Immunomodulation in the critically ill

Anaesthesia and Intensive Care, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
BJA British Journal of Anaesthesia (Impact Factor: 4.85). 08/2009; 103(1):70-81. DOI: 10.1093/bja/aep128
Source: PubMed


Immunotherapy in the critically ill is an appealing notion because of the apparent abnormal immune and inflammatory responses seen in so many patients. The administration of a medication that could alter immune responses and decrease mortality in patients with sepsis could represent a 'magic bullet'. Various approaches have been tried over the last 20 yr: steroids; anti-endotoxin or anti-cytokine antibodies; cytokine receptor antagonists; and other agents with immune-modulating side-effects. However, in some respects, research along these lines has been unsuccessful or disappointing at best. The current state of knowledge is summarized with particular reference to sepsis and the acute respiratory distress syndrome.


Available from: Helen F Galley, Oct 23, 2014
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    • "Inhibiting RAGE decreased the levels of multiple pro-inflammatory mediators implicated in the pathophysiology of sepsis and improved short-term survival in rodent models of sepsis6,7. Clinical trials of interventions designed to modulate the immune response to acute insults and sepsis have been disappointing8,9; therefore, inhibition of the RAGE axis could provide another strategy for improving clinical outcome. However, it is unclear whether blockade of RAGE can influence the host immune response and survival secondary to severe burns in vivo. "
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    ABSTRACT: Aim: The receptor of advanced glycation end products (RAGE) participates in a variety of pathophysiological processes and inflammatory responses. The aim of this study was to investigate the therapeutic potential of an anti-RAGE neutralizing antibody for severe thermal injury in rats, and to determine whether the treatment worked via modulating cellular immune function. Methods: Full-thickness scald injury was induced in Wistar rats, which were treated with the anti-RAGE antibody (1 mg/kg, iv) at 6 h and 24 h after the injury. The rats were sacrificed on d 1, 3, 5, and 7. Blood and spleen samples were harvested to monitor organ function and to analyze dendritic cell (DC) and T cell cytokine profiles. The survival rate was analyzed up to d 7 after the injury. Results: Administration of the antibody significantly increased the 7 d survival rate in thermally injured rats (6.67% in the model group; 33.33% in anti-RAGE group). Treatment with the antibody also attenuated the multiple organ dysfunction syndrome (MODS) following the thermal injury, as shown by significant decreases in the organ dysfunction markers, including serum ALT, AST, blood urea nitrogen, creatinine and CK-MB. Moreover, treatment with the antibody significantly promoted DC maturation and T cell activation in the spleens of thermally injured rats. Conclusion: Blockade of the RAGE axis by the antibody effectively ameliorated MODS and improved the survival rate in thermally injured rats, which may be due to modulation of cellular immune function.
    Acta Pharmacologica Sinica 08/2014; 35(9). DOI:10.1038/aps.2014.56 · 2.91 Impact Factor
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    • "Anesthetic procedures are known to interfere with the inflammatory response (21,22). In a previous NOTES trial, Trunzo et al. (19) discussed the possible effects of non-standardization of the duration of anesthesia and suggested that a lack of standardization may have interfered with their results. "
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    ABSTRACT: To investigate the impact of transgastric peritoneal access on plasma biomarkers of acute inflammatory response in comparison to laparoscopy. This was a prospective and comparative study in a porcine model. Transgastric peritoneal access performed by natural orifice transluminal endoscopic surgery was compared with laparoscopy. Laparotomy and sham groups were used as positive and negative controls, respectively. Thirty-four pigs were assigned to receive transgastric natural orifice transluminal endoscopic surgery (n = 12), laparoscopy (n = 8), laparotomy (n = 8) or a sham procedure involving only anesthesia (n = 6). In the natural orifice transluminal endoscopic surgery group, peritoneoscopy was performed with a gastroscope via transgastric access. Blood samples were collected at baseline and 1, 3, 6, 9 and 24 h after the surgical procedure for measurement of interleukins 1β, 6 and 10 and tumor necrosis factor-α. A complete blood count was performed, and C-reactive protein levels were measured at baseline and at 24 h. All surgical and endoscopic procedures were performed without major complications. Peritoneal cavity inventory showed no signs of peritonitis in any animal. Interleukin 1β, interleukin 10 and tumor necrosis factor-α levels were below the threshold of detection. The mean level of interleukin 6 was statistically significantly higher in the laparotomy group than in the other groups (p<0.05), with no significant differences among the sham, laparoscopy and natural orifice transluminal endoscopic surgery groups (p>0.05). C-reactive protein analysis indicated significant increases in all groups, with no differences among the groups. Complete blood count analysis showed no differences among the groups. Based on the observed interleukin 6 patterns, the systemic inflammatory response resulting from transgastric peritoneal access by natural orifice transluminal endoscopic surgery is similar in intensity to the response that occurs after laparoscopy.
    Clinics (São Paulo, Brazil) 11/2013; 68(11):1433-1439. DOI:10.6061/clinics/2013(11)09 · 1.19 Impact Factor
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    • "Animal models of sedatives in sepsis rarely administered vasopressors for hemodynamic support, but it is conceivable that a particular vasopressor-sedative combination may be preferentially chosen to counterbalance their immunomodulating effects or enhance a specific effect. Septic patients frequently receive other immunomodulating therapies, including corticosteroids, drotrecogin, opioid analgesics, propofol, or immunonutrients [17,18]. How these agents interact with alpha-2 agonists or benzodiazepines is unknown, but presumably the use of these modalities was distributed equally in the few clinical studies conducted to date. "
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    ABSTRACT: In a recent issue of Critical Care, Qiao and colleagues showed in a rat model of sepsis that dexmedetomidine and midazolam suppress the generation of pro-inflammatory mediators but the effects vary between agents. While dexmedetomidine limited apoptosis to a greater extent than midazolam, both agents significantly reduced short-term mortality compared with saline. This study, in addition to those by others, suggests there are disparate immunomodulating effects between sedatives. Clinical studies are warranted to investigate whether these effects impact outcomes of septic patients. Perhaps one day the choice of sedative in septic patients will not be based solely on sedative properties but rather immunosedative profiles.
    Critical care (London, England) 10/2009; 13(5):191. DOI:10.1186/cc8034 · 4.48 Impact Factor
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