, however, the above drug combination did not show a significant effect on infarct size, arrhythmias, or blood flow. ...
... In some studies it has been shown to reduce reperfusion injury, while in other studies it failed to provide any beneficial effect. 14,17,19,[35][36][37] Similarly, contradictory findings exist regarding the effects of desferrioxamine on myocardial reperfusion injury. 12,13 This leads to the conclusion that the effect of antioxidants on reperfusion injury is greatly influenced by the specific experimental conditions and the drug combination used. ...
During reperfusion of ischemic myocardium, oxygen-derived free radicals are produced and can cause deleterious effects, known as reperfusion injury. We aimed to determine if a combination of the antioxidant ascorbic acid and an iron-chelating agent desferrioxamine, which reduces the production of the hydroxyl radical via ferrum-catalyzed reactions, can exert a protective action against reperfusion injury.
Twenty-two young male farm pigs were anesthetized and subjected to 45 mins of ischemia and 3 and a half hours of reperfusion, in the left circumflex coronary artery territory, via the inflation and deflation of an angioplasty balloon. Animals were randomly assigned to receive either an intravenous infusion of 100 mg/ kg ascorbic acid and 60 mg/kg desferrioxamine (treatment group, TG) or an equal amount of normal saline (control group, CG). The I/R ratio, the ratio of the infarcted (necrotic) zone (I) to the myocardial area at risk (R) after 3 and a half hours of reperfusion, was calculated using the tetrazolium staining method. Left ventricular end diastolic pressure (LVEDP), number of episodes of ventricular arrhythmias, TIMI flow in the reperfused vessel, and left ventricular ejection fraction (LVEF) were evaluated within the first hour post reperfusion in order to assess further injury severity.
There was no significant difference in the I/R between the TG (27.9 ± 2.2%) and the CG (32.9 ± 2.4%) (p=0.15). In both groups there was a significant reduction in LVEF (-11.6 ± 2.28% for TG and -12.0 ± 2.27% for CG, p<0.01 for both groups) and a significant increase in LVEDP (+3.2 ± 0.9 mmHg for TG and +4.6 ± 0.9 mmHg for CG, p<0.01 for both groups) compared to the baseline values. No significant difference was noted between groups (p=0.61 for LVEF and p=0.60 for LVEDP values, at one hour post reperfusion). In all other parameters measured, no significant difference was observed between the study groups.
Intravenous treatment with a combination of the antioxidant ascorbic acid and the iron-chelating agent desferrioxamine does not provide significant protection against myocardial reperfusion injury.
... Die von Li verwendete Dosis und Art der Applikation wird in der dritten Vitamin C-Studie aus Xian von Dingchao et al. (1994) beibehalten. An 45 mit Vitamin C behandelten herzchirurgischen Patienten (40 Patienten in der Kontrollgruppe) konnten die von Li beschriebenen geringeren postoperativen Anstiege der CK-und CK-MB-Werte bestätigt werden. ...
... An 45 mit Vitamin C behandelten herzchirurgischen Patienten (40 Patienten in der Kontrollgruppe) konnten die von Li beschriebenen geringeren postoperativen Anstiege der CK-und CK-MB-Werte bestätigt werden. Zusätzlich war der postoperative Herzindex in der Vitamin C Gruppe signifikant größer, die Dauer sowohl der postoperativen Intensivpflege als auch des Krankenhausaufenthaltes kürzer und jedes mit Vitamin C behandelte Herz fing nach Beginn der Reperfusion spontan zu schlagen an, während in der Kontrollgruppe fünfmal eine Defibrillation notwendig war (Dingchao, Zhiduan et al. 1994 (Eddy, Hurvitz et al. 1990). Barta et al. (1991) untersuchten die Wirkung einer Gabe von 2000 IU Vitamin E und 2g Vitamin C unmittelbar vor der Operation auf ihre Wirksamkeit hinsichtlich der Myokardprotektion bei koronarchirurgischen Patienten (Barta, Pechan et al. 1991 Preiss et al. 2003). ...
... Die Ergebnisse unserer Studien zeigten, in Übereinstimmung mit früheren Untersuchungen, dass bei koronarchirurgischen Patienten, die nicht mit Vitamin C behandelt werden, intraoperativ die Vitamin C Plasma Konzentration abnimmt (Ballmer, Reinhart et al. 1994;Sisto, Paajanen et al. 1995;Albiez, Preiss et al. 2003;Lassnigg, Punz et al. 2003) und postoperativ ein Vitamin C Mangelzustand besteht (Ballmer, Reinhart et al. 1994;Albiez, Preiss et al. 2003;Lassnigg, Punz et al. 2003 (Milei, Forcada et al. 2007;Milei, Grana et al. 2007 (Milei, Forcada et al. 2007;Milei, Grana et al. 2007 (Eddy, Hurvitz et al. 1990;Dingchao, Zhiduan et al. 1994;Milei, Forcada et al. 2007), oder eine antioxydative Therapie wird nur für hämodynamisch instabile Patienten und Patienten mit schwer geschädigten Ventrikeln vorgeschlagen (Milei, Forcada et al. 2007). In der Studie von Sisto et al. profitierten hämodynamisch instabile und Notfall-Patienten mit schwer geschädigten Ventrikeln deutlich mehr von einer antioxydativen Behandlung als hämodynamisch stabile, elektiv operierte Patienten (Sisto, Paajanen et al. 1995 (Ferreira, Llesuy et al. 1988;Milei, Grana et al. 2007). ...
Objectives: Both animal and clinical studies indicate that reactive oxygen species, generated during reperfusion, are a major contributory factor of post-ischaemic myocardial dysfunction. There is also some evidence that administration of antioxidants reduces post-ischaemic reperfusion tissue injury. We set out to assess the benefit of high-dose vitamin C infusion during coronary artery bypass grafting (CABG) on post-operative myocardial status, peri-and post-operatively using selected parameters. Methods. In a double-blind experiment, total doses of 3 and 30 g vitamin C or placebo were infused for 24 hours from commencement of anesthesia, in three randomised groups (n=12 for each group) of patients undergoing elective CABG surgery. Cardiac damage was assessed biochemically and electrocardiographically, and blood platelet counts and the oxidation of ascorbate were determined. Results. Early increases in plasma myocardial creatine kinase levels occured after declamping of the aorta and were seen in each group but were significantly less in the high dose vitamin C group. The post-operative incidence of altered ST segments during early reperfusion was also significantly less in this group. Blood platelet counts decreased in all three groups but significantly less so again in the high dose vitamin C group. Monitoring of plasma ascorbate and dehydroascorbate levels during operation revealed that raised ascorbate levels were accompanied by a similar increase in dehydroascorbate levels, indicating ascorbate oxidation. Conclusions. These results confirm that oxidative stress is a vital factor in ischaemia-reperfusion injury in CABG and demonstrate that perioperative infusion of vitamin C, at novel high doses, in CABG appears to be cardioprotective.
... The reestablishment of normal plasma ascorbate levels by supplementation requires administration of intravenous (IV) doses of 2-3 grams per day, which is safe and well tolerated (6,7). Vitamin C supplementation improves patient oxidative state, shortens hospital stay and streamlines wound closure (8,9). ...
... Several studies have evaluated the effects of vitamin C supplementation in patients undergoing CPB. Dingchao et al. (8) reported protective effects of high-dose vitamin C administered before CPB and at the time of aortic declamping. Patients had lower oxidative damage, lower myocardial damage, better postoperative cardiac index and shorter hospital stay. ...
... Emadi et al.(22) administered 5 g of vitamin C before anesthesia induction and another 5 g in the cardioplegic solution. Dingchao et al.(8) studied the effects of two high doses (125 mg/kg), the first 30 min before CPB and the second during CPB, at the time of aortic declamping. The interesting approach of administration before coronary reperfusion was also studied with vitamin E supplementation (23). ...
... Studies have shown that the ascorbic acid acts as a free radical scavenger to reduce the lipid peroxidation in the cell membrane and effectively protects from myocardial damage against ischemic reperfusion, by removing the free radicals during and after surgery [5,6] . ...
... P=0.91). Also, the heart rate of patients in the control group was lower than of those in the treatment group, In studies with a high dose of vitamin C [5,16] , the level of cardiac biomarkers was clearly reduced. In our study, at all times, with any reduction or increase process, the level of biomedical markers in the treatment group was lower than in the control group and this shows the clinical effect of vitamin C on reducing the levels of ischemic enzymes, but there was no statistically significant difference between the two groups, which may be due to a low sample size or a significant increase in biomedical markers at all intervals, especially from the first to the second time, which resulted in large dispersion of data and increased the SD, and the difference between the two groups was not significant. ...
... In the Oktar et al. [16] study, the CK-MB level was lower in vitamin C group than in the control group. In another study, by Dingchao et al. [5] , the levels of CK-MB and LDH were higher in the control group after surgery than in the vitamin C group. In Lee et al. [17] study, troponin I and LDH levels were lower in the treatment group than in the control group, but similarly to our study, the level of CK-MB was not significantly different. ...
Objective:
To evaluate the effect of high-dose vitamin C on cardiac reperfusion injury and plasma levels of creatine kinase-muscle/brain (CK-MB), troponin I, and lactate dehydrogenase (LDH) in patients undergoing coronary artery bypass grafting (CABG).
