General Anesthesia in Psychiatric Patients Undergoing Orthopedic Surgery: A Mechanistic Narrative Review—“When the Brain Is Unstable, Keep It Awake”

Orthopedic and lower limb fracture surgeries are among the most frequent emergency procedures and are commonly performed under general anesthesia (GA). Background and clinical significance: Epidemiologically, postoperative coma after GA is rare (0.005–0.08%), but delayed awakening (2–4%) and postoperative delirium or postoperative cognitive dysfunction (POCD) (15–40%) remain significant. These neurological complications increase markedly in vulnerable brain patients with psychiatric, cerebrovascular, or neurodegenerative disorders. Methods: This mechanistic narrative review synthesizes evidence from clinical and experimental studies (1990–2025) comparing the effects of general versus Regional (RA)/local (LA) or spinal anesthesia in vulnerable neuropsychiatric populations “with pre-existing brain illness” undergoing orthopedic surgery. Domains analyzed include neuropsychiatric medications effects and interactions with the GA process and with general anesthetic agents, alongside alterations in neurotransmitter modulation, cerebrovascular autoregulation, mitochondrial dysfunction, oxidative stress, redox imbalance, and neuroinflammatory activation. The review summarizes evidence on how the choice of anesthesia type influences postoperative brain outcomes in patients with known neurological conditions. Results: From previous studies, patients with psychiatric and/or chronic brain illness have a 3–5-fold increased risk of delayed emergence and up to 60% incidence of postoperative delirium. Pathophysiological mechanisms involve GABAergic overinhibition, impaired perfusion, mitochondrial energy failure, and inflammatory amplification. Regional/local and spinal anesthesia may offer physiological advantages, preserve cerebral perfusion, and lower neurological complication rates. Conclusions: General anesthesia may exacerbate pre-existing brain vulnerability, converting reversible neural suppression into irreversible dysfunction. Therefore, whenever possible, regional/local or spinal anesthesia with or without sedation should be prioritized in those neurologically vulnerable patients to reduce the length of hospital stay (LOS) and to lower postoperative neurological complications and risks in psychiatric and neurologically unstable patients.