Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.
The induction of heme oxygenase-1 (HO-1; Hmox1) by inflammation, for instance in sepsis, is associated both with an anti-inflammatory response and with mitochondrial biogenesis. Here, we tested the idea that HO-1, acting through the Nfe2l2 (Nrf2) transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO-1 induction after LPS stimulated anti-inflammatory IL-10 and IL-1 receptor antagonist (IL-1Ra) expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-␣ expression. This was accompanied by nuclear Nfe2l2 accumulation and led us to identify abundant Nfe2l2 and other mitochondrial biogenesis transcription factor binding sites in the promoter regions of IL10 and IL1Ra compared with pro-inflammatory genes regulated by NF-〉. Mechanistically, HO-1, through its CO product, enabled these transcription factors to bind the core IL10 and IL1Ra promoters, which for IL10 included Nfe2l2, nuclear respiratory factor (NRF)-2 (Gabpa), and MEF2, and for IL1Ra, included NRF-1 and MEF2. In cells, Hmox1 or Nfe2l2 RNA silencing prevented IL-10 and IL-1Ra up-regulation, and HO-1 induction failed post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2 ؊/؊ mice. Nfe2l2 ؊/؊ mice compared with WT mice, showed more liver damage, higher mortality, and ineffective CO rescue in sepsis. Nfe2l2 ؊/؊ mice in sepsis also generated higher hepatic TNF-␣ mRNA levels, lower NRF-1 and PGC-1␣ mRNA levels, and no enhancement of anti-inflammatory Il10, Socs3, or bcl-x L gene expression. These findings disclose a highly structured transcriptional network that couples mitochondrial biogenesis to counter-inflammation with major implications for immune suppression in sepsis.Early survivors of severe sepsis often develop immune suppression (1, 2) and may later die with the multiple organ dysfunction syndrome (3). A key effector of multiple organ dysfunction syndrome is the liver, which is integral to the host response, especially in infections that activate Toll-like receptor 4 and NF-〉-dependent cytokine synthesis (4). The persistence of inflammatory cytokines such as TNF-␣ and IL-1 perpetuates immune activation, causing tissue damage and remodeling (5) and leads to sustained production of anti-inflammatory modulators and suppressors of adaptive immunity (6, 7).These anti-inflammatory modulators include the type II cytokine IL-10, the soluble IL-1 receptor antagonist (sIL-1Ra) 2 (5), and SOCS (suppressor of cytokine signaling) proteins (8). IL-10 is widely expressed in the liver (9, 10) by Kupffer cells (11), stellate cells (12), and hepatocytes (13), where it contributes to LPS tolerance (14). The IL-10 receptor activates JAK/STAT (Janus kinase/signal transducer and activator of transcription) to block the production of TNF-␣ and other NF-〉-dependent mediators (15), the basis for its anti-inflammatory effects (16). IL-10 also suppresses mononuclear cell function (17), and IL-10 secretion by macrophages and neutrophils negatively regulates the respon...
Rationale: Mitochondrial damage is an important component of multiple organ failure syndrome, a highly lethal complication of severe sepsis that lacks specific therapy. Mitochondrial quality control is regulated in part by the heme oxygenase-1 (HO-1; Hmox1) system through the redox-regulated NF-E2-related factor-2 (Nrf2) transcription factor, but its role in mitochondrial biogenesis in Staphylococcus aureus sepsis is unknown. Objectives: To test the hypothesis that Nrf2-dependent up-regulation of the HO-1/carbon monoxide (CO) system would preserve mitochondrial biogenesis and rescue mice from lethal S. aureus sepsis. Methods: A controlled murine S. aureus peritonitis model with and without inhaled CO was examined for HO-1 and Nrf2 regulation of mitochondrial biogenesis and the resolution of hepatic mitochondrial damage. Measurements and Main Results: Sepsis survival was significantly enhanced using inhaled CO (250 ppm once-daily for 1 h), and linked mechanistically to Hmox1 induction and mitochondrial HO activity through Nrf2 transcriptional and Akt kinase activity. HO-1/CO stimulated Nrf2-dependent gene expression and nuclear accumulation of nuclear respiratory factor-1, -2a (Gabpa), and peroxisome proliferator-activated receptor gamma coactivator-1a; increased mitochondrial transcription factor-A and citrate synthase protein levels; and augmented mtDNA copy number. CO enhanced antiinflammatory IL-10 and reduced proinflammatory tumor necrosis factor-a production. By contrast, Nrf2 2/2 and Akt1 2/2 mice lacked CO induction of Hmox1 and mitochondrial biogenesis, and CO rescued neither strain from S. aureus sepsis. Conclusions: We identify an inducible Nrf2/HO-1 regulatory cycle for mitochondrial biogenesis that is prosurvival and counter-inflammatory in sepsis, and describe targeted induction of mitochondrial biogenesis as a potential multiple organ failure therapy.Keywords: Akt/PKB; carbon monoxide; cytokines; oxidative stress; mitochondrial DNA Hospitalization rates for sepsis continue to rise, especially in the elderly (1), and gram-positive bacteria, particularly Staphylococcus aureus species, are responsible for most of the infections (2). Severe sepsis and septic shock cause death from multiple organ failure (MOF) syndrome, most notably when three or more organs fail (3, 4). The pathogenesis of MOF involves damage to mitochondria from immune effectors, such as tumor necrosis factor (TNF)-a (5), and by reactive oxygen species (ROS) and reactive nitrogen species that escape the antioxidant defenses (6). MOF has no specific therapy, but survival is associated with the induction of mitochondrial antioxidant defenses and mitochondrial biogenesis (7,8).The cell's oxidation-reduction (redox) state regulates the antioxidant defenses and broader adaptive genetic responses (9, 10) including those that regenerate mitochondria (11). The induction of mitochondrial biogenesis (12, 13) and the clearance of irreparably damaged organelles by mitophagy (14) are responsible for the maintenance of mitochondrial structure and f...
Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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