Category: Uncategorized

Indications for long-term opioid therapy are far narrower today than they were in the past. Historically, opioids were widely prescribed for chronic non-cancer pain under the assumption that they provided sustained relief with manageable risk. Given what is known today about the risks of opioid use, the decision to initiate long-term opioid therapy—typically defined as use beyond three months—requires a far more critical, evidence-based approach.^1,2

The primary indication for long-term opioid therapy is not a specific diagnosis but a clinical judgment that anticipated benefits in pain relief and functional improvement outweigh known risks. While the risks of long-term opioid use—including opioid use disorder, overdose, and death—are well established, high-quality evidence demonstrating sustained long-term benefit remains limited, with few randomized trials extending beyond short-term follow-up.¹ For example, for chronic non-cancer pain, including conditions like chronic low back pain, osteoarthritis, or neuropathic pain, current guidelines emphasize that opioids should only be considered as a last resort. Instead, alternative therapies are recommended to be considered first, including nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants (e.g., SNRIs), anticonvulsants (e.g., gabapentin), physical therapy, and behavioral interventions. As a result, opioids are now considered a conditional, rather than routine, option for chronic non-cancer pain.²

Despite this general lack of long-term efficacy data, there are specific clinical contexts where long-term opioid therapy remains indicated. Opioids may be appropriate when a patient has a serious illness with a poor prognosis for returning to their previous level of function, when there are specific contraindications to non-opioid therapies, or when both clinician and patient agree that the overriding goal is patient comfort.¹ Certain examples of these scenarios include pain management related to sickle cell disease, cancer-related pain treatment, palliative care, and end-of-life care—situations in which the unique therapeutic goals and the balance of benefits and risks can justify long-term opioid use.¹

When clinicians and patients consider the indications for long-term opioid therapy, it is vital to acknowledge the harms of both the overtreatment and undertreatment of pain. While the dangers of liberal opioid prescribing are well documented, some experts argue that withholding opioids from patients with high-impact chronic pain who have exhausted other alternatives can also cause harm, potentially increasing the risk of mental health crises or suicide.^2,3 Furthermore, if the clinical indication is met to initiate opioid therapy, it must be accompanied by realistic goal-setting. Before starting therapy, clinicians and patients must establish specific, measurable treatment goals for pain and function and must clearly define an exit strategy or tapering plan if the expected benefits do not materialize.¹

Ultimately, the decision to prescribe opioids long-term is highly individualized. It relies not on a rigid sequential failure of other treatments but on a careful, patient-centered assessment that ensures the specific benefits of long-term opioid therapy will meaningfully outweigh the substantial risks.

References

1. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain–United States, 2022. MMWR Recomm Rep. 2022;71(3):1–95.

2. Bicket MC, Bateman BT. Long-term opioid therapy for pain: what is known about harms–and still not known about benefits. JAMA. 2025;334(12):1057–1058.

3. Webster LR. Long-term pain therapy with opioids. JAMA. 2026 Jan 27;335(4):372–373.

The human intestinal microbiome is a complex and dynamic ecosystem that plays a central role in metabolism, immune regulation, and bioactive compound production.¹ Its composition can vary dramatically according to specific genetic and environmental factors and can be disrupted by physiological stressors, such as surgery.² Accumulating evidence demonstrates that both gastrointestinal and non-gastrointestinal surgeries significantly alter gut microbial diversity and composition, with changes observed in specific taxa that persist for weeks to months post-operation. Such alterations have been implicated in adverse outcomes, including postoperative infections and anastomotic complications. While factors such as antibiotic use, bowel preparation, nutrition, and surgical technique are known contributors to microbiome disruption, the independent role of anesthesia remains poorly understood.³ Clarifying the effects of different anesthetic agents such as sevoflurane on the intestinal microbiome is critical to improving patient outcomes.

In a 2021 experimental study, researchers investigated the effect of sevoflurane inhalational anesthesia on the intestinal microbiome by longitudinally assessing microbial changes in mice using rRNA gene sequencing. They also performed untargeted metabolomic analyses to characterize associated functional alterations. Sixteen 6–8-week-old male mice were randomly assigned to receive either 4 hours of sevoflurane anesthesia or no anesthesia, and fecal samples were collected for subsequent analysis.

Results showed sevoflurane anesthesia induced significant, time-dependent alterations in the intestinal microbiome. Principal component and principal coordinate analyses demonstrated clear differences between experimental and control groups on days 1, 3, and 7 after anesthesia, with the magnitude of contrast diminishing by day 14, a marker which suggests partial recovery. The most pronounced difference was on day 7, when the experimental group exhibited the lowest number of unique operational taxonomic units and a significant reduction in alpha diversity; this was followed by a slow trend toward restoration. Sustained compositional shifts were observed, including (semi-permanent) increases of Bacteroides, Alloprevotella, and Akkermansia bacteria and decreased Lactobacillus genera by day 14.

