Pot beta-blocantele să reducă necesarul intraoperator de agenţi anestezici? Romanian Journal of Anaesthesia and Intensive Care 2015 Vol 22 No 2, 77-78
EDITORIAL II
Benefits of antioxidant supplementation in multi-trauma patients
Reactive oxygen species (ROS), which are continually produced during cellular metabolism, are efficiently eliminated by the body’s endogenous defenses to avoid oxidative stress and its associated damage to membranes, proteins, and nucleic acids. These endogenous defenses consist of enzymatic (superoxide dismutase, catalase, etc.) and non-enzymatic (Vitamin E, Vitamin C, etc.) antioxidants. Conditions such as burns, sepsis, and trauma are thought to overburden the body’s antioxidant defenses with massive ROS loads from hyper-metabolism, neutrophil activation, and ischemiareperfusion injury [1]. In patients who have sustained traumatic injuries, the degree of injury is directly correlated with the level of oxidative stress [2, 3]. As such, critically ill trauma patients belong to a population likely to benefit from antioxidant supplementation. The majority of antioxidant research has focused on mixed populations of critically ill patients. A metaanalysis of 20 randomized control trials found that antioxidant supplementation in mixed patient populations, which contained medical, surgical, trauma, and burn ICU patients, was associated with fewer mechanical ventilation days and reduced mortality in high risk patient groups (> 10% mortality in control group) [4]. Because of the different antioxidant therapies, end points, and patient populations, extrapolation of these findings to trauma patients in particular is difficult. However, the high oxidative stress seen after acute trauma makes critically ill multi-trauma patients an attractive population for additional investigation. One of the few trauma-specific studies found that supplementation with Vitamin E, Vitamin C, and selenium was associated with reduced ICU days, hospital days, Adress for correspondence:
Mark J. Rice, MD Department of Anesthesiology Vanderbilt University Medical Center 1211 Medical Center Drive Nashville, TN 37232, USA E-mail: [email protected]
and mortality [5]. These findings suggest that additional studies specific to the trauma population are warranted. In this month’s Romanian Journal of Anaesthesia and Intensive Care, Bedreag and colleagues [6] studied the relationship between antioxidant therapy (Vitamin C, Vitamin B1 [thiamine], and N-acetylcysteine) and important laboratory values, mechanical ventilation time, length of stay, and mortality in trauma patients. Thirty-four patients were retrospectively divided into a treatment (n = 20) and a control arm (n = 14). Unique to this study was the selection criteria for patient inclusion. Because an Injury Severity Score (ISS) > 16 and a systolic blood pressure < 89 mm Hg were required for inclusion, the current study only included the most critically-ill trauma patients. The treatment group received intravenous antioxidant therapy, and these patients were noted to have significantly lower levels of leukocytosis, urea, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). More importantly, the treatment group was noted to have significantly fewer days of mechanical ventilation and reduced mortality. No difference, however, was noted in the incidence of infection, multi-organ dysfunction, or ICU length of stay. Thus, the antioxidant combination chosen improved outcomes in critically ill, multi-trauma patients. Although the combination of Vitamin C, Vitamin B1, and N-acetylcysteine used by Bedreag and colleagues is unique, each antioxidant has been studied individually in various critically ill populations. Vitamin C is an antioxidant known to be depleted during oxidative stress. High doses of Vitamin C can reduce resuscitation requirements in burn patients [7], but its effects in the trauma population are unclear. One study that included Vitamin C supplementation of trauma patients found a trend towards reduced multi-organ dysfunction, ICU length of stay, and mechanical ventilation days, but no significant differences were otherwise noted [8]. However, most of the patient