Methods:
This is a double-blind randomized clinical trial study. Fifty patients (50-80 years old) who had CABG surgery were selected. The intervention group received 5 g of intravenous vitamin C before anesthesia induction and 5 g of vitamin C in cardioplegic solution. The control group received the same amount of placebo (normal saline). Arterial blood samples were taken to determine the serum levels of CK-MB, troponin I, and LDH enzymes. Left ventricular ejection fraction was measured and hemodynamic parameters were recorded at intervals.
Results:
High doses of vitamin C in the treatment group led to improvement of ventricular function (ejection fraction [EF]) and low Intensive Care Unit (ICU) stay. The cardiac enzymes level in the vitamin C group was lower than in the control group. These changes were not significant between the groups in different time intervals (anesthesia induction, end of bypass, 6 h after surgery, and 24 h after surgery) for CK-MB, LDH, and troponin I. Hemodynamic parameters, hematocrit, potassium, urinary output, blood transfusion, arrhythmia, and inotropic support showed no significant difference between the groups.
Conclusion:
Vitamin C has significantly improved the patients' ventricular function (EF) 72 h after surgery and reduced the length of ICU stay. No significant changes in cardiac biomarkers, including CK-MB, troponin I, and LDH, were seen over time in each group.
Irct code:
IRCT2016053019470N33.
... In addition, we checked the reference lists of the included trials, closely related papers and relevant reviews. We identified 18 publications in all [106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123] (Table 1; Table S1 of Supplementary file S1). One publication reported a 2 × 2 factorial trial on vitamin C and vitamin E [122]. ...
... A minus sign (−) indicates that there is concern regarding bias. The Dingchao [106], Ebade [114], and Alshafey [118] trials were particularly poorly reported; see Table S1 in Supplementary file S1. We tried unsuccessfully to contact Dr. Alshafey and Dr. Ebade to ask for details of their methods. ...
... Four trials did not report the methods in sufficient detail to enable conclusions to be drawn about the possibility of bias caused by poor blinding [106,107,114,118]. In our sensitivity analyses for vitamin C effect on ICU stay, we excluded the two particularly poorly reported trials [114,118], and a quasi-randomized trial [121]. ...
A number of controlled trials have previously found that in some contexts, vitamin C can have beneficial effects on blood pressure, infections, bronchoconstriction, atrial fibrillation, and acute kidney injury. However, the practical significance of these effects is not clear. The purpose of this meta-analysis was to evaluate whether vitamin C has an effect on the practical outcomes: length of stay in the intensive care unit (ICU) and duration of mechanical ventilation. We identified 18 relevant controlled trials with a total of 2004 patients, 13 of which investigated patients undergoing elective cardiac surgery. We carried out the meta-analysis using the inverse variance, fixed effect options, using the ratio of means scale. In 12 trials with 1766 patients, vitamin C reduced the length of ICU stay on average by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003). In six trials, orally administered vitamin C in doses of 1–3 g/day (weighted mean 2.0 g/day) reduced the length of ICU stay by 8.6% (p = 0.003). In three trials in which patients needed mechanical ventilation for over 24 hours, vitamin C shortened the duration of mechanical ventilation by 18.2% (95% CI 7.7% to 27%; p = 0.001). Given the insignificant cost of vitamin C, even an 8% reduction in ICU stay is worth exploring. The effects of vitamin C on ICU patients should be investigated in more detail.
... In cardiac surgery with CPB, vitamin C levels decrease with the production of ROS and remain low for days after surgery [49], indicating a greater demand of vitamin C in the setting of surgery and I/R-induced oxidative stress. Oxidative stress and myocardial damage after cardiac surgery with CPB might be decreased by the administration of vitamin C, as demonstrated in an RCT by Dingchao et al. in the 1990s [86]. In this RCT including 85 patients, the intervention group received a total of 250 mg/kg vitamin C before and after CPB. ...
... In this RCT including 85 patients, the intervention group received a total of 250 mg/kg vitamin C before and after CPB. Markers for myocardial injury creatine kinase (CK) and creatine phosphokinase isoenzyme muscle/brain (CK-MB), as well as malondialdehyde as a marker for oxidative stress were significantly lower in patients receiving vitamin C. Clinically, the cardiac index was higher, and the intervention-group patients were less likely to need defibrillation after weaning from cardiopulmonary bypass and had shorter ICU-and hospital-LOS [86]. ...
... Vitamin C treatment also improves ventricular function, reduces vasopressor and fluid demand [86,87] and increases the cardiac index. In a systematic review [88] and in 6 different meta-analyses including 8-15 RCTs [59,60,63,[89][90][91], vitamin C was shown to significantly reduce the occurrence of postoperative cardiac arrhythmia, mainly atrial fibrillation (AF). ...
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.
... This dosage was chosen in line with the dose-finding study by Fowler et al., which was observed it to be most effective. As high-dose vitamin C administration-especially for longer times-may also have negative effects on kidneys, for example occurrence of kidney stones [24], our research group abstained from higher vitamin C dosages, such as 66 mg/kg/h [25] or 125 mg/kg [26], which have previously described by other authors in other clinical settings. ...
... The recovery of the antioxidant capacity in the control group could possibly be explained via mobilization of intracellular reserves of antioxidant molecules into the bloodstream as reaction to the consumption of these molecules. However, the transport of antioxidants between cells and extracellular remains yet to be elucidated [26]. Whether the significant reduction of oxidative stress early after reperfusion will lead to improved kidney function reflected by creatine clearance and reduced kidney damage reflected in histologically observed damage remains unclear in our experiments, which might be due to the short duration of six hours. ...
Systemic and localized ischemia and reperfusion injury remain clinically relevant issues after organ transplantation and contribute to organ dysfunctions, among which acute kidney injury is one of the most common. An in vitro test-circuit for normothermic perfusion of porcine kidneys after warm ischemia was used to investigate the antioxidant properties of vitamin C during reperfusion. Vitamin C is known to enhance microcirculation, reduce endothelial permeability, prevent apoptosis, and reduce inflammatory reactions. Based on current evidence about the pleiotropic effects of vitamin C, we hypothesize that the antioxidant properties of vitamin C might provide organ-protection and improve the kidney graft function in this model of ischemia and reperfusion.
Methods:
10 porcine kidneys from 5 Landrace pigs were perfused in vitro for 6 h. For each experiment, both kidneys of one animal were perfused simultaneously with a 1:1 mixture of autologous blood and modified Ringer's solution at 38 °C and 75 mmHg continuous perfusion pressure. One kidney was treated with a 500 mg bolus injection of vitamin C into the perfusate, followed by continuous infusion of 60 mg/h vitamin C. In the control test circuit, an equal volume of Ringer's solution was administered as a placebo. Perfusate samples were withdrawn at distinct points in time during 6 h of perfusion for blood gas analyses as well as measurement of serum chemistry, oxidative stress and antioxidant capacity. Hemodynamic parameters and urine excretion were monitored continuously. Histological samples were analyzed to detect tubular- and glomerular-injury.
Results:
vitamin C administration to the perfusate significantly reduced oxidative stress (49.8 ± 16.2 vs. 118.6 ± 23.1 mV; p = 0.002) after 6 h perfusion, and increased the antioxidant capacity, leading to red blood cell protection and increased hemoglobin concentrations (5.1 ± 0.2 vs. 3.9 ± 0.6 g/dL; p = 0.02) in contrast to placebo treatment. Kidney function was not different between the groups (creatinine clearance vit C: 2.5 ± 2.1 vs. placebo: 0.5 ± 0.2 mL/min/100 g; p = 0.9). Hypernatremia (187.8 ± 4.7 vs. 176.4 ± 5.7 mmol/L; p = 0.03), and a lower, but not significant decreased fractional sodium excretion (7.9 ± 2 vs. 27.7 ± 15.3%; p = 0.2) were observed in the vitamin C group. Histological analysis did not show differences in tubular- and glomerular injury between the groups.
Conclusion:
Vitamin C treatment increased the antioxidant capacity of in vitro perfused kidney grafts, reduced oxidative stress, preserved red blood cells as oxygen carrier in the perfusate, but did not improve clinically relevant parameters like kidney function or attenuate kidney damage. Nevertheless, due to its antioxidative properties vitamin C might be a beneficial supplement to clinical kidney graft perfusion protocols.
... High-dose vitamin C (ascorbic acid) has been demonstrated to effectively scavenge free radicals, decreasing cell membrane lipid peroxidation 376,382 and indices of myocardial injury, and improving hemodynamics with a shorter ICU and hospital stay. 382 Vitamin E (␣-tocopherol) reduces plasma concentrations of hydrogen peroxide, a marker of free radical concentrations, 383 and decreases cell membrane lipid peroxidation 376 following CPB. ...
... High-dose vitamin C (ascorbic acid) has been demonstrated to effectively scavenge free radicals, decreasing cell membrane lipid peroxidation 376,382 and indices of myocardial injury, and improving hemodynamics with a shorter ICU and hospital stay. 382 Vitamin E (␣-tocopherol) reduces plasma concentrations of hydrogen peroxide, a marker of free radical concentrations, 383 and decreases cell membrane lipid peroxidation 376 following CPB. Preoperative supplementation with a combination of ascorbic acid, ␣-tocopherol, and allopurinol reduced cardiovascular dysfunction in both stable and unstable patients undergoing CABG. ...
... A pretreatment with tocopherol thought to increase the myocardial concentrations at least twice showed small but significant metabolic and functional beneficial effect after coronary bypass surgery [171]. In a Chinese study, Dingchao et al. showed beneficial effect of high-dose ascorbic acid treatment and a decrease in lipid peroxidation products in the serum [172], whereas Demirag et al. did not observe cardioprotection over myocardial reperfusion injury after ascorbic acid administration, but lower doses were used [173] . In another study, in patients undergoing cardiopulmonary bypass, ascorbic acid and -tocopherol supplementation failed to reduce myocardial injury after the operation [174]. ...
