Oxidative metabolism in sepsis and sepsis syndrome

The high mortality associated with sepsis syndrome and multiple organ dysfunction syndrome has persisted despite extraordinary research efforts in the laboratory and the intensive care unit. These syndromes produce systemic tissue damage that is likely to result from widespread inflammation and subsequent endothelial injury. This article reviews the oxidative metabolic effects and responses to sepsis syndrome at several levels: the oxygen transport system, the cell, and the mitochondrion. Specifically, aerobic metabolism of carbon substrates and oxygen is altered in sepsis. As a result of systemic inflammation and nonmetabolic oxygen use, oxidative stress may occur both outside and inside the cell. The consequences of these oxidative processes during sepsis may be ongoing cell damage mediated by reactive oxygen and nitrogen oxide species that culminates in multisystem organ failure.     

Oxidative stress in critically ill patients.

Oxygen-derived free radicals play an important role in the development of disease in critically ill patients. Normally, oxygen free radicals are neutralized by antioxidants such as vitamin E or enzymes such as superoxide dismutase. However, in patients who require intensive care, oxygen free radicals become a problem when either a decrease in the removal or an overproduction of the radicals occurs. This oxidative stress and the damage due to it have been implicated in many diseases in critically ill patients. Many drugs and treatments now being investigated are directed toward preventing the damage from oxidative stress. The formation of reactive oxygen species, the damage caused by them, and the body's defense system against them are reviewed. New interventions are described that may be used in critically ill patients to prevent or treat oxidative damage.     

脓毒症氧化应激与抗氧化治疗研究进展

脓毒症(sepsis)是感染引起的全身炎性反应综合征,是急危重患者的严重并发症之一。氧化应激是机体活性氧簇和活性氮簇产生过多或清除能力下降,导致潜在性损伤的病理过程。氧化应激在脓毒症发生、发展中发挥重要作用,早期进行抗氧化干预可能有益于脓毒症防治。丙酮酸乙酯(ethyl pyruvate,EP)是一种稳定的丙酮酸酯类衍生物,它对于发生急性损伤的器官具有显著的保护作用。本文就脓毒症氧化应激与丙酮酸乙酯抗氧化治疗的最新进展作一综述。     

Reactive oxygen species in vascular biology: role in arterial hypertension

The cellular metabolism of oxygen generates potentially deleterious reactive oxygen species, including superoxide anion, hydrogen peroxide and hydroxyl radical. Under normal physiologic conditions, the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between pro-oxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of the overproduction of oxidants that overwhelms the cellular antioxidant capacity. There is growing evidence that increased oxidative stress and associated oxidative damage are mediators of vascular injury in cardiovascular pathologies, including hypertension, atherosclerosis and ischemia–reperfusion. This development has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates by decreasing the generation of reactive oxygen species and/or by increasing availability of antioxidants may be useful in minimizing vascular injury. This review focuses on the vascular actions of reactive oxygen species, the role of oxidative stress in vascular damage in hypertension and the therapeutic potential of modulating oxygen radical bioavailability in hypertension. In particular, the following topics will be highlighted: chemistry and sources of reactive oxygen species, antioxidant defense mechanisms, signaling events mediated by reactive oxygen species, role of reactive oxygen species in hypertension and the putative therapeutic role of antioxidants in cardiovascular disease.     

Intestinal ischemic reperfusion syndrome: pathophysiology, clinical significance, therapy]

Gut ischemia-reperfusion injury is a serious condition in intensive care patients. Activation of immune cells within the huge endothelial surface area of gut microcirculation may initiate a systemic inflammatory response with secondary injury to distant organs. Translocation of bacteria and toxins through a leaky gut mucosa may amplify or perpetuate systemic inflammation, leading to multiple organ dysfunction syndrome and death in critically ill patients. Gut ischemia promotes regional production of inflammatory mediators, expression of cell adhesion molecules on endothelial and immune cell surfaces and increases the procoagulatory properties of vascular endothelial cells. During reperfusion, gut injury may be amplified by increased production of oxygen radicals and exhaustion of endogenous antioxidant defence mechanisms. Although several therapeutic strategies to interrupt the pathophysiology of ischemia-reperfusion have been shown to be beneficial in animal experiments, none of these interventions has gained clinical relevance. After initial hemodynamic and respiratory stabilisation of critically ill patients, strategies to prevent secondary gut injury by increasing splanchnic oxygen delivery or augment mucosal cell regeneration may be the only therapeutic options for intensive medical specialists at the present time. Early enteral nutrition and treatment with specific vasoactive drugs may reduce morbidity and costs of treatment in certain critically ill patients. However definitive evidence of a reduction in mortality with these therapies has still not be provided.     