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population in this study consisted of young trauma patients with a very low incidence (less than 30%) of shock. It seems likely that the inclusion of patients with low systolic blood pressures in the present study contributed to the noted clinical improvements. Based on these findings, Vitamin C may be more beneficial to higher acuity trauma patients. Vitamin B1 is another antioxidant that may benefit the trauma population. Major trauma has been associated with Vitamin B1 depletion, and Berger et al. showed that supplementation with Vitamin B1, Vitamin C, zinc, and selenium significantly reduced the inflammatory response in trauma patients [9]. While Vitamin B1 supplementation had no effect on the outcomes of burn patients [10], it was noted to decrease lactate levels [11]. Because elevated lactate is associated with poor outcomes in trauma patients, the use of Vitamin B1 may be beneficial in the trauma population and may have facilitated the improved outcomes seen in the current study. Finally, N-acetylcysteine has also been studied in mixed critically ill patient populations. Some data suggest that N-acetylcysteine reduces pulmonary morbidity without affecting ICU length of stay or mortality [12]. Others have shown that N-acetylcysteine increases hepatic blood flow and improves liver function in septic shock [1]. The present study also noted improved respiratory parameters and some element of liver protection with the use of N-acetylcysteine. While N-acetylcysteine’s tendency to promote vasodilation and inhibit platelet aggregation is likely deleterious in acute hemorrhagic shock [13], its association with improved hepatic blood flow may be the reason for the improved liver function tests noted in the current study. The positive findings from mixed ICU populations suggest that trauma patients could benefit from antioxidant therapy. The present study’s use of Vitamin C, Vitamin B1, and N-acetylcysteine further support the use of antioxidants in trauma populations with clear improvement of laboratory parameters. Furthermore, Bedreag and colleagues [6] have shown that this therapy improves survival in the most critical trauma population. However, the mechanism(s) of this treatment have yet to be determined. One intriguing idea is that the combination of thiamine and N-acetylcysteine may help reduce lactate and improve hepatic function. Future studies looking at lactate levels and liver synthetic function would be of interest. While the ideal combination of antioxidants is currently unknown, the low cost, minimal side effects, and improved outcomes associated with antioxidant therapy make nutritional therapy an attractive area for study. As a hallmark of any clinically important study, Bedreag and colleagues’ investigation asks more questions than provides
answers. We look forward to more future studies on the role of antioxidant supplementation therapy in critically ill, multi-trauma patients.
Ryan Parker, MD, PhD and Mark J. Rice, MD Vanderbilt University Medical Center Nashville, TN, USA Conflict of interest Nothing to declare
References 1. Crimi E, Sica V, Williams-Ignarro S, Zhang H, Slutsky AS, Ignarro LJ, et al. The role of oxidative stress in adult critical care. Free Radic Biol Med 2006; 40: 398-406 2. Rael LT, Bar-Or R, Salottolo K, Mains CW, Slone DS, Offner PJ, et al. Injury severity and serum amyloid A correlate with plasma oxidation-reduction potential in multi-trauma patients: a retrospective analysis. Scand J Trauma Resusc Emerg Med 2009; 17: 57 3. Berger MM. Antioxidant micronutrients in major trauma and burns: evidence and practice. Nutr Clin Pract 2006; 21: 43844 9 4. Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care 2012; 16: R66 5. Collier BR, Giladi A, Dossett LA, Dyer L, Fleming SB, Cotton BA. Impact of high-dose antioxidants on outcomes in acutely injured patients. JPEN J Parenter Enteral Nutr 2008; 32: 38438 8 6. Bedreag OH, Rogobete AF, Sărăndan M, Cradigati AC, Păpurică M, Roşu OM, et al. Influence of antioxidant therapy on the clinical status of multiple trauma patients. A retrospective single center study. Rom J Anaesth Int Care 2015; 22: 89-96 7. Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg 2000; 135: 326-331 8. Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002; 236: 814-822 9. Manzanares W, Hardy G. Thiamine supplementation in the critically ill. Curr Opin Clin Nutr Metab Care 2011; 14: 61061 7 10. Soguel L, Chioléro RL, Ruffieux C, Berger MM. Monitoring the clinical introduction of a glutamine and antioxidant solution in critically ill trauma and burn patients. Nutrition 2008; 24(1112): 1123-1132 11. Falder S, Silla R, Phillips M, Rea S, Gurfinkel R, Baur E, et al. Thiamine supplementation increases serum thiamine and reduces pyruvate and lactate levels in burn patients. Burns 2010; 36: 261-269 12. Rinaldi S, Landucci F, De Gaudio AR. Antioxidant therapy in critically septic patients. Curr Drug Targets 2009; 10: 872-880 13. Reddell L, Cotton BA. Antioxidants and micronutrient supplementation in trauma patients. Curr Opin Clin Nutr Metab Care 2012; 15: 181-187