Myocardial ischemia is a major cause of morbidity and mortality in the world. Although restoration of blood flow after prolonged ischemia is essential for cardiomyocytes salvation and to limit myocardial damage and cardiac dysfunction, reperfusion itself exacerbates myocardial injury. Considerable evidence attributes reactive oxygen species (ROS), produced either by the myocardium itself or by infiltrating inflammatory cells, as an early event in this process. Once produced, ROS can lead to cellular damage through a number of pathways including direct damage to membranes and proteins or indirect damage through the activation of pro-apoptotic pathways. While using antioxidants to scavenge free radicals or targeting the sources of ROS, such as xanthine oxidase, may be potential attractive approaches to reduce myocardial reperfusion injury, clinical trials using antioxidant therapies have been largely disappointing. Neither oxidant scavengers like N-acetylcysteine and vitamins E and C, nor xanthine oxidase inhibitor allopurinol have provided indisputable evidence of a clinical benefit despite numerous favourable studies in animal models. Evidence to support a role of ROS in myocardial injury reperfusion is strong, but the clinical approach used has so far been inadequate. Absence of optimal pharmacology, variation in end-points used and low specificity of the compounds used have often been pointed out. In addition, the efficacy of antioxidants is often evaluated based on indirect biomarkers, which are prone to variation. Thus, clinical trials could be improved by the standardisation of the methods to measure oxidative stress and their impact on prognosis outcome.
... CPB during cardiac surgery provokes a vigorous inflammatory response via a variety of mechanisms [2,3], mainly including contact of blood to the foreign surfaces of the CPB circuit, surgical trauma and endotoxaemia. Various technological and pharmacological strategies have been developed aimed at reducing the inflammatory response following cardiac surgery, such as implementation of novel cardiac surgical techniques [4], improvement in the biocompatibility of the extracorporeal circuit [5], maintenance of haemodynamic stability [6] and the use of pharmacologic agents including aprotinin [7], free radical scavengers and anti-oxidants [8]. Significant morbidity associated with CPB is becoming rare, but most patients still experience different degrees of organ dysfunction as the result of the activation of the inflammatory response. ...
Aims:
Cardiopulmonary bypass (CPB) during cardiac surgery is well known to be associated with the development of a systemic inflammatory response. The efficacy of parecoxib in attenuating this systemic inflammatory response is still unknown.
Methods:
Patients undergoing elective mitral valve replacement with CPB were assessed, enrolled and randomly allocated to receive parecoxib (80 mg) or placebo. Blood samples were collected in EDTA vials for measuring serum cytokine concentrations, troponin T, creatinekinase myocardial-brain isoenzyme CK-MB concentrations and white cell counts.
Results:
Compared with the control group, IL-6 and IL-8-values in the parecoxib group increased to a lesser extent, peaking at 2 h after the end of CPB (IL-6 31.8 pg ml⁻¹ ± 4.7 vs. 77.0 pg ml⁻¹ ± 14.1, 95% CI -47.6, -42.8, P < 0.001; IL-8 53.6 pg ml⁻¹ ± 12.6 vs. 105.7 pg ml⁻¹ ± 10.8, 95% CI -54.8, -49.4, P < 0.001). Peak concentrations of anti-inflammatory cytokine IL-10 occurred immediately after termination of CPB and were higher in the parecoxib group (115.7 pg ml⁻¹ ± 10.5 vs. 88.4 pg ml⁻¹ ± 12.3, 95% CI 24.7, 29.9, P < 0.001). Furthermore, the increase in neutrophil counts caused by CPB during cardiac surgery was inhibited by parecoxib. The increases in serum troponin T and CK-MB concentrations were also significantly attenuated by parecoxib in the early post-operative days. Peak serum concentrations of CK-MB in both groups occurred at 24 h post-CPB (17.4 μg l⁻¹ ± 5.2 vs. 26.9 μg l⁻¹ ± 6.9, 95% CI -10.9, -8.1, P < 0.001). Peak troponin T concentrations occurred at 6 h post-bypass (2 μg l⁻¹ ± 0.62 vs. 3.5 μg l⁻¹ ± 0.78, 95% CI -1.7, -1.3, P < 0.001).
Conclusion:
Intra-operative parecoxib attenuated the systemic inflammatory response associated with CPB during cardiac surgery and lowered the biochemical markers of myocardial injury.
... Vitamin C is a known free-radical scavenger and has been shown to inhibit lipid peroxidation in liver (15).As (fig 1), there was a significant increase at 1000& 1500mg /70kg that vitamin C administration plays an important role in increasing the absorption rate of acerbate to reach 98% and this shows a high plasma level but the gradually accumulation in the tissues and its plasma level may reach to the renal reabsorption threshold (1.5mg/dl) in women. The surplus is rapidly excreted in the urine and this agrees with many results (16) and (17), (18)& (19). Or may indicate that concentrations of vitamin C in the plasma were increased with prolongation of the treatment period (20). ...
The present study was conducted to verify the oxidative stress status by using different doses of KMno4 (100,200,300) mg /70kg b.w and role of antioxidant agents at different concentrations of Vitamin C (1000, 1500, 2000) mg /70kg b.w on female infertility. To achieve this aim, 72 female rats with ages of 2-3 months, weighing(180g-250g) Were enrolled .To compare the results, 24 healthy individuals of ages(2-3 months) were also studied which divided to three chief groups: treated with KMno4, Vitamin C and combination of (KMno4+Vitamin C). Serum Vitamin C and ovaries were dissected for histopathological study. The results indicated a significant decrease (p<0.05) of Vitamin C values in sera of groups that treated with (KMno4) alone, when compared with the control group, while Vitamin C levels showed a significant (p<0.05) increase in Vitamin C treated groups in respect with those of the control group. The highest levels of Vitamin C values were found in the groups that combined of treated with (KMno4+Vitamin C). There was a normal histological appearance of ovary in control group, the treatment with 1000 mg/70kg vitC. b wt showed an increase in the blood flow within the parenchyma of ovary representing congestion of blood vessels and numerous of growing follicles and huge graffian follicles. While treatment with different doses of KMno4 resulted in appearance of few number of growing follicles and huge graffian follicles. These results highlighted the involvement of the oxidative stress in female infertility and confirmed the benefits of the use of antioxidants in the medication of this condition, not only to improve the environment of follicles, but also to modulate female infertility hormonal profile.
... Therefore, large amounts of antioxidants have been administered in these studies in order to achieve the maximum benefi t of their effects. 7,8 Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; also referred to as MCI-186), a newly synthesized antioxidant, has a unique pharmacological action (Fig. 1); it can act as a hydroxyl radical scavenger 9,10 and has antioxidant effects against both the hydroxyl radical and iron-dependent lipid peroxidation. 11,12 Recently, edaravone has been used to treat patients with cerebral infarction, and its neuroprotective effects are undisputed. ...
Cardioplegic arrest has been the main mechanism of myocardial protection during open-heart surgery; however, it causes myocardial injury during ischemia-reperfusion. Free radical scavengers are widely known to attenuate ischemia-reperfusion injury in various settings. We investigated the effects of edaravone, a novel free radical scavenger that was originally used for cerebral protection, on myocardial function during ischemia-reperfusion after cardioplegic arrest. Rat hearts were excised and perfused using Langendorff apparatus. The hearts were cardioplegically arrested for 90 min using St. Thomas’ Hospital cardioplegic solution (ST solution) at 4°C every 45 min and then reperfused for 20 min. The hearts were divided into 4 groups (n = 13 in each group). In Group ST, the hearts were arrested using the ST solution alone. In Groups L, M, and H, the hearts were arrested using the ST solution supplemented with a low-dose (1 μM), moderate dose (10 μM), and high dose (100 μM) of edaravone, respectively. Left ventricular function (+dp/dt max) and the levels of the cardiac enzymes released were measured before and after cardioplegic arrest. At the end of the study, the water content and the tissue oxidative stress (8-hydroxy-2′-deoxyguanosine) of the heart were measured. During reperfusion, the edaravone-treated groups showed a greater functional recovery with regard to the +dp/dt max (P P P P
... The most recent randomized controlled trial found a reduction in postoperative atrial fibrillation comparing preoperative ω-3 poly-unsaturated fatty acids with vitamin C and vitamin E supplementation with placebo (see Table 2) [95]. An older Chinese study using a very high dose of intravenous vitamin C (250 mg/kg) found less cardiac injury, better cardiac performance and shorter intensive care and hospital stay [101]. ...
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.
... Clinically, the antioxidant effect of vitamin C has been studied in some surgical models. A study done by Dingchao et al., reported that MDA, creatinine phosphokinase (CPK-MB) and lactate dehydrogenase (LDH) levels decreased following the administration of high-dose vitamin C in patients undergoing open heart surgery which may offer some protection for cardiac muscle [31]. ...
Background: During tourniquet induced ischemic reperfusion, reactive oxygen species and cytokines appear and cause cellular damage and remote tissue injury.
Aim: To compare the effects of preoperative intravenous infusion of N-acetyl cysteine or ascorbic acid on the production of malonyldialdehyde as a marker of oxidative stress and IL-6 and IL-8 as markers of systemic inflammation after ischemic reperfusion as primary outcomes. Also both agents were compared regarding post-deflation hemodynamic effects and post-deflation changes in arterial pH and lactic acid as secondary outcomes.