Oxidative stress in organ preservation: a multifaceted approach to cardioplegia.

Every transplant is a reperfused organ and, therefore, undergoes some degree of oxidative damage. Postischemic reperfusion injury results in non-specific free radical-mediated acute endothelial damage, cell death and organ failure. The endothelium is a key site of injury from reactive oxygen species (ROS), and the endothelial cell dysfunction is central to the pathogenesis of arteriosclerosis. Accelerated arteriosclerosis, secondary to chronic allograft rejection, is a major long-term complication of heart transplantation. Therefore, preservation methods that would decrease injury during reperfusion are very important. We have developed a unique preservation solution, with a multifaceted approach, which best preserves the organ from ROS for an extended period of time before transplantation. The advantages of extending this period of preservation include an expansion of the donor pool, by permitting more distant procurement, the ability to perform detailed tissue typing, therefore, improves histocompatibility match and a reduction in emergency surgery as a result of graft rejection.     

Reactive oxygen species in vascular biology: role in arterial hypertension

The cellular metabolism of oxygen generates potentially deleterious reactive oxygen species, including superoxide anion, hydrogen peroxide and hydroxyl radical. Under normal physiologic conditions, the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between pro-oxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of the overproduction of oxidants that overwhelms the cellular antioxidant capacity. There is growing evidence that increased oxidative stress and associated oxidative damage are mediators of vascular injury in cardiovascular pathologies, including hypertension, atherosclerosis and ischemia-reperfusion. This development has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates by decreasing the generation of reactive oxygen species and/or by increasing availability of antioxidants may be useful in minimizing vascular injury. This review focuses on the vascular actions of reactive oxygen species, the role of oxidative stress in vascular damage in hypertension and the therapeutic potential of modulating oxygen radical bioavailability in hypertension. In particular, the following topics will be highlighted: chemistry and sources of reactive oxygen species, antioxidant defense mechanisms, signaling events mediated by reactive oxygen species, role of reactive oxygen species in hypertension and the putative therapeutic role of antioxidants in cardiovascular disease.     

Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study

Introduction

Critically ill patients suffer from oxidative stress caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Although ROS/RNS are constantly produced under normal circumstances, critical illness can drastically increase their production. These patients have reduced plasma and intracellular levels of antioxidants and free electron scavengers or cofactors, and decreased activity of the enzymatic system involved in ROS detoxification. The pro-oxidant/antioxidant balance is of functional relevance during critical illness because it is involved in the pathogenesis of multiple organ failure. In this study the objective was to evaluate the relation between oxidative stress in critically ill patients and antioxidant vitamin intake and severity of illness.

Methods

Spectrophotometry was used to measure in plasma the total antioxidant capacity and levels of lipid peroxide, carbonyl group, total protein, bilirubin and uric acid at two time points: at intensive care unit (ICU) admission and on day seven. Daily diet records were kept and compliance with recommended dietary allowance (RDA) of antioxidant vitamins (A, C and E) was assessed.

Results

Between admission and day seven in the ICU, significant increases in lipid peroxide and carbonyl group were associated with decreased antioxidant capacity and greater deterioration in Sequential Organ Failure Assessment score. There was significantly greater worsening in oxidative stress parameters in patients who received antioxidant vitamins at below 66% of RDA than in those who received antioxidant vitamins at above 66% of RDA. An antioxidant vitamin intake from 66% to 100% of RDA reduced the risk for worsening oxidative stress by 94% (ods ratio 0.06, 95% confidence interval 0.010 to 0.39), regardless of change in severity of illness (Sequential Organ Failure Assessment score).

