Complex surgical procedures, innovative anesthetic techniques and the need to protect a patient’s airways contribute to the requirement for mechanical ventilation during general anesthesia.1 Anesthesia ventilators are specifically designed to fit the settings associated with general anesthesia, and may be necessary before, during and after a procedure.1 After all, general anesthetic drugs affect breathing control and the activity of respiratory muscles, and surgery-related positioning of patients and potential displacement of intraabdominal and thoracic organs can further affect ventilation.1 General anesthesia reduces functional residual capacity (FRC), which results in lower lung volume2 and elasticity3 and increased airway resistance.3 Positive end-expiratory pressure (PEEP) is a ventilation technology that can increase FRC during general anesthesia, thus combatting the respiratory complications that may arise throughout the perioperative period.3

The technology of PEEP is fairly complex. PEEP works to prevent airways from closing and alveoli (tiny air sacs in the lungs) from collapsing, known as atelectasis.2 Atelectasis is a collapse of lung tissue with loss of volume, which can cause difficulty breathing or respiratory failure.4 Lung collapse is also associated with inflammation and bacterial infections, such as pneumonia.5 Though PEEP may not always improve oxygenation during a procedure,2,3 it is useful in reducing airway closures and atelectasis and is considered protective ventilation.2 PEEP is applied during the end of expiration to maintain alveolar pressure above atmospheric pressure.6 Applying PEEP may affect cardiac function and vital organ perfusion, so anesthesia providers using PEEP should closely monitor patients for complications in non-respiratory organs.6

Several studies have approached the efficacy of PEEP provided during general anesthesia (i.e., extrinsic PEEP).7 According to an article by Hedenstierna, PEEP may be of limited value in patients who are anesthetized for only one to two hours, but could be useful if a procedure lasts for several hours.2 PEEP should be just high enough to keep airways and alveoli open as to not do any harm to the heart or other organs.2 Another recent study by Pereira et al. found that PEEP requirements vary widely among patients receiving mechanical ventilation during anesthesia for abdominal surgery.8 Thus, PEEP settings should be individualized to improve oxygenation, raise driving pressures and prevent postoperative atelectasis.8 Östberg et al. found that in nonabdominal surgery, PEEP was helpful in minimizing atelectasis in healthy lungs and maintaining oxygenation, rendering recruitment maneuvers—which are more sustained, extensive increases in airway pressure9—unnecessary.10 Despite some successes, the perioperative use of PEEP remains controversial and its importance is still unclear.10 Indeed, a systematic review by Barbosa et al. found insufficient evidence on the benefits of intraoperative PEEP for preventing postoperative mortality and respiratory complications.11 While PEEP may be vital for patients with acute respiratory distress, its role in general anesthesia is still up for debate given limited evidence.6

Mechanical ventilation during general anesthesia is complex, often requiring technologies such as PEEP. PEEP works to reduce atelectasis and prevent airway closure, and it may help in maintaining oxygenation as well.2,8,10 Its role in opening alveoli has the potential to prevent postoperative pulmonary complications, but a lack of studies prevents researchers from making conclusions about the efficacy or necessity of intraoperative PEEP. Future studies should focus on the possible short- and long-term benefits of PEEP, along with strategies to individualize PEEP for optimal patient care.

1. Pelosi P, Brusasco C, Abreu MGd. Mechanical Ventilation during General Anesthesia. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. New York: McGraw-Hill Education; December 4, 2012.
2. Hedenstierna G. Optimum PEEP During Anesthesia and in Intensive Care is a Compromise but is Better than Nothing. Turk J Anaesthesiol Reanim. 2016;44(4):161–162.
3. Wahba RW. Perioperative functional residual capacity. Canadian Journal of Anesthesia. 1991;38(3):384–400.
4. Çoruh B, Niven AS. Atelectasis. The Merck Manuals. Kenilworth, NJ: Merck Sharp & Dohme Corporation; April 2019.
5. van Kaam AH, Lachmann RA, Herting E, et al. Reducing atelectasis attenuates bacterial growth and translocation in experimental pneumonia. American Journal of Respiratory and Critical Care Medicine. 2004;169(9):1046–1053.
6. Vargas M, Sutherasan Y, Gregoretti C, Pelosi P. PEEP Role in ICU and Operating Room: From Pathophysiology to Clinical Practice. The Scientific World Journal. 2014;2014:8.
7. Sagana R, Hyzy RC. Positive end-expiratory pressure (PEEP). In: Finlay G, ed. UpToDate. Web: Wolters Kluwer; March 26, 2019.
8. Pereira SM, Tucci MR, Morais CCA, et al. Individual Positive End-expiratory Pressure Settings Optimize Intraoperative Mechanical Ventilation and Reduce Postoperative Atelectasis. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2018;129(6):1070–1081.
9. Hess DR. Recruitment Maneuvers and PEEP Titration. Respiratory Care. 2015;60(11):1688–1704.
10. Östberg E, Thorisson A, Enlund M, Zetterström H, Hedenstierna G, Edmark L. Positive End-expiratory Pressure Alone Minimizes Atelectasis Formation in Nonabdominal Surgery: A Randomized Controlled Trial. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2018;128(6):1117–1124.
11. Barbosa FT, Castro AA, de Sousa‐Rodrigues CF. Positive end‐expiratory pressure (PEEP) during anaesthesia for prevention of mortality and postoperative pulmonary complications. Cochrane Database of Systematic Reviews. 2014(6).