Patient and methods: 60 patients, scheduled for unilateral lower extremity surgery with a pneumatic tourniquet, were included. The study was designed as a randomized controlled parallel arms superiority trial. Baseline collection of blood samples was done and then patients were randomly classified into three groups: Group A; received 1 g Ascorbic acid, group N; received 10 mg/kg NAC and group C (control group): received 100 ml saline infusion. Epidural anesthesia was administrated. Two blood samples were drawn at each assessment time. One sample for arterial blood pH and lactic acid measurement and the other blood sample was centrifuged and stored at −20 °C for subsequent analysis of MDA, IL-6 and IL-8.
Results: Levels of MDA, IL-6, and IL-8 were significantly increased in group C after tourniquet release compared with the baseline. In groups A and N, MDA did not increase over baseline values, but IL-6 and IL-8 levels were increased and their levels were significantly less than in the control group. Changes in hemodynamics, pH and serum lactate were more evident in group C than groups A and N.
Conclusion: Both N-acetyl cysteine and ascorbic acid reduce post-deflation increase in blood levels of markers of oxidative stress and markers of systemic inflammation and thus both are beneficial in preventing post-tourniquet deflation ischemic reperfusion injury in lower limb surgery.
... Antioxidant vitamins have been tested for efficacy in suppressing diseases related to ROS. Some reports have demonstrated that vitamin C attenuates ischemiareperfusion injury 18 and cardiovascular disorders. 19 Vitamin E inhibits ROS chain reactions and lipid peroxidase. ...
Inflammatory or oxidative stress is related to various diseases, including not only inflammatory diseases, but also diabetes, cancer, and atherosclerosis. The aim of this study was to evaluate the anti-inflammatory effects of a new enteral diet, MHN-02, which contains abundant antioxidants and whey peptide. The study also investigated the ability of MHN-02 to attenuate lethality, liver injury, the production of inflammatory cytokines, and the production of oxidized products using a carbon tetrachloride-induced rat model of severe fulminant hepatitis.
Male Sprague-Dawley rats were fed either a control diet or the MHN-02 diet for 14 days and injected with 2 mL/kg of carbon tetrachloride. Survival of rats was monitored from day 0 to day 3. To evaluate liver injury, inflammation, and oxidative stress, blood and liver samples were collected, and aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, interleukin 6, tumor necrosis factor-α, and superoxide dismutase activity as a free radical scavenger were measured. A portion of the liver was evaluated histologically.
The survival rates of rats receiving the MHN-02 diet and the control diet were 90% and 55%, respectively. In the MHN-02 diet group, levels of serum liver enzymes and serum cytokines were significantly lower than in the control group. Superoxide dismutase activity in the MHN-02 diet was significantly higher in the MHN-02 group. Pathological lesions were significantly larger in the control group.
Supplementation of enteral diets containing whey peptide and antioxidants may protect against severe hepatitis.
... Ascorbic acid (AA) is a water-soluble, physiological, extracellular antioxidant that acts as a rapid primary defence against aqueous radicals in the blood [22, 301. It has been used in human cardiopulmonary bypass [5] and in renal transplantation models in animals [6, 151 with promising results. Studies on AA in human renal transplantations are scarce [9]. ...
The cadaveric renal graft is exposed to ischaemic injury during preservation and to oxidative damage during reperfusion. Both these mechanisms are known to cause cell damage, which may impair graft function. Reperfusion injury (RPI) is mediated by reactive oxygen species (ROS). Ascorbic acid (AA) is a potent physiological extracellular scavenger of ROS. We perfused 31 renal grafts immediately before implantation with a solution of Euro-Collins containing 0.5 mg/ml of AA to diminish RPI. From every donor, the contralateral kidney served as a control. The control grafts were perfused with the same perfusion as those of the AA group, only without the AA substitution. We assessed the effect of AA by recording serum creatinine, creatinine clearance, initial graft function and early rejections. The incidence of delayed graft function (DGF) was 32% in the AA group, and 29% in the control group. Other parameters were also similar in both groups, except for the length of DGF, which showed a trend towards a shorter duration in the AA group. The pre-operative systemic AA concentration was significantly ( P=0.01) lower in the haemodialysis patients than in those on peritoneal dialysis. In conclusion, this clinical study could not demonstrate significant benefits of AA in renal transplantation.
... A postoperatively lowered plasma concentration of ascorbic acid (AA) has been shown previously (1)(2)(3)(4)(5) and is interpreted as part of oxidative stress. Oxidative stress is de ned as an imbalance of increased pro-oxidants (radicals, etc.) and reduced antioxidants (vitamins, etc.) (6). ...
was significantly increased in postoperative patients compared with preoperative values. These results are consistent with the postulated increase in perioperative AA consumption. Keywords: ascorbic acid, operation, surgery, vitamin C.
... 20 Mice can synthesize this vitamin from glucose by L-gulonolactone oxidase, 21 but the body stores of vitamins C and E rapidly decrease during liver IR. 22 The efficacy of vitamin C supplementation for treating lung injury associated with sepsis in a mouse model has been reported. 23 In the field of IRI, Dingchao et al 24 reported that high-dose vitamin C (250 mg/kg) protects the myocardium from IR after cardiopulmonary bypass. ...
Background
Liver ischemia and reperfusion injury (IRI) is a major problem associated with liver surgery. This study is aimed to compare the preventive effect of an antioxidative nutrient‐rich enteral diet (Ao diet) with an ordinal enteral diet (control diet) against liver IRI.
Methods
The Ao diet was an ordinary diet comprising polyphenols (catechin and proanthocyanidin) and enhanced levels of vitamins C and E. Male C57BL/6 mice were fed the Ao or control diet for 7 days before ischemic insult for 60 minutes, followed by reperfusion for 6 hours. The levels of inflammatory cytokines, chemokines, and antioxidant enzymes and oxidative stress were evaluated.
Results
After 7 days of pretreatment with the Ao diet, the serum levels of vitamins C and E in mice were markedly elevated. The levels of serum aspartate aminotransferase and alanine aminotransferase, as well as the scores of liver necrosis caused by ischemia and reperfusion, were significantly lower in the Ao diet group than in the control diet group. The gene expression levels of inflammatory cytokines and chemokines, such as interleukin‐6 and CXCL1, were significantly lower in the Ao diet group. In the liver, the levels of antioxidant enzymes superoxide dismutase 1 (SOD1) and SOD2 were significantly higher and the malondialdehyde levels were significantly lower in the Ao diet group. Cell adhesion molecule expression was significantly lower, and neutrophil and macrophage infiltration was less in the Ao diet group.
Conclusions
Antioxidative nutrient supplementation to an ordinary enteral diet may mitigate liver IRI by causing an antioxidant effect and suppressing inflammation.
... Baker 2016 [11] Meta-analysis 5 Carnes 2001 [44] No randomization and retrospective control group 6 Das 2016 [45] Use of inappropriate medication in control group (antacid instead of placebo) 7 Dingchao 1994 [46] No randomization, "divided into two groups" 8 Ebade 2014 [47] No randomization, "divided into three equal groups" 9 Hemilae 2017 [13] Systematic review and meta-analysis 10 Hill 2018 [4] Review 11 Hu 2017 [14] Meta-analysis 12 Kumar 2013 [48] Meta-analysis 13 Li 1990 [49] Randomization strategy not mentioned in abstract. Full text not accessible, attempts to contact author unsuccessful. ...
Background:
Cardiac surgery is associated with oxidative stress and systemic inflammation, which both contribute to postoperative organ dysfunction. Vitamin C is a pleiotropic, antioxidant, and potentially organ-protective micronutrient. Past clinical trials and meta-analyses have focused predominantly on occurrence of postoperative atrial fibrillation. Therefore, we investigated the influence of perioperative vitamin C administration on clinically relevant parameters closer related to the patient's recovery, especially organ function, and overall outcomes after cardiac surgery.
Methods:
Randomized controlled trials (RCTs) comparing perioperative vitamin C administration versus placebo or standard of care in adult patients undergoing cardiac surgery were identified through systematic searches in Pubmed, EMBASE, and CENTRAL on 23 November 2018. Published and unpublished data were included. Assessed outcomes include organ function after cardiac surgery, adverse events, in-hospital mortality, intensive care unit, and hospital length-of-stay. Data was pooled only when appropriate.
Results:
A total of 19 RCTs with 2008 patients were included in this meta-analysis. Vitamin C significantly decreased the incidence of atrial fibrillation (p = 0.008), ventilation time (p < 0.00001), ICU length-of-stay (p = 0.004), and hospital length-of-stay (p < 0.0001). However, on average, vitamin C had no significant effects on in-hospital mortality (p = 0.76), or on the incidence of stroke (p = 0.82). High statistical heterogeneity was observed in most analyses.
Conclusions:
Vitamin C impacts clinically and economically important outcomes, such as ICU and hospital length-of-stay, duration of mechanical ventilation and lowers the incidence of atrial fibrillation. Due to missing reports on organ dysfunction, this meta-analysis cannot answer the question, if vitamin C can improve single- or multiorgan function after cardiac surgery.
... Vitamin C is known to block lipid peroxidation in the cell membrane and scavenge hydroxyl radicals (Zaccaria et al., 1994), and several studies have indicated such protection against reperfusion injury in lung, brain and skin flaps (Zaccaria et al., 1994; Henry and Chandy, 1998; Demertzis et al., 2000). Ascorbic acid was also found to decrease lipid peroxidation in the cell membrane and protect the myocardium against I–R injury (Dingchao et al., 1994). Ascorbic acid was also shown to prevent I–R injury in rat small bowel, in a dose-dependent manner (Nakamura et al., 1997). ...