Conclusion

The critical condition of patients admitted to the ICU is associated with worsening oxidative stress. Intake of antioxidant vitamins below 66% of RDA and alteration in endogenous levels of substances with antioxidant capacity are related to redox imbalance in critical ill patients. Therefore, intake of antioxidant vitamins should be carefully monitored so that it is as close as possible to RDA.     

Mitochondrial dysfunction in muscle tissue of complex regional pain syndrome type I patients

Reactive oxygen species (ROS) are known to be involved in the pathophysiology of complex regional pain syndrome type I (CRPS I). Since the mitochondrial respiratory chain is a major source of ROS, we hypothesized that mitochondria play a role in the pathophysiology of CRPS I. The hypothesis was tested by studying mitochondrial energy metabolism in muscle tissue from amputated limbs of CRPS I patients. We observed that mitochondria obtained from CRPS I muscle tissue displayed reduced mitochondrial ATP production and substrate oxidation rates in comparison to control muscle tissue. Moreover, we observed reactive oxygen species evoked damage to mitochondrial proteins and reduced MnSOD levels. It remains to be established if the mitochondrial dysfunction that is apparent at the end‐stage of CRPS I is also present in earlier stages of the disease, or are secondary to CRPS I. The observation of a reduced mitochondrial energy production combined with reactive oxygen species induced damage in muscle tissue from CRPS I patients warrants further studies into the involvement of mitochondrial dysfunctioning in the pathophysiology of CRPS I.     

Modulating an oxidative-inflammatory cascade: potential new treatment strategy for improving glucose metabolism, insulin resistance, and vascular function

Type 2 diabetes is a result of derangement of homeostatic systems of metabolic control and immune defense. Increases in visceral fat and organ adipose, environmental factors and genetic predisposition create imbalances of these homeostatic mechanisms, ultimately leading to a condition in which the oxidative environment cannot be held in check. A significant imbalance between the production of reactive oxygen species and antioxidant defenses, a condition called to oxidative stress, ensues, leading to alterations in stress-signalling pathways and potentially end-organ damage. Oxidative stress and metabolic inflammation upregulate the expression pro-inflammatory cytokines, including tissue necrosis factor alpha, monocyte chemoattractant protein-1 and interleukin-6, as well as activating stress-sensitive kinases, such as c-Jun N-terminal kinase (JNK), phosphokinase C isoforms, mitogen-activated protein kinase and inhibitor of kappa B kinase. The JNK pathway (specifically JNK-1) appears to be a regulator that triggers the oxidative-inflammation cascade that, if left unchecked, can become chronic and cause abnormal glucose metabolism. This can lead to insulin resistance and dysfunction of the vasculature and pancreatic beta-cell. The series of events set in motion by the interaction between metabolic inflammation and oxidative stress constitutes an 'oxidative-inflammatory cascade', a delicate balance driven by mediators of the immune and metabolic systems, maintained through a positive feedback loop. Modulating an oxidative-inflammation cascade may improve glucose metabolism, insulin resistance and vascular function, thereby slowing the development and progression to cardiovascular diseases and type 2 diabetes.     

胃黏膜pH值监测对多器官功能障碍的早期预警价值

目的探讨胃黏膜pH值(pHi)监测在早期预测危重患者发生多器官功能障碍综合征中的价值。方法测量20例危重患者入院和入院24 h的胃黏膜pH值,并根据多器官功能障碍综合征诊断标准[1]将患者分为多器官功能障碍组(A组)和非多器官功能障碍组(B组),其中A组又分为2个器官功能障碍组(A1组)和>2个器官功能障碍组(A2组),分别比较A和B组以及A1和A2组的胃黏膜pH值。结果 20例危重患者入住ICU 24 h后发生多器官功能障碍者9例,2个器官功能障碍者4例,>2个器官功能障碍者5例。A组的胃黏膜pH值低于B组(P<0.01),A2组的胃黏膜pH值低于A1组(P<0.01)。结论胃黏膜pH值水平与危重患者发生多器官功能障碍有相关性,是早期预测多器官功能障碍的重要监测指标之一。     