Further analyses revealed dynamic changes in microbial gene expression and metabolic pathways across various study time points. Differentially expressed genes were most abundant on days 3 and 14, while fewer were detected on days 1 and 7. Importantly, early alterations (day 1) were associated with pathways related to ribosomal function, nucleotide metabolism, and DNA repair. By day 7, pathways such as sphingolipid metabolism and the pentose phosphate pathway were enriched. By day 14, increased activity was observed in two-component systems, lipopolysaccharide biosynthesis, transcription machinery, and amino acid metabolism. Altogether, these findings indicate that sevoflurane anesthesia not only alters microbial composition but also induces sustained functional and metabolic reprogramming of the gut microbiome.³

Sevoflurane is believed to alter the intestinal microbiome through both direct and indirect mechanisms. Directly, in vitro studies show that sevoflurane exerts antibacterial effects against gram-positive, gram-negative, and even multidrug-resistant bacteria.⁴ Indirectly, it may influence microbial composition via the brain–gut–bacteria axis, a bidirectional communication network that links the central and enteric nervous systems with the gastrointestinal tract and its microbiota; this connection involves afferent (bottom-up) and efferent (top-down) signaling pathways.⁵

Research shows that sevoflurane anesthesia independently induces alterations in the intestinal microbiome’s composition, diversity, and metabolic function, with the most pronounced changes occurring one week after exposure. Although partial recovery was observed, persistent taxonomic and functional changes suggest anesthesia may have lasting effects on the intestinal ecosystem. These findings highlight the need to further investigate the clinical implications of anesthesia-related microbiome modulation, particularly given its potential relevance to postoperative outcomes and host systemic physiology.

References

1. Roux A, Payne SM, Gilmore MS. Microbial Telesensing: Probing the Environment for Friends, Foes, and Food. Cell Host & Microbe. 2009;6(2):115-124. https://doi.org/10.1016/j.chom.2009.07.004

2. Guyton K, Alverdy JC. The gut microbiota and gastrointestinal surgery. Nature Reviews Gastroenterology & Hepatology. 2016;14(1):43-54. https://doi.org/10.1038/nrgastro.2016.139

3. Han C, Zhang Z, Guo N, et al. Effects of Sevoflurane Inhalation Anesthesia on the Intestinal Microbiome in Mice. Frontiers in Cellular and Infection Microbiology. 2021;11. https://doi.org/10.3389/fcimb.2021.633527

4. Martínez-Serrano M, Gerónimo-Pardo M, Martínez-Monsalve A, Crespo-Sánchez MD. Antibacterial effect of sevoflurane and isoflurane. Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia. 2017;30(2):84-89. https://pubmed.ncbi.nlm.nih.gov/28198170/

5. Gracie DJ, Hamlin PJ, Ford AC. The influence of the brain–gut axis in inflammatory bowel disease and possible implications for treatment. The Lancet Gastroenterology & Hepatology. 2019;4(8):632-642. https://doi.org/10.1016/S2468-1253(19)30089-5

Methylene blue is a compound that plays both diagnostic and therapeutic roles in medicine. Originally developed as a textile dye in the late 19th century, it was one of the earliest synthetic agents used clinically. Today, methylene blue serves versatile clinical functions as a dye in imaging and as a medication in the treatment of certain hematological and hemodynamic disorders.

The primary FDA-approved use of methylene blue is the treatment of methemoglobinemia, a condition in which the iron in hemoglobin is oxidized from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state. This transformation prevents normal oxygen binding and transport, leading to tissue hypoxia and cyanosis. Common causes include exposure to oxidizing agents, such as dapsone, benzocaine, and nitrates. Methylene blue functions as an artificial electron carrier within the NADPH-methemoglobin reductase pathway. It is reduced to leucomethylene blue, which donates electrons to convert methemoglobin back to functional hemoglobin. The standard treatment dose is 1 mg/kg of a 1% solution administered intravenously over several minutes, and most patients improve rapidly (1).

In addition to being used as a therapeutic medication, methylene blue is widely used as an intraoperative dye. In breast surgery, it assists in sentinel lymph node mapping by visually tracing lymphatic drainage from the tumor site. The blue-stained nodes can be selectively excised for histologic evaluation, allowing for accurate staging while minimizing tissue dissection. A meta-analysis found that methylene blue alone provides reliable detection rates comparable to radiotracer methods, making it an effective, low-cost option for many surgical centers (2). In endocrine surgery, it is also used identify parathyroid glands during parathyroidectomy. Its preferential uptake by parathyroid tissue allows surgeons to distinguish the glands from adjacent structures, reducing the risk of accidental removal or nerve injury (3).

In cardiac anesthesia and critical care, methylene blue helps manage vasoplegic syndrome, a severe complication characterized by persistent hypotension and low vascular resistance despite high-dose vasopressors. By inhibiting nitric oxide synthase and guanylate cyclase, methylene blue decreases cyclic GMP levels and restores vascular tone. Clinical studies have shown that its use can improve hemodynamics and reduce mortality in vasoplegic patients following cardiac surgery (4). Although not considered first-line therapy, it serves as a valuable rescue option when conventional treatments fail.

Although methylene blue is generally safe at therapeutic doses, clinicians should be aware of potential adverse effects. Common reactions include dizziness, mild headaches, and blue or green discoloration of the urine and skin. Serious complications can arise when methylene blue is administered with serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase (MAO) inhibitors, as it possesses mild monoamine oxidase inhibitory properties. These combinations may cause serotonin syndrome, which is characterized by agitation, tremor, and hyperthermia (5). Methylene blue is also contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because oxidative stress can lead to hemolytic anemia. Additionally, it is contraindicated during pregnancy due to teratogenic risk.

Despite these limitations, methylene blue remains a valuable agent in perioperative medicine. Its ability to function as both a visual aid and a pharmacological treatment makes it particularly useful in complex surgical and critical care situations.