In this prospective controlled study, the aim was to examine the effects of vitamin C, mannitol and verapamil on adnexial ischaemia-reperfusion injury in the rat ovary.
Thirty-six female Wistar rats were used. In the controls (group 1), only laparotomy was performed. In group 2, ovarian ischaemia was produced and the bilateral ovaries were surgically removed 4 h later. In group 3, an ischaemic period of 4 h was followed by reperfusion for 1 h; the bilateral ovaries were then removed. In groups 4, 5 and 6, after 4 h of ischaemia, either vitamin C, mannitol or verapamil respectively was infused before reperfusion; after 1 h of reperfusion the ovaries were removed. Thiobarbituric acid reactive substance (TBARS) levels were measured in all ovary tissues.
TBARS levels of the reperfusion group were significantly higher than those of groups treated with vitamin C or mannitol (P = 0.013 and P = 0.045 respectively), but not of the verapamil group.
Vitamin C and mannitol were found to be effective in reducing ischaemia-reperfusion injury of the ovary during its early stages, but verapamil was ineffective.
... Because increased oxidative stress during I/R is a major cause of myocardial infarction, the ability of antioxidants to protect against I/R-induced cardiac damage has been tested (Marczin et al. 2003). Several studies have shown that supplementation with vitamin C, vitamin E, or the glutathione (GSH) precursor N-acetylcysteine limits oxidative stress and enhances cardiac function after I/R in animals and patients (Dingchao et al. 1994;Ferrari et al. 1991;Mickle et al. 1991). ...
Opening and closing of voltage-gated cation channels allows the regulated flow of cations such as Na(+), K(+), and Ca(2+) across cell membranes, which steers essential physiological processes including shaping of action potentials and triggering Ca(2+)-dependent processes. Classical textbooks describe the voltage-gated cation channels as membrane proteins with a single, central aqueous pore. In recent years, however, evidence has accumulated for the existence of additional ion permeation pathways in this group of cation channels, distinct from the central pore, which here we collectively name non-canonical pores. Whereas the first non-canonical pores were unveiled only after making specific point mutations in the voltage-sensor region of voltage-gated Na(+) and K(+) channels, recent evidence indicates that they may also be functional in non-mutated channels. Moreover, several channelopathies have been linked to mutations that cause the appearance of a non-canonical ion permeation pathway as a new pathological mechanism. This review provides an integrated overview of the biophysical properties of non-canonical pores described in voltage-dependent cation channels (KV, NaV, Cav, Hv1, and TRPM3) and of the (patho)physiological impact of opening of such pores.
... Research suggests vitamin C may be supportive in the following conditions: hypertension, coronary artery disease, angina, reperfusion injury, atherosclerosis, heart failure, acute myocardial infarction, obstructive sleep apnoea, Behçet's syndrome, and Kawasaki disease. [76][77][78][79][80][81][82][83][84][85] Clinical trials investigating these conditions consistently found that vitamin C improved flowmediated vasodilation (FMD). Several of the studies also found that vitamin C infusions given during major surgery, such as a cardiopulmonary bypass, resulted in fewer post-operative complications. ...
... Oxidative stress after cardiac surgery contributes to myocardial stunning and arrhythmias. High-dose i. v. vitamin C administered before CPB and after aortic declamping decreased oxidative stress and myocardial injury [38]. Preoperative ingestion of vitamin E and C supplements attenuated markers of oxidative stress and inhibited ischemic electrocardiographic alterations [39]. ...
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 .
Publisher Summary This chapter focuses on three aspects of Vitamin C—recent studies where a change in the status of vitamin C is associated with a disease state, evidence regarding the proposed mechanism(s) for the observed changes in vitamin C status in disease states, and the effectiveness of vitamin C as a therapeutic or preventative agent. In normal, healthy tissues, dehydroascorbic acid generally appears to be recycled immediately back to ascorbic acid. Maintenance of a high ratio of ascorbic acid to dehydroascorbic acid in a particular tissue may be an indicator of the health of that tissue; for that a normal recycling between the oxidized and the reduced forms of the vitamin is necessary. Dysfunction in ascorbic acid metabolism might have a role in aging and in diseases such as diabetes, leukemia, ocular disease, and chronic inflammatory diseases. Alterations in vitamin C levels may be because of either a disease-related depletion or an impairment of the recycling mechanisms for ascorbic acid. The implication of dysfunction in recycling implies is that cells and tissues are exposed to low levels of ascorbic acid and elevated levels of dehydroascorbic acid, resulting in increased susceptibility of the cell or tissue to oxidative damage. Researchers in diabetes have found decreased leukocyte, plasma, and selected tissue concentrations of ascorbic acid, and persistently increased concentrations of dehydroascorbic acid. High glucose levels can interfere with the action of ascorbic acid and may explain partially the low levels of ascorbate observed in certain tissues. Ascorbic acid levels were observed to be significantly decreased in mucosa from Crohn's disease and ulcerative colitis patients. The chapter discusses transport and accumulation of Vitamin C, importance and the process of recycling/regeneration of Vitamin C, also existence of a specific dehydroascorbate reductase and a specific semidehydroascorbate reductase. Adequate vitamin C levels are essential in maintaining optimal health.
The transport mechanisms of ascorbic acid (AA) are described. The metabolism of AA and its function as an antioxidant are covered in some detail. Subsequently, indications for postoperative substitution are discussed. The supplementation of up to 300 mg of AA per day in postoperative intensive care unit patients during par-/enteral nutrition is recommended to prevent hypovitaminosis. It is not clear if this is the optimal dosage of AA in postoperative/-trauma patients. New aspects for an AA substitution are discussed.
Reperfusion injury is the leading cause of early graft dysfunction after lung transplantation. Activation of neutrophilic granulocytes with generation of free oxygen radicals appears to play a key role in this process. The efficacy of ascorbic acid as an antioxidant in the amelioration of reperfusion injury after lung transplantation has not been studied yet.
An in situ autotransplantation model in sheep is presented. The left lung was flushed (Euro-Collins solution) and reperfused; after 2 hours of cold storage, the right hilus was then clamped (group R [reference], n = 6). Group AA animals (n = 6) were treated with 1 g/kg ascorbic acid before reperfusion. Controls (group C, n = 6) underwent hilar preparation and instrumentation only.
In group R, arterio-alveolar oxygen difference (AaDO2) and pulmonary vascular resistance (PVR) were significantly elevated after reperfusion. Five of 6 animals developed frank alveolar edema. All biochemical parameters showed significant PMN activation. In group AA, AaDO2, PVR, work of breathing, and the level of PMN activation were significantly lower.
The experimental model reproduces all aspects of lung reperfusion injury reliably. Ascorbic acid was able to weaken reperfusion injury in this experimental setup.
Augmentation of antioxidant defenses may help protect tissues against ischemia-reperfusion injury associated with operations involving cardiopulmonary bypass. In this study we examined the effect of pretreating patients with alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on injury to the myocardium. Seventy-six subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo-controlled randomized trial, receiving either placebo or both 750 IU dl-alpha-tocopherol per day for 7 to 10 days and 1 gm ascorbic acid 12 hours before the operation. Plasma alpha-tocopherol concentrations, raised fourfold by supplementation, fell by 70% after the operation in the supplemented group and to negligible levels in the placebo group. There were no significant differences between the groups with respect to release of creatine kinase MB isoenzyme over 72 hours, nor in the reduction of the myocardial perfusion defect determined by thallium 201 uptake. Electrocardiography provided no evidence of a benefit from antioxidant supplementation. Thus the supplementation regimen prevented the depletion of the primary lipid soluble antioxidant in plasma, but provided no measurable reduction in myocardial injury after the operation.
Herzchirurgische Eingriffe prädisponieren zu einer postoperativen systemischen Entzündungsreaktion (SIRS). Das ausgedehnte chirurgische Trauma, die Ischämie mit nachfolgender Reperfusion während extrakorporaler Zirkulation und der Fremdoberflächenkontakt durch Einsatz der HLM tragen dazu bei.
Trotz Fortschritten auf den Gebieten der Pharmakologie, der Perfusions-Technologie, des kardiovaskulären Monitorings und der anästhesiologischen und chirurgischen Techniken kommt es bei einem kleinen Teil der Patienten zu einer schweren SIRS, dessen Ausmaß mit der Anzahl postoperativer Komplikationen korreliert und in abgeschwächter Form bei jedem Patienten auftritt.
Ziel dieser Arbeit war es, den Einfluss des ω-3-haltigen Omegaven® auf die systemische Entzündungsreaktion im Vergleich zu Sojabohnenöl zu untersuchen. Da für den Einsatz von ω-3-Fettsäuren ein hemmender Effekt bei der Entstehung einer SIRS und der beteiligten Mediatoren in einer Reihe von Studien belegt wurde, war eine Studie zum Einfluss auf den Katecholamin- und Volumenbedarf von Bedeutung. Dafür wurde eine randomisierte, doppelblinde, plazebokontrollierte Interventionsstudie an 40 kardiochirurgischen Patienten durchgeführt, die sich einer Bypass-Operation unterzogen. Die Probanden der Verumgruppe erhielten perioperativ vier Infusionen mit Omegaven®, um einen schnellen Einbau in die Zellmembran zu gewährleisten.