EFFECTIVENESS OF REHABILITATION INTERVENTIONS IN ADULTS WITH MULTIORGAN DYSFUNCTION SYNDROME: A RAPID REVIEW

BackgroundMultiple organ dysfunction syndrome, defined as altered organ function in critically ill patients, is a possible consequence of COVID-19. Investigating the current evidence is therefore crucial in this pandemic, as early rehabilitation could be effective for the functioning of patients with multiple organ failure. This rapid review assesses the effectiveness of rehabilitation interventions in adults with multiple organ dysfunction syndrome.MethodsA rapid review was conducted including only randomised control trials, published until 30 November 2020. All databases were investigated and the results synthesized narratively, evaluating the risk of bias and quality of evidence in all included studies.ResultsA total of 404 records were identified through database searches. After removal of duplicates 346 articles remained. After screening, 3 studies (90 participants) met the inclusion criteria. All studies reported positive effects of neuromuscular electrical stimulation on muscle mass preservation compared with no treatment or standard physiotherapy.ConclusionThe lack of evidence on the effectiveness of rehabilitation interventions does not allow any firm conclusion to be drawn. Neuromuscular electrical stimulation might be a possible rehabilitation intervention to prevent muscle volume loss and improve function in patients with multiple organ dysfunction syndrome. However, further studies are needed to support these preliminary findings.LAY ABSTRACTThis paper synthesizes the current evidence on the effects of rehabilitation interventions in patients with multi-organ dysfunction syndrome. The results show that neuromuscular electrical stimulation may be a feasible treatment to prevent muscle mass loss and increase upper and lower limb strength in this population. Following multi-organ dysfunction syndrome people frequently experience new or worsened disabilities. Therefore, it is relevant to provide the clinician with the best current evidence on treatment that could be applied in the acute phase, in order to enhance the recovery of these patients. This is even more applicable while the COVID-19 pandemic is raging globally, as multi-organ dysfunction syndrome is one of the worst possible consequences of the disease.Key words: multiple organ failure, rehabilitation, rapid review

Multiple organ dysfunction syndrome (MODS) is defined as altered organ function in an acutely ill patient (1). MODS usually involves 2 or more organ systems among the respiratory, cardiovascular, renal, hepatic, gastrointestinal, haematological, endocrine, and central nervous system (2). Once the syndrome has developed, there is no effective therapy for modulating the inflammatory response and reducing the severity of MODS. Therefore, treatment is focused on prevention and treating individual organ dysfunction as it develops, and supportive measures are required (3).The survival of critically ill patients is frequently associated with significant functional impairment and reduced health-related quality of life (4). Although the pathophysiology of MODS is not entirely understood, the dysregulated immune response to critical illness plays a central role in determining the severity of the disease (3). MODS can be classified as primary (immediately after several specific traumas, such as extensive injuries of tissues, hypoxia and the ischaemia-reperfusion syndrome) or secondary (end-stage of a systemic inflammatory response syndrome, commonly involving sepsis) (5). The clinical course of MODS is divided by the Sequential Organ Failure Assessment (SOFA) score system into 4 stages, according to the degree of dysfunction of 6 organ systems (respiration, coagulation, liver, cardiovascular, central nervous system, renal). The SOFA score is instrumental in predicting the outcome (6). Independent of the initial score, an increase in SOFA during the first 48 h in the intensive care unit (ICU) predicts a mortality rate of at least 50% (7). The first clinical objective in MODS is always patient survival. Having assured survival, the objective shifts into improvement in as much as possible of health-related quality of life, reducing any organ dysfunction, and preventing all the possible sequelae of MODS or a long period of hospitalization (8). Therefore, rehabilitation interventions could cover an essential role in the accomplishment of functional recovery.MODS is one of the worst possible manifestations of COVID-19, along with respiratory failure, neurological symptoms, septic shock, or a combination of all of these (9). To date, there is no effective treatment for COVID-19, except for supportive care, including oxygen and mechanical ventilation. As with MODS, severely ill patients with COVID-19 require a lengthy period of hospitalization and experience a massive alteration in their life (10). Due to the similarities, rehabilitation interventions for MODS could also help manage patients with COVID-19. Therefore, a rapid review of rehabilitation interventions for MODS could be highly relevant in the current pandemic, because it is a form of knowledge synthesis that accelerates the process of conducting a traditional systematic review, to produce evidence for stakeholders in a resourceefficient manner under pandemic circumstances (11).This rapid review assessed the effectiveness of rehabilitation interventions on functional outcomes in adults with MODS.     