References

1. do Nascimento TS, Pereira RO, de Mello HL, Costa J. Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol. 2008;58(6):651-664. doi:10.1590/s0034-70942008000600011
2. Li J, Chen X, Qi M, Li Y. Sentinel lymph node biopsy mapped with methylene blue dye alone in patients with breast cancer: A systematic review and meta-analysis. PLoS One. 2018;13(9):e0204364. Published 2018 Sep 20. doi:10.1371/journal.pone.0204364
3. Dudley NE. Methylene blue for rapid identification of the parathyroids. Br Med J. 1971;3(5776):680–681.
4. Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004;77(2):496-499. doi:10.1016/S0003-4975(03)01510-8
5. Gillman PK. CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. J Psychopharmacol. 2011;25(3):429-436. doi:10.1177/0269881109359098

Obtaining informed consent is a cornerstone of ethical medical practice, particularly in anesthesia and surgery, where risk, complexity, and uncertainty intersect. Yet even with thorough preoperative discussions, unanticipated developments—changes in anatomy, unexpected bleeding, newly discovered pathology, or equipment-related challenges—can arise once a patient is anesthetized. These moments require clinicians to balance patient autonomy, clinical judgment, and the ethical obligation to prevent harm. As perioperative medicine grows more complex, navigating patient consent when the clinical situation changes unexpectedly during anesthesia and surgery remains a critical topic in medical ethics and patient safety.

A central principle of informed consent is that patients must understand and agree to the nature, risks, benefits, and alternatives of a procedure. However, once a patient is sedated or receives general anesthesia, they are no longer able to participate in further discussion. Anesthesiologists and surgeons typically address the possibility of intraoperative changes during preoperative counseling, but the extent of that discussion varies widely. While some patients explicitly authorize “permission to proceed as necessary” for unforeseen findings, such authorization must not be interpreted as blanket consent for unrelated or elective interventions. Ethical guidelines emphasize that consent is specific to the planned procedure and its reasonably anticipated contingencies.

When the situation changes after induction of anesthesia, clinicians must determine whether immediate action is necessary to protect the patient from imminent harm or if it is more appropriate to discuss further treatment with the patient and obtain consent once the ongoing procedure is complete. If a situation is emergent—life-threatening hemorrhage, rapidly evolving instability, or a discovery that demands urgent correction—surgeons are ethically permitted to perform additional necessary interventions without new consent, guided by the principle of implied consent in emergencies. This standard is widely supported across medical ethics literature, recognizing that delaying treatment to awaken the patient or locate a surrogate could jeopardize the patient’s life or long-term health.

However, not all intraoperative discoveries justify proceeding without further consent. When the new situation is not urgent—for example, detecting a non-emergent hernia, finding a benign mass, or considering an optional repair—best practices call for pausing the operation and seeking consent from the patient’s designated surrogate decision maker. Modern perioperative workflows increasingly incorporate preoperative identification of a surrogate and real-time communication protocols to facilitate ethical decision-making when these scenarios arise. Some institutions even establish structured “intraoperative pause” procedures to enable documentation, communication, and ethical review before any unplanned intervention is undertaken.

Anesthesiologists play a crucial mediating role during such events. Because they maintain physiological control and situational awareness, they determine whether awakening the patient is safe or feasible. They also provide valuable insight into the patient’s preoperative discussions, including statements about preferences, limitations on acceptable surgical expansion, or religious and cultural considerations. Good perioperative practice emphasizes interprofessional communication, with the anesthesia team, surgeons, and nursing staff collaborating to evaluate the clinical and ethical dimensions of the new scenario.

Transparency and postoperative communication are equally essential. Regardless of the decisions made during surgery, clinicians must clearly explain to the awakened patient or their surrogate what occurred, why decisions were made, and what consequences or follow-up needs may result. This conversation is not only ethically required—it also reinforces trust and supports patient understanding during recovery. Thorough documentation in the operative note and consent record further strengthens legal and ethical accountability.

As surgical technology evolves, intraoperative findings may become more common due to advanced imaging, minimally invasive exploration, and broader access to surgical care. To meet these challenges, clinicians and institutions should ensure that informed consent conversations with the patient include explicit discussion of potential contingencies, designate a surrogate decision-maker in advance, and establish feasible protocols for obtaining intraoperative consent if the situation changes. Regular ethics training, simulation exercises, and adherence to professional guidelines can help teams respond consistently and ethically when the unexpected happens.

References

1. American Medical Association. AMA Code of Medical Ethics Opinion 2.1.1: Informed Consent. American Medical Association; 2023. https://code-medical-ethics.ama-assn.org/ethics-opinions/informed-consent

2. American Society of Anesthesiologists. Statement on Informed Consent for Anesthesia Care. ASA; 2022. https://www.asahq.org/standards-and-practice-parameters/statement-on-the-anesthesia-care-team

3. American College of Surgeons. Statements on Principles: Informed Consent. ACS; 2020.

4. Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357(18):1834-1840. DOI: 10.1056/NEJMcp074045

5. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 8th ed. Oxford University Press; 2019. DOI: 10.1080/15265161.2019.1665402

The perioperative management of angiotensin-converting enzyme (ACE) inhibitors is an active area of research in anesthesiology, cardiology, and perioperative medicine. ACE inhibitors are widely prescribed for hypertension, heart failure, and chronic kidney disease, yet their hemodynamic effects may complicate surgical care. A review of current literature highlights the impacts of pre-operative ACE inhibitor use on surgical outcomes.

