Stress is commonly viewed negatively, associated with chronic pressures such as work or health crises. However, not all stress is harmful. Eustress, or “good stress,” promotes recovery by enhancing cellular resilience, while distress, or “bad stress,” predisposes to inflammation and organ dysfunction. The concept of hormesis — where low-dose stressors trigger adaptive benefits — offers a useful framework for perioperative care. First observed in the 19th century by Hugo Schulz, who noted that yeast sometimes thrived under low-dose disinfectant exposure, hormesis activates cellular repair mechanisms, antioxidant defenses, and mitochondrial efficiency. For anesthesia residents, understanding the molecular, pathophysiological, and pharmacological bases of eustress versus distress, and applying the Stress Paradox Protocol (diet, fasting, exercise, thermal stress, cognitive challenge), can help convert surgical stress into a catalyst for recovery.

References: Calabrese EJ, Mattson MP. Hormesis provides a generalized quantitative estimate of biological plasticity. J Cell Commun Signal. 2011;5(1):25-38. doi:10.1007/s12079-011-0119-2

Eustress

Eustress represents a controlled, adaptive response to surgical stress that supports healing. At the molecular level, acute nociceptive signals activate the hypothalamic–pituitary–adrenal axis and stimulate glucocorticoid receptor signaling, producing cortisol that mobilizes glucose and modulates immunity. Sympathoadrenal activation increases circulating epinephrine and norepinephrine and primes the cardiovascular system through β-adrenergic signaling. Moderate cytokine release, including mediators such as IL-6 and IL-10 via NF-κB and JAK-STAT signaling, contributes to wound healing and an appropriate acute-phase response.

Within mitochondria, mild stress increases oxidative phosphorylation to meet higher ATP demand. Low-level reactive oxygen species act as signaling molecules that activate the Nrf2–Keap1 antioxidant pathway and stimulate mitochondrial biogenesis via PGC-1α. This coordinated response enhances cellular resilience, stabilizes endothelial function, and preserves immune balance — analogous to how repeated moderate exercise strengthens muscle and metabolism.

Clinically, eustress is associated with hemodynamic stability, controlled inflammation, and efficient energy metabolism, thereby reducing perioperative complications in routine procedures such as hernia repair.

Distress

Distress emerges when stress is excessive, prolonged, or poorly controlled, as in lengthy operations, severe systemic inflammation, or sepsis. At the molecular level, overactivation of NF-κB promotes a cytokine surge with mediators such as IL-1β and IL-8, often triggered by TLR4 signaling in response to damage-associated molecular patterns. Prolonged HPA axis stimulation can produce cortisol excess with resultant hyperglycemia and immune suppression. Sympathetic overdrive can cause catecholamine toxicity, upregulate inducible nitric oxide synthase, and generate excessive nitric oxide that interferes with mitochondrial complex IV.

Mitochondrial dysfunction is a central feature of distress. Excessive reactive oxygen species damage the electron transport chain, collapse mitochondrial membrane potential, reduce ATP synthesis, and may induce opening of the mitochondrial permeability transition pore. These events trigger apoptosis or necrosis and release mitochondrial DAMPs such as mtDNA, which amplify systemic inflammation. Endothelial glycocalyx shedding, mediated by matrix metalloproteinases and heparanase, leads to capillary leak and hypotension.

Clinically, distress manifests as endothelial dysfunction, coagulopathy, immune dysregulation, and organ failure, increasing the risk of acute respiratory distress syndrome, acute kidney injury, and sepsis.

References: Calabrese EJ, Mattson MP. Hormesis... (same as above). Desborough JP. The stress response to trauma and surgery. Br J Anaesth. 2000;85(1):109–117. doi:10.1093/bja/85.1.109. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014;5(1):66–72. doi:10.4161/viru.26957

Smart Stress: Hormetic Principles in Anesthesia

Hormesis can be intentionally leveraged using evidence-based strategies that promote eustress and blunt distress when applied appropriately in the perioperative period. Five practical domains are particularly relevant.

Plant-based diets: Phytochemicals such as resveratrol, sulforaphane, allicin, and quercetin act as mild cellular stressors that trigger adaptive antioxidant responses through Nrf2 activation, sirtuin pathways, and autophagy. Resveratrol promotes sirtuin signaling and mitochondrial biogenesis; sulforaphane upregulates antioxidant defenses; allicin modulates calcium signaling relevant to repair processes. Perioperative application involves encouraging a preoperative diet rich in diverse, phytochemical-dense foods to increase antioxidant capacity while avoiding excessive intake.