Die Gesamtmenge der applizierten Katecholamine in den ersten 48 Stunden nach Operation war in der Verumgruppe merklich geringer als in der Plazebogruppe, allerdings war der Unterschied statistisch nicht signifikant.
Die Flüssigkeitsbilanz und die Volumensubstitution waren in beiden Gruppen nahezu identisch. Auch die anderen Wirksamkeitsparameter wie kardiale Arrhythmien, Volumengabe, maschinelle Beatmung, hämodynamische Parameter, Intensiv- und Krankenhausverweildauer und die Erfassung der Erkrankungsschwere durch SAPS II und TISS Score zeigten keine relevanten Unterschiede zwischen den Behandlungsgruppen.
Insgesamt lässt sich feststellen, dass die meisten Patienten dieser Arbeit präoperativ eine normale kardiale Pumpfunktion und keine wesentlichen Begleiterkrankungen hatten und damit kein erhöhtes Risiko für das Auftreten eines SIRS bestand.
Eine Reihe von Autoren haben eine eingeschränkte linksventrikuläre Pumpfunktion (EF <40%) und ein verlängertes chirurgisches Prozedere (HLM-Dauer > 97 min) als die wesentlich Risikofaktoren für das Auftreten eines SIRS beschrieben. Sicherlich wäre der Katecholaminbedarf bei der Wahl einer Patientengruppe mit höherer Einschränkung der EF von unter 40 % wesentlich höher.
Neben den relativ gesunden Patienten ist die geringe Fallzahl dieser Singlecenter Studie bestimmt limitierender Faktor für ihre Aussagekraft. Anstelle der ungünstigen Datenerhebung durch ein Singlecenter wäre eine größere Fallzahl mit einem Multicenter-Design und Patienten, die ein höheres Risiko für die Entstehung einer SIRS haben, zu fordern.
Die Anwendersicherheit und Verträglichkeit von ω-3-Fettsäuren an kardiochirurgischen Patienten konnte auch in dieser Studie bestätigt werden. So waren die AEs in Bezug auf die Gesamtzahl aller Patienten und dem geringen Anteil dieser mit AEs in beiden Gruppen vergleichbar. Jedoch waren das Auftreten und die Art unterschiedlich. Bei den meisten Patienten der Plazebogruppe traten die AEs während der Behandlungsphase mit Studienmedikation in Form von Vorhofflimmern auf. Innerhalb der Verumgruppe traten hingegen die AEs meist nach der Behandlungsphase mit Studienmedikation auf und konnten oft in Verbindung mit chirurgischer Intervention und Wundheilungsstörungen gebracht werden. Eine Reihe dieser AEs wie Hämorrhagie, Hämatominfektion und Perikarderguß können mit einer veränderten Blutgerinnung in Zusammenhang gebracht werden, wie sie gewöhnlicherweise nach HLM auftritt. Trotz dem sonst als günstig beschriebenen Einfluss von ω-3-Fettsäuren auf kardiovaskuläre Erkrankungen und die Blutgerinnung traten diese AEs vermehrt in der Verumgruppe auf.
Dem unterschiedlichen Zeitpunkt für das Auftreten von AEs, insbesondere dem Einfluss auf eine Entstehung von Vorhofflimmern, sollte in Zukunft mehr Aufmerksamkeit geschenkt werden. Ein protektiver Einfluss für das Entstehen von Vorhofflimmern ist in letzter Zeit bereits in mehreren Studien bestätigt worden.
Zusammenfassend lässt sich sagen, dass auch diese Arbeit die gute Verträglichkeit und den positiven Einfluss von Omegaven® auf die systemische Entzündungsreaktion bei herzchirurgischen Bypass-Patienten bestätigt.
Ziel der vorliegenden Arbeit war, die Auswirkungen unregelmäßiger Fütterungen auf den antioxidativen Status des Pferdes zu untersuchen. Weiterhin sollte die Stabilität der antioxidativen Parameter TEAC, ACW, GPX und SOD bei unterschiedlicher Aufbereitung bzw. unterschiedlich langer Lagerung vor Aufbereitung der Proben bestimmt werden.
We performed animal experiments to test the hypothesis that active oxygen species (AOS) play a major role in adjuvant-induced arthritis in rats and to determine whether large-dose ascorbic acid administration would suppress the development of arthritis, reducing the level of damaging AOS in the same animal model. Arthritis was induced in male Lewis rats by adjuvant injection into the base of the tail. Ascorbic acid at doses of 0.5, 1.0, and 2.0 g/kg body weight (BW) was injected intraperitoneally twice each week for 3 weeks (9 rats per group). The BW, hind paw edema, and arthritis score of the extremities were monitored during the period. On day 21, synovial tissues obtained from the ankle joints were examined histologically and for the activity of superoxide dismutase (SOD). The SOD activity in the red blood cells (RBC) was also measured. The arthritic control rats showed significant increases in paw volume and arthritis score from day 11. These changes were dose-dependently reduced by ascorbic acid administration. The infiltration of inflammatory cells into the synovial tissues was markedly decreased by ascorbic acid. The increases in SOD activities produced by the adjuvant injection were significantly reduced in both the synovium and the RBC at ascorbic acid doses of 1.0 and 2.0 g/kg BW. In conclusion, large-dose ascorbic acid administration reduced the increases in hind paw inflammatory edema, arthritis in the extremities, and infiltration of the inflammatory cells into the synovial tissue in the adjuvant-induced arthritis rats. Since these anti-arthritic effects were associated with a decrease in SOD activities in both the synovium and RBC, the decrease in SOD activity could be one of the mechanisms underlying the suppressive effects of large-dose ascorbic acid on the development of arthritis in this animal model, inhibiting the damaging AOS.
This study investigated the effects of high-dose vitamin C on oxygen free radical production and cardiac enzymes after tourniquet application and ischaemia-reperfusion injury during bilateral total knee replacement (TKR) in elderly patients. In the vitamin C (VC) group (VC group, n = 16), during surgery, patients received a priming bolus of 0.06 g/kg vitamin C with 100 ml saline followed by 0.02 g/kg vitamin C mixed with 30 ml saline, intravenously. The control group (n = 16) received no intra-operative vitamin C. In the VC group, malondialdehyde levels were lower, and arterial oxygen tension and mean blood pressure were higher, than in controls after post-operative deflation of both knee tourniquets. Troponin I levels were lower in the VC group than in controls 8 h post-operation. Administering high-dose vitamin C during bilateral TKR could prevent oxygen free radical production and a decline in arterial oxygen tension and mean blood pressure induced by ischaemia-reperfusion injury, thereby protecting the myocardium.
The objective of this study was to investigate the effects of dopamine as vasodilator, vitamin C as an antioxidant and combined administration of them on ischaemia-reperfusion (I-R) injury following testicular torsion (TT). Thirty adult male rats were divided into six groups each containing five rats. Testicular ischaemia was achieved by twisting the left testis for 4 h. Group 1 was for determination of the basal values. Group 2 had 4 h TT. Group 3 had 4 h TT and was then treated with dopamine. Group 4 had 4 h TT and was then treated with vitamin C. Group 5 had 4 h TT and was then treated with dopamine and vitamin C. Group 6 was designed as a sham operated group. Testicular torsion caused a significant decrease in the percentage of spermatogenesis and seminiferous tubules diameters compared with the control and sham groups. Administration of dopamine, vitamin C and their combination increased above mentioned parameters and decreased serum malondialehyde levels significantly. However, vitamin C had better results than the other treatments (P < 0.05). In conclusion, a potent antioxidant like vitamin C was found to be more effective than increasing blood flow by a vasodilator like dopamine on improving I-R injury following TT.
Ventricular Assist Devices (VADs) have been used as bridges to heart transplantation. However, VAD circulation is complicated by the incidence of thromboembolism, prolonged bleeding, and activation of the inflammatory cascade. We hypothesize that platelet and neutrophil activation are interrelated and linked to the activation of the glycoprotein (GP) IIb/IIIa platelet receptor. The purpose of this study is to evaluate the effects of Tirofiban, a platelet GP IIb/IIIa receptor inhibitor, on platelet and neutrophil activation during simulated VAD circulation. Two groups of five in vitro VAD circuits were simulated with and without Tirofiban using 450 cc of human blood. Blood samples were drawn at specific time intervals up to 72 hours, measuring leukotriene C4 (LTC4), platelet factor four (PF4), and neutrophil elastase. Tirofiban decreased serum levels of PF4 and LTC4 during VAD circulation. Neutrophil elastase secretion was not affected by Tirofiban administration. Preconditioning of VAD circulation with Tirofiban attenuated platelet activation as demonstrated by a decrease in serum PF4 levels. Tirofiban administration ameliorates the inflammatory response by altering platelet-neutrophil interaction as demonstrated by a decrease in LTC4 production. Continued elastase secretion indicates that the inflammatory response is not completely inhibited by Tirofiban administration. These results suggest that neutrophils may be activated by alternative mechanisms. Early complement activation has been demonstrated during in vivo and in vitro VAD circulation and may play a role in mediating inflammatory and thromboembolic reactions during VAD use.
Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.
In acute myocardial ischemia (AMI) the optimal treatment is rapid revascularization by angioplasty or pharmacological thrombolysis. While this is essential to resuscitate the ischemic myocardium, it results in further reperfusion injury and extension of the infarction. The main hypothesis for the mechanism of reperfusion injury is the generation of reactive oxygen species (ROS) to such a degree that endogenous antioxidant mechanisms are overcome and tissue injury results. There is growing evidence that ROS-induced injury may continue for weeks to months as a result of activation of apoptosis. In the longer term, this may result in ventricular remodeling and cardiac failure. Although a number of antioxidants have produced beneficial effects in animal models of AMI, none have proved efficacious in subsequent clinical trials. Drugs that are more specific for the source of ROS generation and that are better able to target the sources of oxidant stress may have greater potential for the prevention of reperfusion injury.