Bench-to-bedside review: brain-lung interaction in the critically ill--a pending issue revisited

Brain and/or lung injury is the most frequent cause of admission to critical care units and patients in this setting frequently develop multiple organ dysfunction with high rates of morbidity and mortality. Mechanical ventilation is commonly used in the management of these critically ill patients and the consequent inflammatory response, together with other physiological factors, is also thought to be involved in distal organ dysfunction. This peripheral imbalance is based on a multiple-pathway cross-talk between the lungs and other organs, including the brain. Interestingly, acute respiratory distress syndrome survivors frequently present some cognitive deterioration at discharge. Such neurological dysfunction might be a secondary marker of injury and the neuroanatomical substrate for downstream impairment of other organs. Brain-lung interactions have received little attention in the literature, but recent evidence suggests that both the lungs and brain are promoters of inflammation through common mediators. This review addresses the current status of evidence regarding brain-lung interactions, their pathways and current interventions in critically ill patients receiving mechanical ventilation.     

Regional carbon dioxide monitoring to assess the adequacy of tissue perfusion

PURPOSE OF REVIEW: Tissue dysoxia is now widely regarded as the major factor leading to organ dysfunction in critically ill patients. Recent data suggests that early aggressive resuscitation of critically ill patients, which limits and/or reverses tissue dysoxia may prevent progression to organ dysfunction and improve outcome. The traditional clinical and laboratory markers used to assess tissue dysoxia are, however, insensitive and have numerous limitations. Regional carbon dioxide monitoring appears to be ideally suited to monitoring the adequacy of resuscitation. This review provides an update on this evolving technology. RECENT FINDINGS: Gastric intramucosal carbon dioxide as measured by gastric tonometry has proven to be useful as a prognostic marker, in evaluating the response to specific therapeutic interventions and as an end point of resuscitation. Gastric tonometry is, however, cumbersome and has a number of limitations that may have prevented its widespread adoption. The measurement of carbon dioxide in the sublingual mucosa by sublingual capnometry is technically simple, noninvasive, and provides near instantaneous information. Clinical studies have demonstrated a good correlation between gastric intramucosal carbon dioxide and sublingual mucosa carbon dioxide. Sublingual mucosa carbon dioxide responds more rapidly to therapeutic interventions than does gastric intramucosal carbon dioxide and may be a better prognostic marker. SUMMARY: Sublingual capnometry may be the ideal technology for guiding early goal directed therapy. This technology may be useful for monitoring tissue oxygenation, titrating therapeutic interventions, and as an end point for resuscitation in critically ill and injured patients.     

Place des anti-oxydants dans la nutrition du patient septique

Reactive oxygen species are involved in numerous pathological processes. In this review, we report the studies showing that oxidative stress occurs in critically ill patients and we discuss the evidence suggesting that antioxidant treatment might be beneficial for these patients.     

Bench-to-bedside review: Brain-lung interaction in the critically ill – a pending issue revisited

Brain and/or lung injury is the most frequent cause of admission to critical care units and patients in this setting frequently develop multiple organ dysfunction with high rates of morbidity and mortality. Mechanical ventilation is commonly used in the management of these critically ill patients and the consequent inflammatory response, together with other physiological factors, is also thought to be involved in distal organ dysfunction. This peripheral imbalance is based on a multiple-pathway cross-talk between the lungs and other organs, including the brain. Interestingly, acute respiratory distress syndrome survivors frequently present some cognitive deterioration at discharge. Such neurological dysfunction might be a secondary marker of injury and the neuroanatomical substrate for downstream impairment of other organs. Brain-lung interactions have received little attention in the literature, but recent evidence suggests that both the lungs and brain are promoters of inflammation through common mediators. This review addresses the current status of evidence regarding brain-lung interactions, their pathways and current interventions in critically ill patients receiving mechanical ventilation.     

