Mitochondrial Dysfunction in Critical Illness: Implications for Nutritional Therapy.

PURPOSE OF THE REVIEW: This paper will review the evidence for mitochondrial dysfunction in critical illness, describe the mechanisms which lead to multiple organ failure, and detail the implications of this pathophysiologic process on nutritional therapy. RECENT FINDINGS: Mitochondria are particularly sensitive to increased oxidative stress in critical illness. The functional and structural abnormalities which occur in this organelle contribute further to the excessive production of reactive oxygen species and the reduction in generation of adenosine triphosphate (ATP). To reduce metabolic demand, mitochondrial dysfunction develops (a process likened to hibernation), which helps sustain the life of the cell at a cost of organ system failure. Aggressive feeding in the early phases of critical illness might inappropriately increase demand at a time when ATP production is limited, further jeopardizing cell survival and potentiating the processes leading to multiple organ failure. Several potential therapies exist which would promote mitochondrial function in the intensive care setting through support of autophagy, antioxidant defense systems, and the biogenesis and recovery of the organelle itself. Nutritional therapy should supplement micronutrients required in the mitochondrial metabolic pathways and provide reduced delivery of macronutrients through slower advancement of feeding in the early phases of critical illness. A better understanding of mitochondrial dysfunction in the critically ill patient should lead to more innovative therapies in the future.

Cannabinoid CB1 Receptor Antagonist Rimonabant Decreases Levels of Markers of Organ Dysfunction and Alters Vascular Reactivity in Aortic Vessels in Late Sepsis in Rats.

Sepsis is a life-threatening condition with high mortality rates that is caused by dysregulation of the host response to infection. We previously showed that treatment with the cannabinoid CB1 receptor antagonist rimonabant reduced mortality rates in animals with sepsis that was induced by cecal ligation and puncture (CLP). This improvement in the survival rate appeared to be related to an increase in arginine vasopressin (AVP) levels 12 h after CLP. The present study investigated the effects of rimonabant on organ dysfunction, hematologic parameters, and vascular reactivity in male Wistar rats with sepsis induced by CLP. Intraperitoneal treatment with rimonabant (10 mg/kg, 4 h after CLP) abolished the increase in the plasma levels of lactate, lactate dehydrogenase, glucose, and creatinine kinase MB without altering hematological parameters (i.e., leukopenia and a reduction of platelet counts). CLP increased plasma levels of nitrate/nitrite (NOx) and induced vasoconstriction in the tail artery. The treatment of CLP rats with rimonabant did not alter NOx production but reduced the vasoconstriction. Rimonabant also attenuated the hyperreactivity to AVP induced by CLP without affecting hyporesponsiveness to phenylephrine in aortic rings. These results suggest that rimonabant reduces organ dysfunction during sepsis, and this effect may be related to AVP signaling in blood vessels. This effect may have contributed to the higher survival rate in rimonabant-treated septic animals.

The use of defibrotide in blood and marrow transplantation.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; P = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.

Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi-organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded-access treatment programme (T-IND; NCT00628498). In the completed T-IND, the Kaplan-Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7-61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8-71·6%) and 47·1% (95% CI, 42·3-51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T-IND study was similar to previous reports.

Pharmaconutrition with selenium in critically ill patients: what do we know?