One of the most consistently reported concerns is the increased risk of intraoperative hypotension among patients who continue ACE inhibitors up to the day of surgery. Multiple randomized trials and meta-analyses demonstrate higher rates of anesthesia-related hypotension in these patients, often requiring vasopressor support. While this hypotension does not always translate into worse postoperative outcomes, it poses challenges for intraoperative management and remains a key reason many clinicians elect to hold the medication on the morning of surgery. Despite this, some studies suggest that the hemodynamic instability associated with pre-operative ACE inhibitors is transient and may not significantly impact major surgical outcomes.

Renal outcomes appear more complex. Earlier cohort studies found an increased risk of postoperative acute kidney injury (AKI) among cardiac surgery patients taking ACE inhibitors preoperatively, likely due to altered renal autoregulation during cardiopulmonary bypass. However, more recent meta-analyses have reported a small but statistically significant reduction in AKI among patients receiving renin-angiotensin system inhibitors before surgery. These benefits seem more pronounced in noncardiac surgery populations and in patients with preexisting chronic kidney disease, suggesting that patient selection and surgical context are crucial modifiers of risk.

Emerging evidence indicates that continuation of ACE inhibitors as normal before surgery may provide mortality benefits in specific settings. Retrospective analyses of large cardiac surgery databases show that patients maintained on ACEIs have lower in-hospital mortality, reduced sepsis, and fewer postoperative complications. Some studies even suggest a dose-response relationship, with medium -dose therapy offering the most protection. Outside of cardiac surgery, population-based studies of older adults demonstrate reduced mortality and functional decline when ACE inhibitors are continued perioperatively compared with alternative antihypertensives.

Despite these promising findings, the literature is far from uniform. In coronary artery bypass grafting (CABG) patients, some studies report no significant association between preoperative ACE inhibitor use and mortality, renal failure, or long-term survival. Additionally, a few analyses note increased heart failure-related readmissions among ACE inhibitor users, raising questions about postoperative management strategies.

Given these mixed outcomes, current guideline perspectives advocate individualized decision-making. Many Enhanced Recovery After Surgery programs recommend withholding ACE inhibitors on the day of surgery to reduce hypotension risk but restarting them early in the postoperative period once hemodynamic stability is achieved. The optimal strategy likely varies based on patient comorbidities, ACE inhibitor dose, and the type of surgery.

In conclusion, the effect of pre-operative ACE inhibitor therapy on surgical outcomes is multifaceted. While continuation may reduce mortality and improve renal outcomes in select populations, it also increases the likelihood of intraoperative hypotension. Clinicians must balance these considerations and tailor decisions to each patient’s cardiovascular profile and surgical risk. Additional randomized controlled trials are needed to establish standardized perioperative protocols that optimize both safety and long-term outcomes.

References

1. Shi P, Li Z, Young N, Ji F, Wang Y, Moore P, Liu H. The effects of preoperative renin-angiotensin system inhibitors on outcomes in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 2013 Aug;27(4):703-9. doi: 10.1053/j.jvca.2013.01.012

2. Li WC, Kennedy AC, Potts RJ, et al. The impact of dose and discontinuation timing of preoperative ACE inhibitors on survival outcomes in cardiac surgery: A MIMIC-IV database analysis. Crit Care Med. 2023. doi: 10.1371/journal.pone.0334889

3. Wallace CM, Walker PM, Morris KP, et al. Withholding vs continuing angiotensin-converting enzyme inhibitors or angiotensin receptor blockers before surgery: a systematic review and meta-analysis. Anaesthesia. 2008;63(11):1358-1364. doi: 10.1080/07853890.2025.2566873

4. Arora P, Rajagopalam S, Ranjan R, et al. Preoperative use of ACE inhibitors/ARBs is associated with increased risk for acute kidney injury after cardiovascular surgery. Clin J Am Soc Nephrol. 2008;3(5):1266-1273. doi: 10.2215/CJN.05271107

5. Wikström B, Bäck M, Agvald-Åman M, et al. Preoperative renin-angiotensin system inhibitors linked to reduced acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2015;87(3):555-564. doi: 10.1093/ndt/gfv023

Understanding how molecular physiology diverges between natural sleep and general anesthesia, which produces pharmacologic unconsciousness, is valuable clinically and for sleep research. Broadly, sleep is an active, homeostatically regulated process that engages cell type-specific transcriptional, translational, and post-translational programs, whereas general anesthesia suppresses brain activity by acting on a constellation of molecular targets, some overlapping with sleep pathways but many unique to anesthetic drugs.

At the transcriptional and proteomic level, recent single-cell and cell-type proteomics studies show that sleep need and sleep deprivation produce rapid, cell-specific changes in gene expression and phosphorylation, particularly in astrocytes and neurons of cortex, hypothalamus, and brainstem. Immediate-early genes, transcription factors related to synaptic scaling, and pathways linked to mitochondrial function and protein phosphorylation are modulated—signatures that appear tailored to restore synaptic homeostasis and metabolic balance after wakefulness. In contrast to sleep, the molecular actions of general anesthesia are better characterized at the level of receptor and ion-channel pharmacology. GABA-A receptor potentiation (propofol, volatile agents, benzodiazepines), NMDA receptor antagonism (ketamine), and modulation of two-pore K+ channels or HCN channels are canonical mechanisms of anesthesia that reduce neuronal excitability and alter synaptic transmission. These direct protein-level interactions produce rapid changes in synaptic efficacy and network synchrony that do not require the slower gene-expression cascades characteristic of physiological sleep.