Rom J Anaesth Int Care 2015; 22: 77-78
EDITORIAL II
Benefits of antioxidant supplementation in multi-trauma patients
Reactive oxygen species (ROS), which are continually produced during cellular metabolism, are efficiently eliminated by the body’s endogenous defenses to avoid oxidative stress and its associated damage to membranes, proteins, and nucleic acids. These endogenous defenses consist of enzymatic (superoxide dismutase, catalase, etc.) and non-enzymatic (Vitamin E, Vitamin C, etc.) antioxidants. Conditions such as burns, sepsis, and trauma are thought to overburden the body’s antioxidant defenses with massive ROS loads from hyper-metabolism, neutrophil activation, and ischemiareperfusion injury [1]. In patients who have sustained traumatic injuries, the degree of injury is directly correlated with the level of oxidative stress [2, 3]. As such, critically ill trauma patients belong to a population likely to benefit from antioxidant supplementation. The majority of antioxidant research has focused on mixed populations of critically ill patients. A metaanalysis of 20 randomized control trials found that antioxidant supplementation in mixed patient populations, which contained medical, surgical, trauma, and burn ICU patients, was associated with fewer mechanical ventilation days and reduced mortality in high risk patient groups (> 10% mortality in control group) [4]. Because of the different antioxidant therapies, end points, and patient populations, extrapolation of these findings to trauma patients in particular is difficult. However, the high oxidative stress seen after acute trauma makes critically ill multi-trauma patients an attractive population for additional investigation. One of the few trauma-specific studies found that supplementation with Vitamin E, Vitamin C, and selenium was associated with reduced ICU days, hospital days, Adress for correspondence:
Mark J. Rice, MD Department of Anesthesiology Vanderbilt University Medical Center 1211 Medical Center Drive Nashville, TN 37232, USA E-mail: [email protected]
and mortality [5]. These findings suggest that additional studies specific to the trauma population are warranted. In this month’s Romanian Journal of Anaesthesia and Intensive Care, Bedreag and colleagues [6] studied the relationship between antioxidant therapy (Vitamin C, Vitamin B1 [thiamine], and N-acetylcysteine) and important laboratory values, mechanical ventilation time, length of stay, and mortality in trauma patients. Thirty-four patients were retrospectively divided into a treatment (n = 20) and a control arm (n = 14). Unique to this study was the selection criteria for patient inclusion. Because an Injury Severity Score (ISS) > 16 and a systolic blood pressure < 89 mm Hg were required for inclusion, the current study only included the most critically-ill trauma patients. The treatment group received intravenous antioxidant therapy, and these patients were noted to have significantly lower levels of leukocytosis, urea, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). More importantly, the treatment group was noted to have significantly fewer days of mechanical ventilation and reduced mortality. No difference, however, was noted in the incidence of infection, multi-organ dysfunction, or ICU length of stay. Thus, the antioxidant combination chosen improved outcomes in critically ill, multi-trauma patients. Although the combination of Vitamin C, Vitamin B1, and N-acetylcysteine used by Bedreag and colleagues is unique, each antioxidant has been studied individually in various critically ill populations. Vitamin C is an antioxidant known to be depleted during oxidative stress. High doses of Vitamin C can reduce resuscitation requirements in burn patients [7], but its effects in the trauma population are unclear. One study that included Vitamin C supplementation of trauma patients found a trend towards reduced multi-organ dysfunction, ICU length of stay, and mechanical ventilation days, but no significant differences were otherwise noted [8]. However, most of the patient
78
Parker and Rice