As a non-toxic endogenous antioxidant, the semi-essential amino acid taurine is a potential attenuator of oxidative damage
such as that produced by ischaemia-reperfusion injury. Ischaemia-reperfusion injury is a well established if paradoxical phenomenon
whereby ischaemic tissue, doomed to necrosis if it is not reperfused, is actually further damaged by oxidative attack when
perfusion is restored.
This chapter is a review of the literature concerning therapeutic strategies in ischaemia-reperfusion injury, including non-pharmacological
and pharmacological interventions. There is consistent experimental evidence of an important role of taurine in ischaemia-reperfusion
injury, with a clinical role emerging in human trials of taurine administered prior to coronary artery bypass grafting and
heart valve surgery.
Keywordsantioxidants-ischaemia-reperfusion injury-lipid peroxidation-oxidative stress-reperfusion-taurine
Ischemia and reperfusion (I/R) leads to oxidative stress with free radical formation. With respect to liver surgery and transplantation this can lead to deleterious clinical effects. Protection of the liver against I/R injury is of major concern. Thus, in this study, we examined the effect of an antioxidant vitamin solution (vitamin E, C and ß-carotene) on warm I/R injury. Twelve pigs of the German landrace (7 animals in the vitamin group and 5 untreated controls) were examined in this animal model. Twenty-four hours before laparotomy, the vitamin group was initiated with a single intravenous infusion of the vitamin cocktail. The duration of complete warm ischemia of the liver was 4 hours. Serum liver enzyme levels (AST and ALT) and with thiobarbituric acid reacting substances (TBARS) in liver tissue were measured. Furthermore, immunohistochemical staining of oxidative products (oxidized proteins and 4-hydroxy-nonenal = 4-HNE) in liver tissue was made. The maximum accumulation of oxidized proteins was seen six days postoperatively in the controls whereas in the vitamin group only small amounts were seen. 4-HNE showed a marked accumulation in the controls but was almost not detectable in the vitamin group. TBARS were lower in the vitamin group compared to controls. Although the emulsifier necessary for the vitamin solution leads to increased liver enzyme levels in the vitamin group, the values returned to normal more rapidly. Antioxidant vitamins are able to improve warm I/R liver injury. Oxidative stress is directly verifiable at the tissue level. Future animal experiments as well as clinical trials are necessary to explore the optimization of the combination of antioxidative vitamins for the maximum protection from I/R injury. Key words: Ischemia and reperfusion -liver – oxidative stress – antioxidative vitamins.
Cardiac surgery is accompanied by the risk of ischaemia-reperfusion injury to both myocardial and peripheral tissues like the kidney due to the generation of oxygen-derived free radicals. Supplementation with chain-breaking antioxidants may trap free radicals and help protect tissues from injury. We therefore examined the effect of pre-treating cardiac surgery patients with α-tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on a hypoxia-sensitive tissue, the renal proximal tubule. Sixty-nine subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo controlled randomized trail, receiving either placebo or both 750 IU/dL-α-tocopherol per day for 7-10 days, and 1 g ascorbic acid 12 h prior to surgery. Plasma α-tocopherol concentrations fell from elevated to normal levels in the supplemented group and from normal to negligible levels in the placebo group. Renal tubular markers (N-acetyl-β-D-glucosaminidase, adenosine deaminase binding protein, and γ-glutamyl transpeptidase) increased significantly relative to creatinine in both groups following surgery (P > 0.001). However, there were no differences between the two patient groups. Thus, although antioxidant supplementation prior to cardiac surgery prevented the depletion of the primary lipid-soluble antioxidant in plasma (α-tocopherol), renal tubular injury was not measurably reduced.
Acetaminophen (paracetamol) continues to be one of the leading, international over-the-counter analgesics. Unlike the COX-2 inhibitors, no adverse cardiovascular effects have been associated with acetaminophen usage in safe, therapeutic dosages. There are few rigorous physiological investigations of its actions/mechanisms of action. Several investigations, in recent years, have questioned its potential activity in the mammalian cardiovascular system. Our laboratory has found some positive salutary effects in myocardial ischemia/reperfusion injury and during myocardial infarction. In addition, another laboratory found concomitant cardioprotective effects during the acute phase of myocardial infarction. They report similar effects of the ability of acetaminophen to reduce the severity of myocardial infarction and ultimately result in improved mortality rates. They also postulate that this attenuation in myocardial damage is mediated through antioxidant means. Others have not found similar results but have reported no detrimental cardiovascular actions of acetaminophen in experimental animals. The inconsistency in results probably reflects multiple differences in experimental approaches, including use of different species, different experimental preparations, different drug concentrations, and different routes/modes of administering/preparing the drug. The current review focuses on this recent research and tries to provide new perspectives for future investigations. In particular, we have identified new cellular/subcellular targets at which acetaminophen might be acting. These include matrix metalloproteinases and the mitochondrial permeability transition pore. Future work will help identify additional tissue/organ actions of acetaminophen and its as-yet-unknown mechanisms of action.
Toxic oxygen free radicals (OFRs) are produced after ischemia-reperfusion injury, which can be observed during cardiopulmonary bypass (CPB). In a pilot study conducted in a tertiary care pediatric intensive care unit, we sought to determine plasma malondialdehyde (MDA) levels, a marker of OFR production, in children undergoing CPB, and to relate the findings to gastric intramucosal pH and PCO2 (pHi, PiCO2) and serum lactate. Thirteen nonconsecutive children (age: 56 ± 58 months) were included in the study. After induction of general anesthesia and endotracheal intubation, a tonometer nasogastric tube was positioned in the stomach; gastric pHi and PiCO2, arterial PCO2 (PaCO2), MDA, and lactate were measured 1 hour later (time 0) and 1 to 48 hours after initiation of CPB (times 1, 4, 8, 12, 16, 20, 24, 32, 40, and 48). Data for each variable were compared with baseline values for statistical significance. Free MDA levels increased by more than 50% in 11 patients (85%) and a statistically significant difference was found between the highest and the baseline free MDA concentrations (p < .0025). Low gastric pHi after the first 8 hours post-CPB was significantly associated with a late rise in MDA levels. A stepwise multivariate regression analysis showed that the highest PiCO2:PaCO2 ratio was correlated to the highest MDA level (p < .0001). A low gastric pHi later than 8 hours after CPB or a high PiCO2: PaCO2 ratio, as observed in this study, may indicate secondary splanchnic hypoperfusion with increased OFR production.
Use of Antioxidants in Intensive Care Patients This article summarizes the available clinical studies regarding an antioxidative treatment in critically ill patients. There are several lines of evidence showing an increased oxidative stress during critical illness. The oxidative damage to cells and tissues possibly contributes to organ failure. Therefore a prophylactic or preventive treatment with antioxidants should reduce the oxidative stress and lead to an improved pathophysiological situation in critically ill patients. The results of the clinical studies found in the literature are contradictory because of heterogeneous patient populations, different antioxidants (single substances or combinations), different quantities, application times, start and/or duration of the study. From the present clinical data no firm conclusion for antioxidative treatment in critically ill patients can be drawn. Nevertheless, there is sufficient evidence from experimental studies suggesting that antioxidative therapy is an interesting treatment concept during critical illness.
Background: Postoperatively lowered ascorbic acid (AA) plasma concentration is postulated to be due to an increased perioperative activity (radical scavenging activity, cofactor for enzymes, etc) and consumption in response to surgical trauma. Objective: To test this hypothesis by measuring total clearance (Cl tot) of AA in plasma. Any alteration in AA consumption would be due to an altered Cl tot of AA in plasma. Unaltered postoperative Cl tot would exclude the postulated theory of an increased perioperative AA consumption. Design: The Cl tot of AA in plasma was calculated for 17 tumour patients undergoing major maxillofacial surgery on the first and third postoperative days compared with the preoperative values after bolus injection of 4 mg kg -1 body weight AA was given intravenously. Blood samples were taken before and 15, 30, 45, 60 and 120 min after injection. AA in plasma was analysed by high-performance liquid chromatography. Results: The concentration of Cl tot [median (25%/75% percentile)] was 10.2 (7.9/12.5) 1 h -1 preoperatively. On the first and third postoperative days [median: 17.6 (10.9/27.9) and 15.3 (12.1/30.5) 1 h -1, respectively] the Cl tot was significantly increased (p < 0.05). Conclusions: Cl tot was significantly increased in postoperative patients compared with preoperative values. These results are consistent with the postulated increase in perioperative AA consumption.
Background:
Several antioxidants have been found to have conflicting results in attenuating myocardial reperfusion injury. These studies were done primarily in experimental protocols that did not approximate clinical situations.
Objective:
The aim of this study was to test the efficacy of 3 different antioxidants (ascorbic acid [AA], desferrioxamine, and N-acetylcysteine [NAC]) administered IV alone and in combination in a closed-chest pig model.