Adenosine signaling and neuromodulator withdrawal are a notable point of convergence in the molecular pathways of sleep and general anesthesia. Sleep pressure is tightly linked to adenosine accumulation and downstream effects on A1/A2 receptors and neuronal excitability. Adenosine antagonists (such as caffeine) accelerate emergence from certain anesthetics in animal and human studies, implicating adenosine pathways in both sleep homeostasis and anesthesia emergence. However, whereas sleep invokes coordinated homeostatic gene programs that dissipate adenosine-linked pressure, anesthetic exposure typically produces an abrupt pharmacologic blockade of arousal circuits without engaging the same restorative transcriptional responses. Electrophysiologic correlates reflect these molecular differences. Both NREM sleep and several anesthetics show prominent slow-delta oscillations and spindles, but higher-dose anesthetic states can produce burst suppression and cortical isoelectricity—patterns not seen in physiological sleep—reflecting deeper, drug-specific suppression of cortical and thalamocortical circuit function. Molecularly, these EEG changes parallel agent-specific modulation of synaptic proteins and ion channels rather than the phased transcriptional programs seen in sleep recovery.

Clinically, these distinctions matter. Anesthetics can disrupt circadian clock gene expression and selectively affect memory consolidation by interfering with hippocampal oscillations and synaptic plasticity. Postoperative cognitive dysfunction and delirium likely arise from a complex interplay between direct drug effects on synaptic function, altered sleep architecture after surgery, and patient vulnerability such as age or neurodegenerative disease. Emerging molecular data suggest that perioperative strategies that support sleep-related restorative pathways (such as preserving NREM architecture and minimizing nocturnal circadian disruption) may mitigate cognitive sequelae after anesthesia, but prospective clinical translation remains limited.

To a limited extent, sleep and general anesthesia overlap at the level of network signatures in the brain and in some neuromodulatory systems, but they differ fundamentally in timescale and molecular depth: sleep engages coordinated, cell-specific transcriptional and proteomic responses that restore homeostasis, whereas anesthetics produce relatively rapid, receptor- and channel-mediated suppression of excitability and information integration. For anesthesiologists, integrating molecular insights with EEG and circuit-level knowledge can help tailor anesthetic choice and perioperative care to reduce cognitive risk and optimize recovery.

References

1. Jha PK, Valekunja UK, Ray S, Nollet M, Reddy AB. Single-cell transcriptomics and cell-specific proteomics reveals molecular signatures of sleep. Commun Biol. 2022;5:846. DOI: 10.1038/s42003-022-03800-3.
2. Moody OA, Zhang ER, Vincent KF, et al. The neural circuits underlying general anesthesia and sleep. Anesth Analg. 2021;132(5):1254-1264. DOI: 10.1213/ANE.0000000000005361.
3. Franks NP, Wisden W. The inescapable drive to sleep: overlapping mechanisms of sleep and sedation. Science. 2021;374(6567):556-559. DOI: 10.1126/science.abi8372.
4. Liu H, Yang Z, Chen Y, et al. Neural oscillations and memory: unraveling the mechanisms of anesthesia-induced amnesia. Front Neurosci. 2024. https://doi.org/10.3389/fnins.2024.1492103.
5. Date A, Bashir K, Uddin A, Nigam C. Differences between natural sleep and the anesthetic state. Future Sci OA. 2020;6(10):FSO664. DOI: 10.2144/fsoa-2020-0149.

For more than half a century, researchers have studied how volatile anesthetics affect ion channels and receptors. However, their precise molecular mechanisms remain unclear. Evidence suggests that volatile anesthetics may also target cytoplasmic proteins like tubulin, which forms microtubules, a critical part of the cytoskeleton that is essential for neuronal structure, intracellular transport, and receptor function. Experimental findings demonstrate volatile anesthetics at high concentrations can bind to tubulin and interfere with its polymerization into microtubules.¹ Additionally, microtubule destabilization and neuronal protein interference (for proteins such as tau) are linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. To better understand how anesthesia causes these deleterious interactions, computational methods such as molecular dynamics and binding site prediction are being used to complement experimental approaches, which do not account for protein dynamics and neglect local protein atom rearrangement and the resulting change in binding site availability.

In a 2012 computational study, molecular dynamics simulations and homology modeling were used to generate minimized structures of human tubulin isotypes, including both the protein body and C-terminal tails. In parallel, microtubule polymerization assays with purified bovine brain tubulin were performed to test the effects of halothane (alone and with paclitaxel) on microtubule assembly.²

In this study, the researchers show how halothane, a volatile anesthetic, interacts with tubulin, the building block of microtubules. The researchers predicted multiple binding sites for halothane on both the tubulin body and the flexible C-terminal tails, with binding primarily driven by van der Waals forces from halothane’s chlorine and bromine atoms. Importantly, some predicted binding sites overlapped with known drug-binding regions for microtubule-modifying agents like colchicine and vinblastine, suggesting that halothane could interfere with microtubule-targeting drugs.