Time-restricted eating (TRE): Intermittent fasting or a restricted feeding window lowers insulin, favors ketogenesis, and upregulates stress-resistance pathways such as SIRT1 and FOXO3, enhancing autophagy and metabolic flexibility. Perioperative TRE (for example, supervised overnight fasting strategies like a 14:10 feeding window) can be used selectively to reduce postoperative hyperglycemia and improve resilience.

Exercise: Moderate aerobic exercise and appropriately dosed high-intensity interval training induce controlled oxidative and metabolic stress that activates PGC-1α and increases mitochondrial content and function. Exercise also promotes BDNF-mediated neuroprotection, improves insulin sensitivity, and enhances cognitive reserve. Recommend prehabilitation programs when feasible, for example 30 minutes of moderate aerobic activity most days of the week with tailored intervals.

Thermal stress: Short-duration cold exposure increases noradrenaline and catecholamine-mediated alerting responses; heat exposure such as sauna stimulates heat shock proteins, improves vascular function, and reduces inflammation. Carefully selected thermal stress (cold showers or sauna sessions) in low-risk patients may upregulate protective heat shock protein responses; avoid in frail or unstable patients.

Cognitive challenges: Targeted cognitive activity, learning, or meditation elevates BDNF and supports neural plasticity, reducing the risk of postoperative cognitive dysfunction in susceptible patients. Encourage preoperative cognitive exercises and mindfulness practices, especially in the elderly.

References: Longo VD, Panda S. Fasting... Cell Metab. 2016; Chan MTF et al. BIS-guided anesthesia decreases postoperative delirium. Ann Surg. 2013; Laukkanen JA et al. Sauna bathing and cardiovascular outcomes. JAMA Intern Med. 2018.

Pharmacological Modulation — Steering Eustress and Mitigating Distress

HPA axis modulation: Dexamethasone (4–8 mg IV preoperatively) acts on glucocorticoid receptors to suppress NF-κB–mediated cytokine release and reduce perioperative inflammation. In critical illness with suspected relative adrenal insufficiency, hydrocortisone (50–100 mg IV q6h) may be indicated to support hemodynamics and modulate excessive inflammation.

Sympathetic drive control: Agents such as dexmedetomidine (alpha-2 agonist infusion 0.5–1 mcg/kg/hr), esmolol (50–200 mcg/kg/min infusion titrated to effect), and clonidine (1–2 mcg/kg PO preoperatively) blunt catecholamine surges, stabilize hemodynamics, and reduce catecholamine-driven mitochondrial oxidative stress.

Pain and inflammation management: Low-dose ketamine (0.1–0.5 mg/kg IV) attenuates central sensitization and reduces inflammatory cytokines; systemic lidocaine infusions (1–2 mg/kg bolus followed by 1–2 mg/kg/hr) have analgesic and anti-inflammatory effects; NSAIDs reduce prostaglandin-mediated inflammation; gabapentinoids may modulate perioperative nociceptive processing. These agents reduce nociceptive drive and help maintain immune competence.

Mitochondrial protection: Vitamin C (1–2 g IV daily) acts as an ROS scavenger and supports electron transport, while melatonin (3–5 mg PO nightly) stabilizes complexes I and III and reduces mPTP opening. Coenzyme Q10 may enhance electron transport chain efficiency (investigational dosing 100–200 mg PO daily). Methylene blue (1–2 mg/kg IV) can be used in refractory shock to restore cellular respiration by bypassing complex IV inhibition, although this is off-label and reserved for specific scenarios.

References: Venn RM, Grounds RM. Comparison between dexmedetomidine and propofol... Br J Anaesth. 2001. Holford P et al. Vitamin C—an adjunctive therapy... Nutrients. 2020. Tanaka M et al. Mitochondrial quality control... Br J Pharmacol. 2021.

Practical Management Strategies

Preoperative preparation: Reduce anticipatory stress with anxiolysis using agents such as dexmedetomidine infusion or modest doses of midazolam when appropriate. Implement prehabilitation components of the Stress Paradox Protocol: recommend a phytochemical-rich diet, supervised time-restricted eating to promote metabolic flexibility, tailored exercise regimens to enhance mitochondrial capacity, safe thermal exposures in low-risk patients, and cognitive activities to build neurocognitive reserve. Screen patients for mitochondrial vulnerability (for example, poorly controlled diabetics) and for potential adrenal insufficiency in those with sepsis or trauma; consider targeted pharmacologic support such as perioperative dexamethasone or vitamin C in selected patients.

