Perioperative Organ Failure: A Preventable Complication?

See Articles, p 1667, p 1679, p 1693, p 1708, p 1721, p 1730, p 1751, p 1765, p 1781, p 1789 Advances in training, medication, equipment, and monitoring, as well as implementation of checklists and clinical practice guidelines, made anesthesia steadily safer during the past century.1 Direct anesthesia-related mortality is <1% in the general surgical patient population.2 However, postoperative complications lead to high perioperative mortality, in particular after major surgery and in patients with comorbidities. Perioperative mortality is considered the third-leading cause of death worldwide following cancer and ischemic heart disease.3 It is expected that at least 4.2 million people worldwide die within 30 days of surgery each year.4 The increasing complexity of surgical procedures and an aging population with more comorbidities is associated with a higher incidence of postoperative complications and a failure to recover. These high-risk patients have a worse perioperative outcome.5 However, integrating patient- and procedure-related risk factors into an individualized, perioperative optimization strategy might improve patient’s outcome. Enhanced recovery after surgery (ERAS) programs or the perioperative surgical home concept are effective in improving patient-centered outcomes.6 Although numerous preventive measures have been implemented during the past years, perioperative acute organ dysfunction or injury is a common complication and associated with an increased morbidity and mortality in the perioperative setting.4,7 Perioperative organ dysfunction affects the brain,8 heart,9 lung,10 kidney,11 liver,12 and intestine.13 Dysfunction of these organs is mainly triggered by ischemia and inflammation. An insufficient organ perfusion or the surgical insult during the perioperative period might trigger an inflammatory response that is caused by the release of different proinflammatory chemokines and cytokines. The dysregulated immune response with a prolonged and excessive inflammatory response as well as oxidative stress might lead to tissue damage and organ dysfunction.14 This immunologic imbalance is amplified by hypoxia caused by the immunological activity of recruited leukocytes and an increased oxidative metabolism.15 Hypoxia and inflammation can potentiate each other by bidirectional pathways.16 Although several experimental studies demonstrated that several drugs can be used to prevent or treat organ failure, none of the drugs have been proven effective in clinical trials yet. Therefore, current therapeutic options remain limited to organ-supportive strategies. Further understanding of the molecular mechanisms of organ injury and dysfunction is important to identify novel therapeutic options to ameliorate perioperative care. In this issue on perioperative organ protection, we compiled articles that cover molecular mechanisms as well as clinical implications of various perioperative complications. Based on the knowledge of the molecular mechanisms of different diseases and syndromes, interventions have been developed that substantially improved patient’s care. However, articles in this issue also highlight current knowledge gaps and identify future research topics. Margraf et al17 elaborate on the general mechanisms of a systemic inflammatory response syndrome after surgery. The authors discuss different molecules and signaling pathways that are involved in leukocyte activation and recruitment, endothelial dysfunction, and inflammation-induced tissue destruction or organ dysfunction. In addition, therapeutic options that depend on uncovering the molecular mechanisms of inflammation-induced organ dysfunction are discussed. Mechanisms of perioperative endothelial dysfunction are discussed in the review of Juffermans et al.18 The authors emphasize the pivotal role of the endothelium in the development of organ failure in critically ill patients. Mechanistically, endothelial dysfunction is caused by inflammation, shedding of the glycocalyx, activation of the endothelium, and coagulation system. In addition, the impact of different fluids on the glycocalyx and therapeutic options to protect the integrity of the glycocalyx is reviewed. The article by Conrad and Eltzschig19 summarizes the general aspects of surgical-induced inflammation and tissue hypoxia on patient’s outcome. The inflammation-induced organ dysfunction causes complications that are responsible for the mortality in the perioperative period. As no therapeutic options are currently available to prevent organ dysfunction, the authors discuss recent knowledge of molecular pathways leading to organ injury and exemplify potential therapeutic options in preventing or treating organ injury. The molecular mechanisms and clinical implications of surgery-associated acute kidney injury (AKI) are addressed by Molinari et al20 and Saadat-Gilani et al.21 AKI is a common complication in the perioperative setting and associated with an increased morbidity and mortality. The multifactorial etiology of perioperative AKI suggests different underlying mechanisms. Both articles aim to provide recent findings from studies examining molecular mechanisms, epidemiology, and risk factors of perioperative AKI, as well as different renoprotective strategies. Lung-protective intraoperative ventilation might prevent lung injury and postoperative pulmonary complications, thereby decreasing mortality. However, lung-protective measures such as low tidal volume ventilation might render the patient more prone to atelectasis. Based on recent evidence, Hol et al22 and Ball et al23 critically discuss intraoperative ventilator settings, in particular low tidal volume, positive end-expiratory pressure (PEEP), and a high inspired oxygen fraction (Fio2), aimed at protecting the lung and/or prevent postoperative morbidity and mortality. Pharmacological-induced conditioning encompasses a variety of different substances routinely used in the perioperative setting (eg, volatile anesthetics, noble gases, opioids, propofol, dexmedetomidine, phosphodiesterase inhibitors) and remains a promising strategy in rendering the heart protective against myocardial ischemia and reperfusion injury. Roth et al24 and Torregroza et al25 review various cardioprotective strategies, including ischemic and remote ischemic preconditioning. Essentially, activation of intracellular signaling cascades, including the reperfusion injury salvage kinase and survivor activating factor enhancement pathway, that prevent opening of the mitochondrial permeability transition pore and ultimately avert cell damage are emphasized on. While results from experimental studies have been promising, translating these cardioprotective strategies into the clinical setting remains challenging, presumably due to confounding factors like comorbidities, age, gender, or comedications. Last but not least, the original article by Richards et al26 deals with musculoskeletal trauma. In a retrospective analysis, the authors investigated variables that are associated with late femur fracture fixation and the association between late fracture fixation and the development of multiple organ failure (MOF). In this patient cohort, the authors demonstrated that trauma patients with femur fractures, greater injury severity, and depth of shock are associated with late operative fixation. Late fixation was also associated with MOF. As this is a retrospective study, several limitations apply. Therefore, it remains to be determined whether or not early fixation with concomitant and aggressive intraoperative resuscitation in the setting of elevated serum lactate will improve clinical outcomes and potentially reduce the incidence of MOF. Further investigations are necessary to fully clarify time of operative intervention, the impact of perioperative resuscitation, and MOF in multisystem trauma patients with a femur fracture. DISCLOSURES Name: Alexander Zarbock, MD, PhD. Contribution: This author helped write the manuscript. Conflicts of Interest: A. Zarbock is an Executive Section Editor‚ Basic Science, with Anesthesia & Analgesia. Name: Markus W. Hollmann, MD, PhD, DEAA. Contribution: This author helped write the manuscript. Conflicts of Interest: M.W. Hollmann is an Executive Section Editor‚ Pharmacology, with Anesthesia & Analgesia. This manuscript was handled by: Jean-Francois Pittet, MD.