Young Investigators Ushering in a New Era of Sepsis Management: From the Microbiome and Toll-Like Receptors to Cerebral Autoregulation

Christian S. Guay, MD

Despite significant progress in the diagnosis and management of sepsis, which affects approximately 1.7 million adults in the United States each year, this heterogeneous condition still contributes to more than 250,000 deaths yearly. Thankfully, young investigators are sustaining long-term efforts to better understand sepsis and decrease its deadly toll, highlighted in a session cosponsored by the Early-Stage Anesthesiology Scholars (eSAS), “Sepsis Research from Bench to Bedside – Insights from Young Investigators,” on Sunday, April 16 at the IARS 2023 Annual Meeting.

Mara Serbanescu, MD, Assistant Professor of Anesthesiology at Duke University, opened the session by exploring how the microbiome contributes to the development of postoperative sepsis. A patient’s microbiome is influenced by multiple perioperative factors, including preoperative diet, lifestyles and medications, intraoperative exposure to opioids, antibiotics, surgical stress and high concentrations of oxygen, and postoperative fasting, medications and antibiotics. Dr. Serbanescu presented compelling data suggesting that prolonged exposure to 100% FiO₂ can induce the loss of commensal bacteria, thereby shifting the delicate balance of a patient’s microbiome and increasing susceptibility to postoperative complications. Indeed, the microbiome itself influences how a patient metabolizes drugs and glucose, modulates inflammatory responses and susceptibility to pathogens, and in part determines bacterial translocation from the gut and immune reconstitution after sepsis. Although the perioperative microbiome is still a young field, it holds promise in identifying therapeutic targets to modulate perioperative immune responses and decrease the incidence and severity of postoperative sepsis.

Brittney Williams, MD, Associate Professor of Anesthesiology at the University of Maryland, followed with a deep dive into the translation of toll-like receptor (TLR) modulation from bench work to clinical trials. Activation of TLRs induces upregulation of cytokine gene expression during the immune response to pathogens, therefore making them prime targets in the quest to improve outcomes in sepsis. Furthermore, TLRs are highly evolutionarily conserved between mice and humans which increases the efficiency of translation across animal and human studies. Although initial studies focused on the most powerful TLRs, complete blockade of these signalling pathways can also be detrimental. For example, anti-TLR4 monoclonal antibodies can improve survival in an endotoxemia model of sepsis, but complete blockade or deficiency actually increases mortality during polymicrobial sepsis because of resulting coagulopathy and inability to clear bacterial infections. In other words, TLR4 may be too critical for the maintenance of homeostasis to be a viable therapeutic target to attenuate the immune response during sepsis. Therefore, investigators have started to turn their attention towards more downstream receptors such as TLR7, which can effectively be antagonized without compromising vital immune defenses.  

The brain is intimately connected to all other body systems. Therefore, it’s no surprise that cognitive dysfunction is common in septic patients, with estimates for the incidence of sepsis-associated encephalopathy reaching as high as 70%. Although the underlying mechanisms are still poorly understood, oxidative stress, blood brain barrier permeability, direct cytokine neurotoxicity and disrupted cerebral autoregulation have all been implicated. Kathryn Rosenblatt, MD, MHS, Assistant Professor of Anesthesiology and Critical Care and Program Co-Director, Neurosurgical Anesthesia Fellowship at Johns Hopkins University, is developing methods to personalize blood pressure management in septic patients to account for disrupted cerebral autoregulation, thus reducing the incidence of cerebral hypo- and hyperperfusion which have been associated with impaired neurological function.

By correlating cerebral oxygen saturation with mean arterial pressure (MAP) over time, it is possible to determine a measure of cerebral autoregulation: the cerebral oximetry index (COx). A patient’s optimal mean arterial pressure (MAP_OPT) is then defined as the MAP associated with the most robust autoregulation (i.e., lowest COx). This is a significant advance over standard care which aims to keep MAP greater than 65 mmHg for all patients. A pilot trial is investigating if it is feasible to continuously estimate MAP_OPT in the critical care setting, and if time spent outside of MAP_OPT +/- 5 mmHg is associated with clinical outcomes. Preliminary results from the first 65 patients are encouraging and efforts are underway to transition from a purely observational paradigm to an interventional one. Future directions also include combining this method with electroencephalography and machine learning to further personalize cerebral perfusion and improve brain health in septic patients.