Methods:
Farm-raised domestic male pigs (aged 3-5 months, weight of 30-35 kg) were assigned to 1 of 5 groups to receive treatment as follows: group A, AA 100 mg/kg; group B, desferrioxamine 60 mg/kg; group C, a loading dose of NAC 100 mg/kg for 20 minutes and a 20-mg/kg maintenance dose; group D, all 3 drugs in combination; and group E, normal saline (control group). The infusion of all drugs was started 15 minutes before and completed 5 minutes after reperfusion, except for the administration of NAC, which was terminated 60 minutes postreperfusion. Myocardial ischemia (45 minutes) and reperfusion (210 minutes) were achieved percutaneously by circumflex artery balloon occlusion. Ejection fraction, left ventricular end-diastolic pressure (LVEDP), flow in the infarcted artery, and all ventricular arrhythmias were recorded. Oxidative stress was estimated by serial measurements of thiobarbituric acid reactive substance (TBARS) concentration in coronary sinus blood. Infarct size was assessed as a percentage of the area at risk (I/R ratio) using the tetrazolium red staining method.
Results:
The 25 pigs were divided into 5 groups of 5 pigs each. No significant between-group differences were found in I/R ratio or in oxidative stress (as measured by TBARS concentration). Group C developed significantly more ventricular atrhythmias than the control group (80% vs 0%, P = 0.02). No other differences among groups were found. LVEDP was significantly elevated in all treatment groups (mean LVEDP difference [SD] for group A, 6.0 [1.6] mm Hg; group B, 17.6 [1.9] mm Hg; group C, 3.6 [1.7] mm Hg; group D, 6.8 [3.2] and group E, 5.4 [3.4] mm Hg). LVEDP elevation was found to be significantly higher in group B compared with all the other groups (all, P < 0.001). No significant between-group differences were found in the other parameters measured.
Conclusion:
In this experimental pig model, the antioxidants AA, desferrioxamine, and NAC administered alone or in combination did not reduce the deleterious effects of reperfusion injury and specifically the extent of myocardial necrosis.
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.
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.
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.
The purpose of this investigation is to study the effect of rest duration in interval training and consumption of vitamin C supplement on serum lactate dehydrogenase (LDH) and creatine Phosphokinase (CPK) enzyme concentration. To this end, three groups were selected. The first group had one minute rest between two sets of 400 meters run, the second group had three minutes rest between two sets of 400 meters run and the final group had three minutes rest between two sets of 400 meters run with consumption of vitamin C supplement. The data of the research were analyzed using spss10 software. To test research hypothesis, descriptive statistics with 0.05 significant level and deductive statistics were used. Statistic tests applied were T-test and ANOVA. Each group consisted of ten participants. Results of the investigation indicate that serum CPK and LDH enzymes increasing significantly due to physical activity. Also rest duration did not have significant effect on concentration of serum CPK. The result also showed that the group with more rest time had lower concentration of these enzymes. Vitamin C consumption caused a significant decrease in serum CPK level.
The heart works without resting, requiring enormous amounts of energy to continuously pump blood throughout the body. Because of its considerable energy requirements, the heart is vulnerable to oxidative stress caused by the generation of endogenous reactive oxygen species (ROS). Therefore, the heart has effective regulatory and adaptive mechanisms to protect against oxidative stress. Inherited or acquired mitochondrial respiratory chain dysfunction disrupts energy metabolism and causes excessive ROS production and oxidative stress. The physiological cardiac response to oxidative stress can strengthen the heart, but pathological cardiac responses or altered regulatory mechanisms can cause heart disease. Therefore, mitochondria-targeted antioxidants have been tested and some are used clinically. In this review, we briefly discuss the role of mitochondrial DNA mutations, mitochondrial dysfunction, and ROS generation in the development of heart disease and recent developments in mitochondria-targeted antioxidants for the treatment of heart disease.
The pleiotropic biochemical and antioxidant functions of Vitamin C (Vit C) have recently sparked interest in its application in intensive care. Vit C protects important organ systems such as the cardiovascular, neurologic and renal system during inflammation and oxidative stress. Vit C also influences the systems of coagulation and inflammation and its application might prevent the development of organ damage. The current evidence of Vit C’s effect on the pathophysiological reactions during various acute stress events, such as sepsis, shock, trauma, burn and ischemia-reperfusion injury imposes the question, if the application of Vit 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 Vit C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between Vit C and clinical health outcomes are reviewed with special emphasis on its application in cardiac surgery. Additionally, this review pragmatically discusses evidence regarding the administration of Vitamin C in every day clinical practice, tackling the issues of safety, monitoring, dosage and most the appropriate application strategy.
Objective:
To conduct a pilot feasibility and physiologic efficacy study of high-dose vitamin C in patients with vasoplegia after cardiac surgery.
Design:
Prospective, double-blind, randomized, controlled trial.
Setting:
Two tertiary intensive care units (ICUs).
Participants:
Post-cardiac surgery patients with vasoplegia.
Interventions:
The authors randomly assigned the patients to receive either high-dose intravenous vitamin C (1,500 mg every 6 hours) or placebo. The primary outcome was time from randomization to resolution of vasoplegia. Secondary outcomes included total norepinephrine equivalent dose in the first 2 days, ICU length of stay, ICU mortality, and in-hospital mortality.
Measurements and main results:
The authors studied 50 patients (25 patients in each arms). The mean (standard deviation) time to resolution of vasoplegia was 27.0 (16.5) hours in the vitamin C group versus 34.7 (41.1) hours in the placebo group (mean decrease with vitamin C of 7.7 hours, 95% confidence interval -10.5 to 25.9, p = 0.40). The median (interquartile range) norepinephrine equivalent dose in the first 2 days was 64.9 (23.5-236.5) µg/kg versus 47.4 (21.4-265.9) µg/kg in the vitamin C and placebo group (p = 0.75). The median duration of ICU admission was similar (1.4 [0.5-2.5] days and 1.5 [0.5-3.3] days in the vitamin C and placebo group; p = 0.36). Only 1 patient, in the vitamin C arm, died.
Conclusion:
In patients with post-cardiac surgery vasoplegia, high-dose vitamin C infusion was feasible, appeared safe, and, within the limitations of a pilot study, did not achieve statistically faster resolution of vasoplegia.
Feeding a cholesterol-rich diet (0.3%) to rabbits resulted in an intimal thickening and lipid infiltration of the aorta. The prostacyclin production by the vascular endothelium was significantly decreased, after a transient increase after 2 weeks of diet. The arachidonic acid metabolism in platelets was hardly changed. Addition of a low dose vitamin C (150 mg/day) to the cholesterol rich diet resulted in decreased lipid infiltration and intimal thickening and the transient increase of the prostacyclin production was postponed to the 4th week. Although this dose of vitamin C could not restore the decreased prostacyclin production observed after 6 weeks diet, a higher dose of vitamin C (600 mg/day), besides its beneficial effect on the lipid infiltration and the intimal thickening in the thoracic aorta, kept the intimal prostacyclin production at normal levels for at least 8 weeks.
Serum malanodialdehyde (MDA) levels in 40 smokers and 23 non-smokers belonging to different age groups were estimated. The MDA levels were high in smokers of all age groups having a history of smoking for less than 10 years. MDA levels, however, were not elevated in smokers with a history of smoking for more than 10 years. These results are discussed and are interpreted as suggestive that MDA might alter the LDL and lead to deposition of cholesterol in arterial wall macrophages explaining thereby the risk of ischaemic heart disease in cigarette smokers.
We strongly support the original intriguing hypothesis of Hearse et al. that the oxygen paradox and the calcium paradox are facets of the same problem. We would propose that the major similarity is a final common pathway leading to intracellular calcium overload and the sequelae of the resultant increase in intracellular calcium. In addition, we would propose that the oxygen paradox and ischemic/reperfusion injury are also facets of the same problem with the major similarity being the reintroduction of molecular oxygen to a previously hypoxic myocardium. Finally, we would suggest that the common pathway leading to intracellular calcium overload in the oxygen paradox and ischemic/reperfusion injury and to a lesser extent the calcium paradox involves the generation of oxygen free radicals. The source of oxygen free radical generation in the calcium paradox is perhaps less obvious than in the oxygen paradox. It is proposed that during calcium-free perfusion, calcium is leached from the plasmalemma of the myocyte. There is a resulting increase in membrane fluidity. Within the plasmalemma are a number of calcium sensitive phospholipases. Upon reperfusion with a calcium replete medium, calcium could pool around these membrane bound phospholipases initiating a chain reaction of lipid peroxidation which actually is perpetuated by free radical generation (Equations 5A-5C). Lipid peroxidation opens channels within the plasmalemma rendering a 'leaky' sarcolemma. It is through these channels that calcium could flow down its concentration gradient into the cell. The increased calcium accumulation at the mitochondria would lead to an uncoupling of oxidative phosphorylation. With depleted energy stores, the mitochondria and sarcoplasmic reticulum no longer serve as calcium sinks. This would contribute to the calcium overload seen upon reperfusion. The role of oxygen free radical production would appear to occur during the hypoxic phase of the oxygen paradox and the ischemic phase of ischemic/reperfusion injury and during the reoxygenation/reperfusion phases. With the onset of hypoxia and/or myocardial ischemia there is an increase in reducing equivalents, disturbance and dissociation of intramitochondrial electron transport and release of ubisemiquinone, flavoproteins and superoxide radicals. The increase in reducing equivalents includes NADPH and, in ischemia, catecholamines, hypoxanthine and an increase on xanthine oxidase activity. All of these substrates are capable of participating in free radical production. This increase in free radical production in ischemic tissue is enhanced by acidosis which in the ischemic and hypoxic myocardium approaches pH 6.0-6.4.(ABSTRACT TRUNCATED AT 400 WORDS)