Postoperative Mortality After Major Surgery

Postoperative mortality

Postoperative mortality is a significant and often under-recognized global health issue. Every year, millions of people undergo life-changing surgical procedures, but a substantial number of them do not survive the recovery period. Recent data suggests that the global rate of postoperative mortality is nearly 8 million deaths per year – a statistic on par with cancer and fatal injuries.1 Anesthesia and major surgery place heavy physiological stress on the body, triggering a cascade of responses, including inflammation, immune suppression, and cardiovascular strain, all of which can increase the risk of complications and postoperative mortality.2

Immediately upon the induction of anesthesia, the body begins experiencing stress. Operationally defined, surgical stress is the body’s acute reaction to disruptions in its protective barriers, caused by sterile injury (including incisions, manipulation, or pain), pathogen invasion (including bacterial translocation from open wounds), and/or the effects of anesthesia. It can also be caused by intraoperative bleeding, coagulation dysfunction, cardiac compromise, metabolic dysregulation, and organ failure. The stress response begins with increased sympathetic activity, which can disrupt bodily homeostasis, leading to inflammation, changes in blood clotting, alterations in immune function and T cell activity, increased vulnerability to infections, and reduced oxygen supply to bodily tissues. This can in turn affect multiple organ systems, increasing the risk of organ dysfunction or failure by interfering with critical networks connecting the brain, heart, lungs, kidneys, liver, gut, and muscles.3 The severity of a patient’s stress response is heavily influenced by the type and duration of surgery, in addition to patient demographics such as age, gender, ethnicity, health status, medication profile, surgical history, and more. Open surgical procedures generally are more likely to cause a stress response than less invasive laparoscopic or robotic surgeries. Major surgery involves much greater physiological disruption, thus increasing the risk of postoperative mortality.

Surgical stress is associated with activation of the central hypothalamic-pituitary adrenal (HPA) axis. This network influences nearly all bodily functions, including cardiovascular, endocrine, immune, inflammatory, thermal, endothelial and metabolic processes.2 HPA axis activation begins when a stressor stimulates the paraventricular nucleus in the hypothalamus to produce corticotropin-releasing hormone (CRH) and vasopressin (VPR), two peptide hormones whose production stimulates the pituitary to release adrenocorticotropic hormone (ACTH), the precursor to cortisol. Cortisol is produced by the adrenal cortex and is often associated with stress. This glucocorticoid can alter cellular signaling, as well as the transcription of a large range of genes involved in immune function, mitochondrial metabolism, inflammation, and cognition. Cortisol can also affect cardiovascular contractions, modulate catecholamines, and suppress the production of vasodilators. As such, an overactive HPA axis can contribute to excessive cortisol levels, resulting in pathological states, such as impaired cardiac function, low immune protection, and homeostatic failure.4 

To reduce surgical stress and postoperative mortality, researchers have attempted to study ways to prevent the CNS from entering “overdrive” after receiving damage signals from stressors. Recognizing the anesthetized brain is still very much physiologically “awake” and targeting areas of the HPA axis may improve cardiac function, arterial compliance, endothelial function, tissue perfusion, and energy production. In addition, methods that inhibit sympathetic (the fight or flight response) output and increase parasympathetic (the rest and digest response) output may have anti-inflammatory effects, reducing the possibility of further injury.  Since cardiovascular complications are known to be the leading cause of death within 30 days after non-cardiac surgery, suppressing CNS neurohormonal outflows before surgical stress occurs may be crucial to protecting cardiovascular function and secondary injury progression.5 Another possible method is greater regulation of ventricular-arterial (VA) coupling, which connects the CNS to cardiac output, endothelial health, and mitochondrial energy production. Incomplete or impaired VA coupling can activate the endothelium, which can lead to shedding of the glycocalyx, a layer of cells whose absence causes widespread inflammation, coagulopathy, platelet dysfunction, altered immune functionalities, and loss of vascular tone. Endothelial injury also releases syndecan-1, hyaluronan, heparan sulfate, thrombomodulin, annexin-II, and von Willebrand factor, all of which can lead to further myocardial injury and increase 30-day postoperative mortality.6

As is quite common in the sphere of healthcare, there are still more questions than answers regarding optimal management strategies and pharmaceutical therapies for preventing postoperative mortality after major surgery. Nonetheless, it’s crucial for healthcare practitioners to understand the anesthetized brain remains physiologically awake and responsive to the stresses of surgery. An approach that aims to restore the balance between sympathetic and parasympathetic systems, as well as targets CNS-endothelial connections, could help develop new therapies that reduce the progression of postoperative injury and improve patient outcomes.

References

  1. Roth, Gregory A., et. al. “Global, Regional, and National Age-Sex-Specific Mortality for 282 Causes of Death in 195 Countries and Territories, 1980–2017: A Systematic Analysis for the Global Burden of Disease Study 2017.” The Lancet, vol. 392, no. 10159, Nov. 2018, pp. 1736–88. https://doi.org/10.1016/S0140-6736(18)32203-7.
  2. Dobson, Geoffrey P. “Trauma of Major Surgery: A Global Problem That Is Not Going Away.” International Journal of Surgery, vol. 81, Sept. 2020, pp. 47–54. https://doi.org/10.1016/j.ijsu.2020.07.017 
  3. Menger, Michael D., and Brigitte Vollmar. “Surgical Trauma: Hyperinflammation Versus Immunosuppression?” Langenbeck’s Archives of Surgery, vol. 389, no. 6, Nov. 2004, pp. 475–84. https://doi.org/10.1007/s00423-004-0472-0 
  4. Burford, Natalie G., et. al. “Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System.” International Journal of Molecular Sciences, vol. 18, no. 10, Oct. 2017, p. 2150. https://doi.org/10.3390/ijms18102150
  5. Devereaux, P. J., and Daniel I. Sessler. “Cardiac Complications in Patients Undergoing Major Noncardiac Surgery.” New England Journal of Medicine, edited by Dan L. Longo, vol. 373, no. 23, Dec. 2015, pp. 2267.  https://doi.org/10.1056/NEJMra1502824
  6. Ekeloef, S., et al. “Endothelial Dysfunction in the Early Postoperative Period After Major Colon Cancer Surgery.” British Journal of Anaesthesia, vol. 118, no. 2, Feb. 2017, pp. 200–06. https://doi.org/10.1093/bja/aew410