Functionally, these interactions point to a role of halothane in altering microtubule stability and dynamics,since binding at these critical regions may reduce tubulin’s ability to polymerize into microtubules. The authors note that halothane reduces colchicine binding to tubulin and may subtly disrupt microtubule assembly. These findings suggest that volatile anesthetics like halothane may contribute to side effects such as postoperative cognitive dysfunction by directly perturbing the microtubule cytoskeleton in neurons.²

A 2013 pre-clinical study exposed neonatal rats (n=37) to either sevoflurane, also a volatile anesthetic, or air and then subjected their hippocampi to histological, Western blot, and real-time polymerase chain reaction analyses. Rats exposed to 3% sevoflurane for 6 hours showed disrupted microtubule organization, with structures appearing disordered and nonparallel compared to the neat arrangement in their control counterparts. Sevoflurane exposure also increased tau mRNA levels at 1 and 7 days, although this effect stabilized and returned to “normal” levels by day 14.³

In addition, tau protein showed excessive phosphorylation at Ser396 and Ser404 after sevoflurane anesthesia, with elevations persisting for up to 14 days at Ser404. These changes in tau phosphorylation are closely tied to microtubule instability, as hyperphosphorylated tau detaches from microtubules, leading to cytoskeletal disarray. Overall, the findings suggest that sevoflurane disrupts microtubule structure by altering tau regulation, potentially contributing to anesthesia-related neurotoxicity in the developing brain.³ In support of these findings, a separate murine study found rats exposed to sevoflurane anesthesia (1 MAC) had significantly less tubulin protein, suggesting sevoflurane negatively affects the cytoskeleton by down-regulating tubulin and preventing its polymerization into microtubules.⁴

Taken together, these studies suggest that volatile anesthetics not only act on ion channels and receptors but also affect the neuronal cytoskeleton. By binding to tubulin and disrupting microtubule polymerization, halothane may alter neuronal stability and interfere with the function of other microtubule-targeting drugs. Similarly, sevoflurane has been shown to cause microtubule disarray and promote tau hyperphosphorylation, both of which compromise microtubule integrity. These mechanisms provide a plausible link between anesthetic exposure and postoperative cognitive dysfunction or neurotoxicity. Further research is needed to clarify the long-term neurological risks of volatile anesthetics and identify strategies that minimize their cytoskeletal effects.

References

1. Hinkley R.E., Samson F.E., Anesthetic-Induced Transformation of Axonal Microtubules. Journal of Cell Biology. 1972;53(1), 258-263. https://doi.org/10.1083/jcb.53.1.258
2. Travis, Marc St. George, Freedman H., et al. Computational Predictions of Volatile Anesthetic Interactions with the Microtubule Cytoskeleton: Implications for Side Effects of General Anesthesia. PLOS ONE. 2012;7(6) 37251-37251. https://doi.org/10.1371/journal.pone.0037251
3. Hu Z., Jin H., Xu L., Zhu Z., Jiang Y., Seal R., Effects of Sevoflurane on the Expression of Tau Protein mRNA and Ser396/404 Site in the Hippocampus of Developing Rat Brain. Pediatric Anesthesia. 2013;23(12):1138-1144. https://doi.org/10.1111/pan.12263
4. Armin Kalenka, Jochen Hinkelbein, Feldmann R.E., Wolfgang Kuschinsky, Waschke K.F., Maurer M.H., The Effects of Sevoflurane Anesthesia on Rat Brain Proteins: A Proteomic Time-Course Analysis. Anesthesia & Analgesia. 2007;104(5):1129-1135. https://doi.org/10.1213/01.ane.0000260799.37107.e6

Nerve stimulators are tools that are primarily used in perioperative regional anesthesia to accurately locate peripheral nerves, enhancing the safety and efficacy of nerve blocks. By delivering low-intensity electrical impulses, nerve stimulators help anesthesiologists identify motor responses that indicate specific nerve territories. They enable the precise placement of local anesthetic, which minimizes complications such as intraneural injections and ensures adequate anesthesia with lower drug volumes.

Although using nerve stimulators on their own can demonstrably improve procedural outcomes, they can also be used concurrently with ultrasound-guided nerve blocks. Combining ultrasound with nerve stimulation has demonstrated superior outcomes in terms of block success rates and patient safety. Recent anatomical investigations have shown that ultrasound-guided PNS targeting the femoral, iliohypogastric, and ilioinguinal nerves can enhance block precision without increasing the risk of nerve injury (1).

Beyond nerve localization, the emerging use of peripheral nerve stimulation (PNS) suggests benefits in postoperative pain management and autonomic function modulation. For instance, vagus nerve stimulation (VNS) is increasingly being studied in surgical contexts, not only for chronic neurological conditions but also as a potential intervention for postoperative fatigue and inflammation. One study of elderly patients undergoing colorectal cancer surgery suggested that perioperative VNS could modulate inflammatory pathways and reduce postoperative fatigue syndrome. This opens a new area of research in neuromodulation for surgical recovery, highlighting a growing interest in using autonomic modulation to improve surgical outcomes (2).

Nerve stimulator use is not without risks. Case reports have highlighted rare but serious complications, such as asystole and laryngospasm following vagus nerve stimulator generator replacement. These complications can be caused by excessive vagal activation during surgery (3). These findings emphasize the importance of meticulous intraoperative monitoring and a comprehensive understanding of the device’s physiological effects when used perioperatively.

Technological advancements in nerve stimulators have expanded the range of conditions for which they can be used, including for perioperative anesthesia. The American Society of Pain and Neuroscience has endorsed 60-day peripheral nerve stimulation therapy for managing acute and subacute pain, with applications extending into the perioperative setting (4). These devices provide a non-opioid approach to pain management, which is particularly relevant in the context of the opioid crisis. Short-term peripheral nerve stimulation therapies can be tailored to individual patients and integrated into enhanced recovery after surgery protocols, which could reduce reliance on systemic analgesics and improve patient satisfaction.

Additionally, perioperative nerve stimulation may impact cardiovascular stability through autonomic modulation. A systematic review emphasized the impact of autonomic nervous system imbalance on surgical outcomes. This review suggests that targeted nerve stimulation could mitigate perioperative complications related to sympathetic overdrive, including hypertension, arrhythmias, and delayed recovery (5). As more evidence emerges, the therapeutic scope of nerve stimulators in perioperative anesthesia may expand beyond nerve localization and analgesia to include modulation of systemic responses to surgical stress.