Selenium is a component of selenoproteins with antioxidant, anti-inflammatory, and immunomodulatory properties. Systemic inflammatory response syndrome (SIRS), multiorgan dysfunction (MOD), and multiorgan failure (MOF) are associated with an early reduction in plasma selenium and glutathione peroxidase activity (GPx), and both parameters correlate inversely with the severity of illness and outcomes. Several randomized clinical trials (RCTs) evaluated selenium therapy as monotherapy or in antioxidant cocktails in intensive care unit (ICU) patient populations, and more recently several meta-analyses suggested benefits with selenium therapy in the most seriously ill patients. However, the largest RCT on pharmaconutrition with glutamine and antioxidants, the REducing Deaths due to Oxidative Stress (REDOXS) Study, was unable to find any improvement in clinical outcomes with antioxidants provided by the enteral and parenteral route and suggested harm in patients with renal dysfunction. Subsequently, the MetaPlus study demonstrated increased mortality in medical patients when provided extra glutamine and selenium enterally. The treatment effect of selenium may be dependent on the dose, the route of administration, and whether administered with other nutrients and the patient population studied. Currently, there are few small studies evaluating the pharmacokinetic profile of intravenous (IV) selenium in SIRS, and therefore more data are necessary, particularly in patients with MOD, including those with renal dysfunction. According to current knowledge, high-dose pentahydrate sodium selenite could be given as an IV bolus injection (1000-2000 µg), which causes transient pro-oxidant, cytotoxic, and anti-inflammatory effects, and then followed by a continuous infusion of 1000-1600 µg/d for up to 10-14 days. Nonetheless, the optimum dose and efficacy still remain controversial and need to be definitively established.

Influencia de los simbióticos en la disfunción multiorgánica: ensayo aleatorizado / The influence of symbiotics in multi-organ failure: Randomised trial

Fundamento y objetivo: Valorar si la utilización de simbióticos mejora la evolución del síndrome de disfunción multiorgánica (SDMO), la respuesta inflamatoria, el patrón de colonización y las infecciones en la Unidad de Cuidados Intensivos (UCI). Pacientes y método: Ensayo clínico de grupos paralelos con distribución aleatoria sobre administración durante 7 días de Simbiotic Drink® en pacientes con SDMO. Si existía contraindicación para su administración, pancreatitis o neutropenia, los pacientes fueron excluidos. Las variables evaluadas son: evolución delSequential Organ Failure Assessment (SOFA), valores sanguíneos de lactato, fibrinógeno y dímero-D, número de infecciones nosocomiales y patrón de colonización. Resultados: Se incluyeron 89 pacientes, 46 en grupo simbiótico (GS) y 43 en grupo control (GC). La edad mediana fue de 69 años y el 68,5% eran varones. No hubo diferencias en las variables demográficas, puntuaciones de gravedad, variables evolutivas y mortalidad, ni en la evolución del SOFA. El GS presenta menor valor de lactato el segundo día, mayor valor de fibrinógeno los días 5 y 7 y menor valor de los dímeros-D el día 7 de evolución. Se tomaron 895 cultivos para valorar la colonización con 528 gérmenes aislados; no se observaron diferencias en los gérmenes resistentes; en mucosas existió mayor colonización por Candida a partir del tercer día en GC, que desaparece tras el cese de la administración de simbióticos. Veintidós pacientes desarrollaron 33 infecciones en UCI, 14 en el GS (42,4%) y 19 en el GC (57,6%), sin diferencias en los microorganismos, con predominio de candidiasis (4 frente a 0 casos). Conclusiones: La administración de simbióticos presenta una tendencia a mejorar los valores precoces de lactato y los tardíos de fibrinógeno/dímeros-D, y colonización menor por Candida en mucosas. Sin embargo, no tiene influencia en la evolución del SDMO (AU)