population in this study consisted of young trauma patients with a very low incidence (less than 30%) of shock. It seems likely that the inclusion of patients with low systolic blood pressures in the present study contributed to the noted clinical improvements. Based on these findings, Vitamin C may be more beneficial to higher acuity trauma patients. Vitamin B1 is another antioxidant that may benefit the trauma population. Major trauma has been associated with Vitamin B1 depletion, and Berger et al. showed that supplementation with Vitamin B1, Vitamin C, zinc, and selenium significantly reduced the inflammatory response in trauma patients [9]. While Vitamin B1 supplementation had no effect on the outcomes of burn patients [10], it was noted to decrease lactate levels [11]. Because elevated lactate is associated with poor outcomes in trauma patients, the use of Vitamin B1 may be beneficial in the trauma population and may have facilitated the improved outcomes seen in the current study. Finally, N-acetylcysteine has also been studied in mixed critically ill patient populations. Some data suggest that N-acetylcysteine reduces pulmonary morbidity without affecting ICU length of stay or mortality [12]. Others have shown that N-acetylcysteine increases hepatic blood flow and improves liver function in septic shock [1]. The present study also noted improved respiratory parameters and some element of liver protection with the use of N-acetylcysteine. While N-acetylcysteine’s tendency to promote vasodilation and inhibit platelet aggregation is likely deleterious in acute hemorrhagic shock [13], its association with improved hepatic blood flow may be the reason for the improved liver function tests noted in the current study. The positive findings from mixed ICU populations suggest that trauma patients could benefit from antioxidant therapy. The present study’s use of Vitamin C, Vitamin B1, and N-acetylcysteine further support the use of antioxidants in trauma populations with clear improvement of laboratory parameters. Furthermore, Bedreag and colleagues [6] have shown that this therapy improves survival in the most critical trauma population. However, the mechanism(s) of this treatment have yet to be determined. One intriguing idea is that the combination of thiamine and N-acetylcysteine may help reduce lactate and improve hepatic function. Future studies looking at lactate levels and liver synthetic function would be of interest. While the ideal combination of antioxidants is currently unknown, the low cost, minimal side effects, and improved outcomes associated with antioxidant therapy make nutritional therapy an attractive area for study. As a hallmark of any clinically important study, Bedreag and colleagues’ investigation asks more questions than provides
answers. We look forward to more future studies on the role of antioxidant supplementation therapy in critically ill, multi-trauma patients.
Ryan Parker, MD, PhD and Mark J. Rice, MD Vanderbilt University Medical Center Nashville, TN, USA Conflict of interest Nothing to declare
References 1. Crimi E, Sica V, Williams-Ignarro S, Zhang H, Slutsky AS, Ignarro LJ, et al. The role of oxidative stress in adult critical care. Free Radic Biol Med 2006; 40: 398-406 2. Rael LT, Bar-Or R, Salottolo K, Mains CW, Slone DS, Offner PJ, et al. Injury severity and serum amyloid A correlate with plasma oxidation-reduction potential in multi-trauma patients: a retrospective analysis. Scand J Trauma Resusc Emerg Med 2009; 17: 57 3. Berger MM. Antioxidant micronutrients in major trauma and burns: evidence and practice. Nutr Clin Pract 2006; 21: 43844 9 4. Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care 2012; 16: R66 5. Collier BR, Giladi A, Dossett LA, Dyer L, Fleming SB, Cotton BA. Impact of high-dose antioxidants on outcomes in acutely injured patients. JPEN J Parenter Enteral Nutr 2008; 32: 38438 8 6. Bedreag OH, Rogobete AF, Sărăndan M, Cradigati AC, Păpurică M, Roşu OM, et al. Influence of antioxidant therapy on the clinical status of multiple trauma patients. A retrospective single center study. Rom J Anaesth Int Care 2015; 22: 89-96 7. Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg 2000; 135: 326-331 8. Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002; 236: 814-822 9. Manzanares W, Hardy G. Thiamine supplementation in the critically ill. Curr Opin Clin Nutr Metab Care 2011; 14: 61061 7 10. Soguel L, Chioléro RL, Ruffieux C, Berger MM. Monitoring the clinical introduction of a glutamine and antioxidant solution in critically ill trauma and burn patients. Nutrition 2008; 24(1112): 1123-1132 11. Falder S, Silla R, Phillips M, Rea S, Gurfinkel R, Baur E, et al. Thiamine supplementation increases serum thiamine and reduces pyruvate and lactate levels in burn patients. Burns 2010; 36: 261-269 12. Rinaldi S, Landucci F, De Gaudio AR. Antioxidant therapy in critically septic patients. Curr Drug Targets 2009; 10: 872-880 13. Reddell L, Cotton BA. Antioxidants and micronutrient supplementation in trauma patients. Curr Opin Clin Nutr Metab Care 2012; 15: 181-187
Rom J Anaesth Int Care 2015; 22: 77-78