Nerve stimulators play a multifaceted role in perioperative anesthesia, from guiding regional blocks to managing postoperative pain and influencing autonomic dynamics. Although technological advancements and clinical guidelines have improved their safety profile, careful patient selection and device-specific considerations are still essential. Continued research is essential to understanding their full capabilities and integrating them into comprehensive perioperative care strategies.

References

1. Cho JS, Grisham A, Wang A, et al. Focused Anatomic Review: Ultrasound-Guided Peripheral Nerve Stimulation of the Femoral, Iliohypogastric, and Ilioinguinal Nerves. Pain Med. Published online April 24, 2025. doi:10.1093/pm/pnaf047
2. Yin X, Qiao S, Zhang L, et al. New intervention strategy for postoperative fatigue syndrome in elderly patients with colorectal cancer: a clinical hypothesis study based on vagus nerve stimulation. Front Med (Lausanne). 2025;12:1588850. Published 2025 Jun 2. doi:10.3389/fmed.2025.1588850
3. Manohara N, Byrappa V, Maiti T, Jain A, Lobo FA. Asystole and Laryngospasm After Vagal Nerve Stimulator Generator Replacement: A Case Report. A A Pract. 2025;19(5):e01967. Published 2025 May 1. doi:10.1213/XAA.0000000000001967
4. Gill B, Tidwell C, Hagedorn JM, et al. Consensus Guidelines from the American Society of Pain and Neuroscience for the Use of 60-Day Peripheral Nerve Stimulation Therapy. A NEURON Living Guideline Project. J Pain Res. 2025;18:3117-3139. Published 2025 Jun 24. doi:10.2147/JPR.S521788
5. Pan WT, Ji MH, Ma D, Yang JJ. Effect of perioperative autonomic nervous system imbalance on surgical outcomes: a systematic literature review. Br J Anaesth. Published online July 3, 2025. doi:10.1016/j.bja.2025.06.004

Pharmacological management of hypotension during anesthesia is essential to ensure adequate organ perfusion and reduce perioperative complications. Intraoperative hypotension commonly arises due to vasodilation, myocardial depression, or autonomic suppression, each of which may be triggered or exacerbated by anesthetic agents. A successful pharmacological approach depends on identifying the dominant mechanism and selecting an agent that corrects it effectively and safely.

Peripheral vasodilation is a common cause of intraoperative hypotension, particularly during neuraxial anesthesia, where sympathetic blockade reduces systemic vascular resistance (SVR). In these cases, alpha-1 agonists like phenylephrine and ephedrine are first-line agents. By inducing vasoconstriction, phenylephrine raises SVR and restores arterial pressure, though it may also decrease cardiac output due to reflex bradycardia and increased afterload. Ephedrine, which stimulates both alpha and beta receptors, improves vascular tone while also increasing heart rate and contractility. This dual action makes it especially useful when hypotension is accompanied by bradycardia or reduced cardiac output. In obstetric anesthesia, ephedrine is often the preferred pharmacological intervention for hypotension because of its ability to maintain uteroplacental perfusion without significant fetal compromise (1).

Patients who are chronically treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) present a unique challenge. These medications are commonly prescribed to manage hypertension, heart failure, and diabetic nephropathy. However, they interfere with the renin-angiotensin-aldosterone system, which impairs the body’s ability to compensate for hypotension via vasoconstriction. During anesthesia, this blunted compensatory mechanism can lead to severe hypotension that does not respond to traditional adrenergic vasopressors, such as phenylephrine or ephedrine. In such cases, vasopressin becomes a critical alternative. Vasopressin acts on V1 receptors through a non-adrenergic pathway, restoring vascular tone independently of the sympathetic nervous system. Its efficacy in patients treated with ACE inhibitors or ARBs has been well documented, and it is now considered a second-line agent for refractory hypotension in this setting (2).

Ketamine is another valuable pharmacological agent for managing hypotension, particularly during anesthesia induction. Unlike most anesthetic agents, which suppress sympathetic tone and lower blood pressure, ketamine stimulates the sympathetic nervous system and inhibits norepinephrine reuptake. This results in increased heart rate, cardiac output, and SVR. These properties make ketamine ideal for patients with hemodynamic instability, including those with hypovolemia, pericardial tamponade, or aortic stenosis. Its potential drawbacks include increased myocardial oxygen consumption and emergence reactions. However, when used appropriately, its ability to provide cardiovascular stability is a major advantage in high-risk populations (3).

Identifying patients at increased risk for hypotension before anesthesia and surgery allows for proactive planning. Reich et al. conducted a large, prospective analysis of more than 4,000 patients undergoing non-cardiac surgery. They found that advanced age, female sex, low baseline systolic blood pressure, and higher (ASA) physical status scores were all associated with post-induction hypotension. They also observed a consistent, dose-dependent hypotensive effect with fentanyl, an opioid often used during induction, highlighting the need for careful agent selection in vulnerable patients.

A mechanism-based approach improves the precision and safety of anesthetic management. Alpha-adrenergic agents, such as phenylephrine, are effective in treating vasodilatory hypotension. When bradycardia or low cardiac output is present, agents with beta activity, such as ephedrine or low-dose epinephrine, provide additional chronotropic and inotropic support. For patients taking ACE inhibitors or ARBs, vasopressin restores vascular tone via non-adrenergic pathways. Ketamine reliably stabilizes hemodynamics during induction in patients with limited cardiovascular reserve. Aligning drug selection with the dominant physiologic disturbance ensures effective, targeted treatment across a range of clinical scenarios.