Background and objective: To assess whether the administration of symbiotic preparations in patients with multi-organ failure (MOF) diminishes the evolution of the failure, the inflammatory response generated, the colonization pattern and the Intensive Care Unit (ICU) infectious illness. Patients and method: Randomized and controlled trial. All patients with MOF were included. Neutropenia and acute pancreatitis patients were excluded. A symbiotic (Simbiotic Drink1) was administered via enteral feeding during the first 7 days. Variables of interest were: Sequential Organ Failure Assessment (SOFA) score evolution, systemic concentrations of lactate, fibrinogen and D-dimer; skin and mucosa colonization and infectious disease register. Results: Eighty-nine patients were included; 46 in the symbiotic group (SG) and 43 in the control group (CG). There were 68.5% males, with a median age of 69 years. There were no significant differences in the patients’ fundamental characteristics (medical history, age, reason for admission, severity scores), nor in the length of ICU stay or in mortality. Comparing the SG with the CG, there were lower lactate levels on the second day, more fibrinogen levels on the days 5 and 7, and lower D-dimer levels on the day 7. Eight hundred and ninety-five cultures were performed for colonization assessment, with isolation of 528 microorganisms. No differences in microbiological resistance were found; there were more colonization in the SG by Candida in mucous membranes after the third day; this situation resolved after stopping symbiotic administration. Twenty-two patients suffered an infectious disease in ICU, 14 in SG (42.4%) and 19 in CG (57.6%). Although no differences were found in the microbiological pattern, there was a predominance of Candida spp. over other microorganisms (4 vs. 0 cases). Conclusions: The symbiotic preparation Simbiotic Drink1, administered in MOF, results in differences to improve the early lactate levels and late fibrinogen/D-dimer levels as well as mucosa colonization by Candida. There were no differences in the ICU evolution (AU)

Microbiota intestinal en el paciente crítico. Una aproximación positiva mediante el aporte de simbióticos / Intestinal microbiota in the critical patient. A positive approach through the contribution of symbiotics

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Supplementation of Nigella sativa fixed and essential oil mediates potassium bromate induced oxidative stress and multiple organ toxicity.

The plants and their functional ingredients hold potential to cure various maladies and number of plants hold therapeutic potential. The present research was designed study the health promoting potential of black cumin (Nigella sativa) fixed oil (BCFO) and essential oil (BCEO) against oxidative stress with special reference to multiple organ toxicity. For the purpose, thirty rats (Strain: Sprague Dawley) were procured and divided into three groups (10 rats/group). The groups were fed on their respective diets i.e. D1 (control), D2 (BCFO @ 4.0%) and D3 (BCEO @ 0.30%) for a period of 56 days. Mild oxidative stress was induced with the help of potassium bromate injection @ 45 mg/Kg body weight. Furthermore, the levels of cardiac and liver enzymes were assayed. The results indicated that oxidative stress increased the activities of cardiac and liver enzymes. However, supplementation of BCFO and BCEO was effective in reducing the abnormal values of enzymes. Elevated levels of lactate dehydrogenase (LDH), CPK and CPK-MB were reduced from 456 to 231, 176 to 122 and 45 to 36mg/dL, respectively. Similarly, liver enzymes were also reduced. However, the results revealed that BCEO supplementation @ 0.30% is more effectual in ameliorating the multiple organ toxicity in oxidative stressed animal modelling. In the nutshell, it can be assumed that black cumin essential oil is more effective in reducing the extent of potassium bromate induced multiple organ toxicity (cardiac and liver enzymes imbalance) that will ultimately helpful in reducing the extent of myocardial and liver necrosis.

Bench-to-bedside review: metabolism and nutrition.

Acute kidney injury (AKI) develops mostly in the context of critical illness and multiple organ failure, characterized by alterations in substrate use, insulin resistance, and hypercatabolism. Optimal nutritional support of intensive care unit patients remains a matter of debate, mainly because of a lack of adequately designed clinical trials. Most guidelines are based on expert opinion rather than on solid evidence and are not fundamentally different for critically ill patients with or without AKI. In patients with a functional gastrointestinal tract, enteral nutrition is preferred over parenteral nutrition. The optimal timing of parenteral nutrition in those patients who cannot be fed enterally remains controversial. All nutritional regimens should include tight glycemic control. The recommended energy intake is 20 to 30 kcal/kg per day with a protein intake of 1.2 to 1.5 g/kg per day. Higher protein intakes have been suggested in patients with AKI on continuous renal replacement therapy (CRRT). However, the inadequate design of the trials does not allow firm conclusions. Nutritional support during CRRT should take into account the extracorporeal losses of glucose, amino acids, and micronutrients. Immunonutrients are the subject of intensive investigation but have not been evaluated specifically in patients with AKI. We suggest a protocolized nutritional strategy delivering enteral nutrition whenever possible and providing at least the daily requirements of trace elements and vitamins.