Among health professionals, it is common knowledge that children are “not just little adults.”1 Children have anxieties,2 anatomies3 and pathologies4 that are unique from those found in adults. Children’s different perspectives and reactions are particularly important to surgery, which can be induce trauma for young people.5 Behavioral preparation programs that focus on skills acquisition and modeling are sometimes offered to pediatric patients and their families to prepare everyone for surgery.5 Because untreated anxiety and pain have implications for children’s short- and long-term recovery, future interactions with the medical system and mental health, it is crucial that clinicians take special precautions for children undergoing procedures.5 Given their role in pain management, anesthesia providers are essential to making the child’s experience as pleasant as possible.6 Anesthesiology practitioners have opportunities before, during and after a child’s procedure to ensure satisfactory pain management and anxiety reduction.7

The anesthesia provider should begin by providing the patient and family with preoperative education and preparation.7 A review by Fortier and Kain recommends individualized web-based behavioral preparation programs, as they are convenient and can provide unique care to patients and families based on at-home dynamics.5 The pediatric anesthesiologist, perhaps along with a Child Life Specialist,8 should provide parents and children with information about anesthesia induction and equipment in order to reduce anxiety.9 A study by Bogusaite et al. on pediatric preoperative information needs found that parents and children most often requested information about duration of anesthesia, recovery from anesthesia, the postoperative regimen and postoperative pain management.10 The families also preferred information provided in written form on the day before the procedure.10 In addition to speaking with families, the anesthesia provider is also responsible for picking appropriate anesthetic drugs and preparing the surgical space. The American Academy of Pediatrics (AAP) has developed guidelines for preparing the pediatric anesthesia environment, including tailoring pain management to the procedure, the patient’s pain perception and the options available for analgesia.9 The anesthesia provider should collaborate with other health professionals to prepare the operating room with appropriate-sized equipment.9

After patient education and preparation are complete, the anesthesia provider should remain vigilant throughout the procedure. Different medications may be useful depending on the child’s condition or procedure type. Topical anesthetics may be useful for outpatient pediatric procedures, but may be ineffective for more invasive surgeries.11 In their study of pain management for pediatric urology procedures, Morrison et al. found that nerve blocks were the most commonly used intraoperative anesthetics, followed by epidural or caudal.12 Some discrepancies existed with regards to opioid use and age limits.12 While recent researchers aim use local anesthetics and reduce opioid use,13 there is a lack of consensus in pain management for many types of procedures.12,14 This may be due to the individualized nature of pediatric anesthesia.14 For example, Nowicki et al. found that a variety of medications could be used in pediatric orthopedic surgery depending on the patient’s perception of pain, including nonopioid and opioid analgesia; local anesthetic injection; and regional analgesia such as intrathecal morphine, epidural therapy and peripheral nerve blocks.14 Another study found that intraoperative use of methadone for children undergoing the Nuss procedure was effective in reducing postoperative pain.15 Thus, intraoperative medication administration depends on the patient’s age and condition, the type of procedure and the family’s choices.

The anesthesia provider should base postoperative pain management on the pediatric patient’s own perception of pain, using a pain management “ladder.”16 The type of drug used can range from a nonsteroidal anti-inflammatory (NSAID) to intravenous opioids, depending on the type of procedure and pain level.16 Corticosteroids may also be useful in reducing postoperative nausea and vomiting (PONV) and pain.16 In addition to providing pain relief, the anesthesiology practitioner should monitor the patient’s status to prevent complications. Vital signs monitoring standards differ by age, co‐morbidities, extent and complexity of the surgery and use of sedative medications, with particular attention given to infants less than one year of age.16 Before the patient is discharged, the anesthesia providers should give the family detailed instructions for pain management, perhaps with a highly structured format.17

Pain management for pediatric patients is dissimilar from pain management for adults. The anesthesia provider is responsible for preparing the child and family for the procedure, for providing accurate dosing of appropriate anesthetic medications and for closely monitoring the patient after surgery.7 Pain management may depend on the child’s perception of pain, age, stage of development, condition and type of procedure. Future research should aim to standardize pediatric pain management and provide education to pediatric health professionals.18

