Major surgery and the immune system: from pathophysiology to treatment.

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of the immune response to major surgery, and the ways in which it may be modulated to improve postoperative outcomes. RECENT FINDINGS: Data from patients who have undergone a variety of tissue injuries (surgery, burns, sepsis, trauma) have shown the presence of a conserved 'genomic storm' that alters the leukocyte transcriptome, with upregulation of the innate immune response and concomitant downregulation of the adaptive immune response. The innate and adaptive immune systems are often regarded largely distinct. However, more recent evidence suggests there are critical connections between the two arms of the immune response, whereby innate immune cells are able to suppress the adaptive response. SUMMARY: The immune system is critical to the host response to tissue injury occurring due to surgery. However, the physiological processes required to resolve the surgical insult can also contribute to sequelae such as cognitive decline, pneumonia and acute kidney injury. Our understanding of the immune pathogenesis underlying these complications is improving, leading to interest in the development of immunomodulatory therapies, which aim to permit host defence whilst ameliorating postoperative complications

ARDS subphenotypes: searching for Rorschach among the roentgenograms?

In 1967, Ashbaugh and colleagues first described acute respiratory distress syndrome (ARDS) - an acute illness, characterised by tachypnoea, hypoxaemia and loss of lung compliance occurring after a variety of pulmonary and non-pulmonary insults (including trauma, acute pancreatitis, viral pneumonitis)1. This concept is retained as the ARDS illness model within the current consensus definitions, with acute defined as within 7 days of insult, and hypoxaemia categorised using partial pressure of oxygen/fraction of inspired oxygen concentration (PaO2/FiO2 ratio) into mild (5 cm water2.MS-H is supported by the National Institute for Health Research Clinician Scientist Award (NIHR-CS-2016-16-011). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the UK National Institute for Health Research or the Department of Health. ACM is supported by an MRC Clinician Scientist Fellowship (MR/V006118/1)

Towards an ecological definition of sepsis: a viewpoint

In critically ill patients with sepsis, there is a grave lack of effective treatment options to address the illness-defining inappropriate host response. Currently, treatment is limited to source control and supportive care, albeit with imminent approval of immune modulating drugs for COVID-19-associated lung failure the potential of host-directed strategies appears on the horizon. We suggest expanding the concept of sepsis by incorporating infectious stress within the general stress response of the cell to define sepsis as an illness state characterized by allostatic overload and failing adaptive responses along with biotic (pathogen) and abiotic (e.g., malnutrition) environmental stress factors. This would allow conceptualizing the failing organismic responses to pathogens in sepsis with an ancient response pattern depending on the energy state of cells and organs towards other environmental stressors in general. Hence, the present review aims to decipher the heuristic value of a biological definition of sepsis as a failing stress response. These considerations may motivate a better understanding of the processes underlying “host defense failure” on the organismic, organ, cell and molecular levels

Statin therapy in critical illness : an international survey of intensive care physicians' opinions, attitudes and practice

Background Pleotropic effects of statins on inflammation are hypothesised to attenuate the severity of and possibly prevent the occurrence of the host inflammatory response to pathogen and infection-related acute organ failure. We conducted an international survey of intensive care physicians in Australia, New Zealand (ANZ) and United Kingdom (UK). The aims of the survey were to assess the current prescribing practice patterns, attitudes towards prescribing statin therapy in critically ill patients and opinions on the need for an interventional trial of statin therapy in critically ill patients. Methods Survey questions were developed through an iterative process. An expert group reviewed the resulting 26 items for face and content validity and clarity. The questions were further refined following pilot testing by ICU physicians from Australia, Canada and the UK. We used the online Smart SurveyTM software to administer the survey. Results Of 239 respondents (62 from ANZ and 177 from UK) 58% worked in teaching hospitals; most (78.2%) practised in ‘closed’ units with a mixed medical and surgical case mix (71.0%). The most frequently prescribed statins were simvastatin (77.6%) in the UK and atorvastatin (66.1%) in ANZ. The main reasons cited to explain the choice of statin were preadmission prescription and pharmacy availability. Most respondents reported never starting statins to prevent (65.3%) or treat (89.1%) organ dysfunction. Only a minority (10%) disagreed with a statement that the risks of major side effects of statins when prescribed in critically ill patients were low. The majority (84.5%) of respondents strongly agreed that a clinical trial of statins for prevention is needed. More than half (56.5%) favoured rates of organ failure as the primary outcome for such a trial, while a minority (40.6%) favoured mortality. Conclusions Despite differences in type of statins prescribed, critical care physicians in the UK and ANZ reported similar prescription practices. Respondents from both communities agreed that a trial is needed to test whether statins can prevent the onset of new organ failure in patients with sepsis

Butyrate Supplementation Exacerbates Myocardial and Immune Cell Mitochondrial Dysfunction in a Rat Model of Faecal Peritonitis

Mitochondrial dysfunction and immune cell dysfunction are commonplace in sepsis and are associated with increased mortality risk. The short chain fatty acid, butyrate, is known to have anti-inflammatory effects and promote mitochondrial biogenesis. We therefore explored the immunometabolic effects of butyrate in an animal model of sepsis. Isolated healthy human volunteer peripheral mononuclear cells were stimulated with LPS in the presence of absence of butyrate, and released cytokines measured. Male Wistar rats housed in metabolic cages received either intravenous butyrate infusion or placebo commencing 6 h following faecal peritonitis induction. At 24 h, splenocytes were isolated for high-resolution respirometry, and measurement of mitochondrial membrane potential (MMP), reactive oxygen species (mtROS), and intracellular cytokines (TNF alpha, IL-10) using flow cytometry. Isolated splenocytes from septic and septic butyrate treated rats were stimulated with LPS for 18 h and the effects of butyrate on cytokine release assessed. Ex vivo, butyrate (1.8 mM) reduced LPS-induced TNF alpha (p = 0.019) and IL-10 (p = 0.001) release by human PBMCs. In septic animals butyrate infusion reduced the respiratory exchange ratio (p < 0.001), consistent with increased fat metabolism. This was associated with a reduction in cardiac output (p = 0.001), and increased lactate (p = 0.031) compared to placebo-treated septic animals (p < 0.05). Butyrate treatment was associated with a reduction in splenocyte basal respiration (p = 0.077), proton leak (p = 0.022), and non-mitochondrial respiration (p = 0.055), and an increase in MMP (p = 0.007) and mtROS (p = 0.027) compared to untreated septic animals. Splenocyte intracellular cytokines were unaffected by butyrate, although LPS-induced IL-10 release was impaired (p = 0.039). In summary, butyrate supplementation exacerbates myocardial and immune cell mitochondrial dysfunction in a rat model of faecal peritonitis