References

1. Ferré F, Martin C, Bosch L, Kurrek M, Lairez O, Minville V. Control of Spinal Anesthesia-Induced Hypotension in Adults. Local Reg Anesth. 2020;13:39-46. Published 2020 Jun 3. doi:10.2147/LRA.S240753
2. Mets B. Management of hypotension associated with angiotensin-axis blockade and general anesthesia administration. J Cardiothorac Vasc Anesth. 2013;27(1):156-167. doi:10.1053/j.jvca.2012.06.014
3. Morgan P. The role of vasopressors in the management of hypotension induced by spinal and epidural anaesthesia. Can J Anaesth. 1994;41(5 Pt 1):404-413. doi:10.1007/BF03009863
4. Reich DL, Hossain S, Krol M, et al. Predictors of hypotension after induction of general anesthesia. Anesth Analg. 2005;101(3):622-628. doi:10.1213/01.ANE.0000175214.38450.91

Preoperative blood transfusion is a component of perioperative management aimed at optimizing hemoglobin levels, improving oxygen delivery, and minimizing perioperative morbidity and mortality, particularly in high-risk surgical patients. The decision to transfuse blood before surgery is complex and must be individualized based on patient factors such as underlying anemia, comorbid conditions, type of surgical procedure, and anticipated blood loss. There is no universal hemoglobin threshold for transfusion; however, guidelines generally recommend considering transfusion when hemoglobin levels fall below 7-8 g/dL in stable patients and higher thresholds in patients with cardiovascular disease or active bleeding (1).

Patients undergoing procedures with a high risk of blood loss, such as orthopedic or cardiovascular surgery, may benefit from preoperative transfusion if they have moderate to severe anemia. In particular, the use of preoperative blood transfusion in neurosurgical procedures such as craniotomy for tumor resection has shown relevance due to the potential for sudden and significant blood loss during surgery. Aziz et al (2025) highlighted that preoperative identification of patients at risk allows for proactive transfusion strategies that improve intraoperative hemodynamics and postoperative outcomes (1).

Preoperative autologous blood donation (PABD) has been explored as a strategy to reduce the need for allogeneic transfusion. In a study focused on spine surgery, Qi et al (2024) demonstrated that PABD can effectively reduce donor blood exposure while maintaining perioperative safety, especially in elective surgery (2). However, PABD requires adequate planning and patient stability, making it unsuitable for emergency or urgent surgery. In addition, the limited shelf life and logistical challenges associated with autologous blood storage present barriers to its broader implementation.

Evaluation of coagulation parameters, such as international normalized ratio (INR) and activated partial thromboplastin time (aPTT), is often part of the preoperative evaluation to predict bleeding risk. However, these parameters do not reliably predict the need for plasma transfusion in all settings. D’Albuquerque et al (2025) reported that INR and aPTT were poor predictors of actual plasma transfusion requirements in liver transplantation, suggesting that clinical judgment and comprehensive assessment remain essential (3).

Patient Blood Management (PBM) programs are increasingly emphasized to optimize transfusion practices. These programs include identification and correction of anemia before surgery, minimization of blood loss during surgery, and use of restrictive transfusion strategies. Barkeji et al (2024) analyzed the utility of routine preoperative “group and save” testing and emphasized that many low-risk surgeries may not require routine pretransfusion testing unless patients have specific risk factors for bleeding or transfusion (4). Such stratification reduces unnecessary laboratory testing and conserves resources without compromising patient safety.

Overall, indications for preoperative blood transfusion are based on clinical judgment, patient-specific risk profiles, and the nature of the surgical procedure. Evidence suggests that targeted transfusion strategies and integration of PBM principles can optimize outcomes while reducing exposure to allogeneic blood products. However, ongoing research is essential to refine transfusion thresholds, improve patient stratification tools, and develop individualized management protocols tailored to surgical risk and comorbidities.

References

1. Aziz N, Waqar U, Bukhari MM, Uzair M, Ahmed S, Naz H, Shamim MS. Blood transfusions in craniotomy for tumor resection: Incidence, risk factors, and outcomes. J Clin Neurosci. 2025 Feb;132:111009. doi: 10.1016/j.jocn.2024.111009. Epub 2024 Dec 27. PMID: 39732040.
2. Qi J, Hu Y, Niu X, Dong Y, Zhang X, Xu N, Chen Z, Li W, Tian Y, Sun C. Efficacy of Preoperative Autologous Blood Donation for Surgical Treatment of Thoracic Spinal Stenosis: A Propensity-Matched Cohort Study. Orthop Surg. 2024 Dec;16(12):3068-3077. doi: 10.1111/os.14249. Epub 2024 Oct 2. PMID: 39356001; PMCID: PMC11967701.
3. Marinho DS, Rocha Filho JA, Figueira ERR, et al. International normalized ratio and activated partial thromboplastin time do not predict plasma transfusion in liver transplantation. Arq Bras Cir Dig. 2025;37:e1855. doi:10.1590/0102-6720202400061e1855
4. O’Leary L, Sherwood WB, Fadel MG, Barkeji M. Assessment of routine pre-operative group and save testing in patients undergoing cholecystectomy: a retrospective cohort study. NIHR Open Res. 2024 Oct 23;4:17. doi: 10.3310/nihropenres.13543.2. PMID: 39473540; PMCID: PMC11519620.