Bench-to-bedside review: Potential strategies to protect or reverse mitochondrial dysfunction in sepsis-induced organ failure

The pathogenesis of sepsis-induced multiple organ failure may crucially depend on the development of mitochondrial dysfunction and consequent cellular energetic failure. According to this hypothesis, interventions aimed at preventing or reversing mitochondrial damage may have major clinical relevance, although the timing of such interventions will be critical to both ensuring benefit and avoiding harm. Early correction of tissue hypoxia, strict control of glycaemia, and modulation of oxidative and nitrosative stress may afford protection during the initial, acute systemic inflammatory response. The regulated induction of a hypometabolic state resembling hibernation may protect the cells from dying once energy failure has developed, allowing the possibility of functional recovery. Repair of damaged organelles through stimulation of mitochondrial biogenesis and reactivation of cellular metabolism may accelerate resolution of the multiple organ failure syndrome.     

Chemical and biological activity of free radical 'scavengers' in allergic diseases

Reactive oxygen species (ROS) are generated constantly in vivo. They can lead to lipid peroxidation and oxidation of some enzymes, as well as protein oxidation and degradation. Cells possess several biological systems, defined as 'scavengers', to protect themselves from the radical-mediated damage. Immune cells may discharge their arsenal of toxic agents against host tissues, resulting in oxidative damage and inflammation. Therefore, free radical production and disturbance in redox status can modulate the expression of a variety of immune and inflammatory molecules, leading to inflammatory processes, both exacerbating inflammation and effecting tissue damage. Recently, abnormal immunity has been related to oxidative imbalance, and antioxidant functions are linked to anti-inflammatory and/or immunosuppressive properties. Currently, allergy is one of the most important human diseases. We studied the role of the primary antioxidant defence system, constituted by the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, protecting cells from toxic oxygen. We analyzed how they are involved in blood cells detoxification, and how the imbalance of reactive oxygen species is related to inflammation in allergic diseases by affecting immune cells. Finally, we discuss the published data that relates anti-free radical therapy to the management of human allergic diseases.     

Oxidative stress and antioxidant defense systems in patients after heart transplantation

Heart transplantation ranks among those surgical interventions associated with ischemia-reperfusion injury to the donor heart as well as to the recipient. These events are connected with increased production of reactive oxygen species which evoke metabolic, structural and functional disturbances. Twenty-four transplant patients were investigated for oxidative stress (plasma levels of thiobarbituric acid reactive substances, TBARS) and antioxidant capacity (plasma total antioxidant status, TAS), and for activities of erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx) during the first year after heart transplantation. The post-transplant period was characterized by progressive decrease of plasma TAS, indicating a significant long-term drop of antioxidant reserves in patients after successful heart transplantation. The decrease in plasma TAS is accompanied by long-lasting increase of TBARS levels, which may represent oxidative stress of the organism. We conclude that additional therapy with antioxidant substances should be an important component of the complex therapeutic programme of patients after heart transplantation.     

Gastric and sublingual capnometry

PURPOSE OF REVIEW: Tissue hypoperfusion is a common pathophysiologic process leading to multiple organ dysfunction and death. Increases in tissue PCO2 can reflect an abnormal oxygen supply to the cells, so that monitoring tissue PCO2 by the use of gastric or sublingual capnometry may help identify circulatory abnormalities and guide their correction. This review provides an update on these technologies. RECENT FINDINGS: Gastric tonometry aims at monitoring PCO2 in the stomach, an organ that becomes ischemic quite early when the circulatory status is jeopardized. Despite substantial initial enthusiasm, this technique has never been widely implemented due to methodological problems. The measurement of sublingual mucosal PCO2 (PslCO2) by sublingual capnometry is technically simple and noninvasive. Experimental studies have suggested that PslCO2 is a reliable marker of tissue perfusion. Clinical studies have demonstrated that high PslCO2 values are associated with impaired microcirculatory blood flow and a worse prognosis in critically ill patients. SUMMARY: Gastric tonometry was proposed for regional PCO2 monitoring, but it is prone to a number of technical limitations. Sublingual capnometry could offer a valuable alternative for tissue PCO2 monitoring in clinical practice, representing a simple, noninvasive method to monitor tissue perfusion and titrate therapeutic interventions in critically ill patients.