Las formas de nutrición en los pacientes graves y el síndrome de disfunción múltiple de órganos / The forms of nutrition in the serious patients and the syndrome of multiple dysfunction of organs

Las formas de nutrición han sido relacionadas en el desarrollo del síndrome de disfunción múltiple de órganos (SDMO). Por esta razón decidimos identificar la presencia del SDMO y las formas de nutrición. Se realizó un estudio longitudinal retrospectivo, de tipo descriptivo en pacientes fallecidos en la UCI del ISMM Dr. Luis Díaz Soto y que recibieron soporte nutricional. Se estudió la mucosa intestinal, para determinar la presencia de atrofia de las vellosidades intestinales y el estado de los folículos linfoides en el intestino delgado. Se estudiaron 86 pacientes de los cuales 46 presentaron SDMO (53,4 por ciento) y 40 no portadores (46,6 por ciento). No se encontró diferencia estadística significativa en las variables edad, sexo, estadía, y el ingreso calórico proteico. Comparando los 2 grupos se destaca que aquellos que no presentaron SDMO y no tuvieron linfocitos escasos o atrofia de las vellosidades recibieron de forma predominante nutrición enteral. Los pacientes con afecciones quirúrgicas presentaron con mayor frecuencia SDMO y alteraciones microscópicas de la mucosa. La condición de haberse sometido a una intervención quirúrgica y recibir la nutrición de forma parenteral aumenta las probabilidades de presentar este síndrome

Soporte nutricional del paciente crítico / Nutritional support of the critical patient

La sobrevida de los pacientes con grandes fallas orgánicas ha sido demostrada con las modernas técnicas de monitoreo y soporte de sistemas y órganos vitales. Un factor importante que mejora la recuperación del paciente crítico, es la preservación del estado nutricional. El rol de la nutrición como una modalidad de soporte de vida, es discutido en muchos aspectos, pero esta controversia tal vez se daba ala heterogeneidad de los estados de enfermedad agrupadas bajo el término "enfermedades críticas". El profesional a cargo del soporte nutricional de un paciente injuriado, debe conocer la respuesta metabólica al trauma y a la sépsis, focalizando su atención en las alteraciones metabólicas de los sustratos regionales y de todo el organismo. De esta manera podrá intervenir eficazmente con el tratamiento en el período inicial, en la fase hipermetabólica y durante la recuperación. El propósito de este y futuros artículos, es proveer lineamientos prácticos para el manejo nutricional de los pacientes críticos, presentando recientes descubrimientos con relevancia en modalidades actuales y futuras de tratamiento (AU)

Soporte nutricional del paciente crítico / Nutritional support of the critical patient

La sobrevida de los pacientes con grandes fallas orgánicas ha sido demostrada con las modernas técnicas de monitoreo y soporte de sistemas y órganos vitales. Un factor importante que mejora la recuperación del paciente crítico, es la preservación del estado nutricional. El rol de la nutrición como una modalidad de soporte de vida, es discutido en muchos aspectos, pero esta controversia tal vez se daba ala heterogeneidad de los estados de enfermedad agrupadas bajo el término "enfermedades críticas". El profesional a cargo del soporte nutricional de un paciente injuriado, debe conocer la respuesta metabólica al trauma y a la sépsis, focalizando su atención en las alteraciones metabólicas de los sustratos regionales y de todo el organismo. De esta manera podrá intervenir eficazmente con el tratamiento en el período inicial, en la fase hipermetabólica y durante la recuperación. El propósito de este y futuros artículos, es proveer lineamientos prácticos para el manejo nutricional de los pacientes críticos, presentando recientes descubrimientos con relevancia en modalidades actuales y futuras de tratamiento