Intraoperative management: Regional anesthesia (epidural or peripheral nerve blocks) lowers nociceptive signaling, cortisol and catecholamine release, and IL-6 production; thoracic epidurals in major abdominal surgery are associated with reduced stress biomarkers. Carefully titrate sedatives and analgesics, using dexmedetomidine to stabilize sympathetic tone, dexamethasone to blunt cytokine surges, and ketamine for analgesia when indicated. Avoid prolonged etomidate infusions because of CYP11B1 inhibition and exercise caution with high-dose propofol in patients with suspected mitochondrial vulnerability. Maintain normothermia to minimize ROS surge, control blood glucose to prevent glycocalyx shedding (target ranges individualized but generally avoid large hyperglycemic excursions), and optimize oxygen delivery to preserve aerobic metabolism and prevent mPTP opening.

Postoperative care: Follow enhanced recovery pathways emphasizing early mobilization, early nutrition, and multimodal analgesia to dampen prolonged HPA activation. Monitor laboratory markers including glucose, lactate, and inflammatory indices; lactate above 2 mmol/L can suggest mitochondrial dysfunction. Consider mitochondrial support strategies such as intravenous vitamin C or nightly melatonin as adjuncts where clinically appropriate.

References: Desborough JP. The stress response to trauma and surgery. Br J Anaesth. 2000. Singer M. The role of mitochondrial dysfunction in sepsis. Virulence. 2014. Longo VD, Panda S. Fasting... Cell Metab. 2016. Kehlet H. Multimodal approach to control postoperative pathophysiology. Br J Anaesth. 1997.

Special Populations and Tailored Management

Elderly and frail patients have reduced mitochondrial reserve and are at higher risk of postoperative delirium and organ dysfunction; favor regional techniques and consider low-dose dexmedetomidine for sedation and delirium prevention, while monitoring for critical illness-related corticosteroid insufficiency.

Patients with diabetes commonly show mitochondrial complex I/III dysfunction and increased oxidative stress; tighter perioperative glucose control (individualized targets) and mitochondrial antioxidant support such as vitamin C may be beneficial.

In septic or severely traumatized patients, a blunted or dysregulated HPA axis, mtDNA release, and catastrophic mitochondrial injury raise organ failure risk; hydrocortisone and rescue strategies such as methylene blue may be considered in refractory circulatory failure, acknowledging limited evidence and the need for individualized risk–benefit assessment.

References: Singer M. Mitochondrial dysfunction in sepsis. Virulence. 2014. Venn RM, Grounds RM. Dexmedetomidine vs. propofol. Br J Anaesth. 2001. Holford P et al. Vitamin C... Nutrients. 2020. Tanaka M et al. Mitochondrial quality control... Br J Pharmacol. 2021.

Clinical Pearls for Residents

Anticipate distress in complex or prolonged surgeries and prepare interventions that address inflammation and mitochondrial health. Balance anesthetic depth with tools such as BIS monitoring to avoid overly deep anesthesia that may suppress adaptive pathways while preventing awareness. Collaborate proactively with surgical and intensive care teams to implement ERAS and distress-monitoring strategies; use biomarkers such as lactate to help detect early mitochondrial dysfunction. Finally, apply hormetic principles where safe and feasible: preoperative lifestyle interventions and judicious pharmacologic modulation can help shift the perioperative stress response toward eustress and improve outcomes.

References (selected): Calabrese EJ, Mattson MP. Hormesis... J Cell Commun Signal. 2011. Singer M. Mitochondrial dysfunction in sepsis. Virulence. 2014. Chan MTF et al. BIS-guided anesthesia decreases postoperative delirium. Ann Surg. 2013. Kehlet H. Multimodal approach... Br J Anaesth. 1997.

Conclusion

Eustress and distress are driven by distinct molecular pathways such as NF-κB and Nrf2 and by mitochondrial mechanisms including the electron transport chain and mPTP dynamics. By applying the Stress Paradox Protocol — phytochemical-rich diets, supervised fasting strategies, exercise, controlled thermal stress, and cognitive training — anesthesiologists can prime patients toward adaptive eustress. Combining these lifestyle and behavioral strategies with targeted pharmacologic interventions (for example, dexmedetomidine, dexamethasone, vitamin C) and regional anesthetic techniques helps mitigate distress, especially in vulnerable populations. For anesthesia residents, incorporating these approaches transforms perioperative management from reactive to proactive, making you an architect of patient resilience and improving surgical outcomes.