1. Arbuckle R, Abetz-Webb L. “Not Just Little Adults”: Qualitative Methods to Support the Development of Pediatric Patient-Reported Outcomes. The Patient: Patient-Centered Outcomes Research. 2013;6(3):143–159.
2. Kingery JN, Roblek TL, Suveg C, Grover RL, Sherrill JT, Bergman RL. They’re not just “little adults”: Developmental considerations for implementing cognitive-behavioral therapy with anxious youth. Journal of Cognitive Psychotherapy. 2006;20(3):263.
3. Thomas NJ, Jouvet P, Willson D. Acute Lung Injury in Children—Kids Really Aren’t Just “Little Adults”. Pediatric Critical Care Medicine. 2013;14(4):429–432.
4. Schroeder KM, Hoeman CM, Becher OJ. Children are not just little adults: Recent advances in understanding of diffuse intrinsic pontine glioma biology. Pediatric Research. 2014;75(1):205–209.
5. Fortier MA, Kain ZN. Treating perioperative anxiety and pain in children: A tailored and innovative approach. Pediatric Anesthesia. 2015;25(1):27–35.
6. Blount RL, Zempsky WT, Jaaniste T, et al. Management of pediatric pain and distress due to medical procedures. Handbook of Pediatric Psychology, 4th Ed. New York, NY, US: The Guilford Press; 2009:171–188.
7. Howard D, Davis KF, Phillips E, et al. Pain management for pediatric tonsillectomy: An integrative review through the perioperative and home experience. Journal for Specialists in Pediatric Nursing. 2014;19(1):5–16.
8. What Is a Certified Child Life Specialist? The Child Life Profession 2018.
9. Section on Anesthesiology. Guidelines for the Pediatric Perioperative Anesthesia Environment. Pediatrics. 1999;103(2):512–515.
10. Bogusaite L, Razlevice I, Lukosiene L, Macas A. Evaluation of Preoperative Information Needs in Pediatric Anesthesiology. Medical Science Monitor. 2018;24:8773–8780.
11. Maclaren JE, Cohen LL. Interventions for paediatric procedure-related pain in primary care. Paediatrics & Child Health. 2007;12(2):111–116.
12. Morrison K, Herbst K, Corbett S, Herndon CDA. Pain Management Practice Patterns for Common Pediatric Urology Procedures. Urology. 2014;83(1):206–210.
13. Frizzell KH, Cavanaugh PK, Herman MJ. Pediatric Perioperative Pain Management. The Orthopedic Clinics of North America. 2017;48(4):467–480.
14. Nowicki PD, Vanderhave KL, Gibbons K, et al. Perioperative pain control in pediatric patients undergoing orthopaedic surgery. The Journal of the American Academy of Orthopaedic Surgeons. 2012;20(12):755–765.
15. Singhal NR, Jones J, Semenova J, et al. Multimodal anesthesia with the addition of methadone is superior to epidural analgesia: A retrospective comparison of intraoperative anesthetic techniques and pain management for 124 pediatric patients undergoing the Nuss procedure. Journal of Pediatric Surgery. 2016;51(4):612–616.
16. Vittinghoff M, Lönnqvist P-A, Mossetti V, et al. Postoperative pain management in children: Guidance from the pain committee of the European Society for Paediatric Anaesthesiology (ESPA Pain Management Ladder Initiative). Pediatric Anesthesia. 2018;28(6):493–506.
17. Walther-Larsen S, Aagaard GB, Friis SM, Petersen T, Møller-Sonnergaard J, Rømsing J. Structured intervention for management of pain following day surgery in children. Pediatric Anesthesia. 2016;26(2):151–157.
18. Lundeberg S. Pain in children—are we accomplishing the optimal pain treatment? Pediatric Anesthesia. 2015;25(1):83–92.

Chronic kidney disease (CKD) is a general term for a group of heterogenous disorders affecting kidney structure and function.1 CKD is classified according to disease severity, which is based on glomerular filtration rate (GFR) and albuminuria, and clinical diagnosis, which involves cause and pathology.1 Worldwide, diabetes mellitus is the most common cause of CKD, but herbal and environmental toxins can also play a role.2 Though CKD can be detected with routine laboratory tests1 and prevented with interventions,2 it can lead to various health complications and ultimately mortality.2 Awareness of CKD remains low in many communities and even among physicians,2 so health professionals of all specialties should look for signs of possible CKD in their patients. For example, anesthesia providers must account for CKD before, during and after a procedure to avoid complications or fatality. Given the higher rates of perioperative morbidity and mortality among patients with CKD,3 anesthesiology practitioners should be especially cautious with patient care.

Before a procedure begins, the anesthesiologist is responsible for screening for CKD and comorbid conditions.3,4 Patients with CKD may present with chronic or acute renal failure, may be undergoing dialysis or may have impaired renal function after a transplant.3 Mortality rates for patients with CKD are particularly high, with estimated mortality rates of 10 to 20 percent for patients with end-stage renal disease who undergo cardiac surgery.3 Given these data, anesthesia providers should do their best to prepare patients for surgery. For one, obtaining an acceptable potassium level before surgery may be important to avoiding complications.3 Treatment for high potassium levels include polystyrene binding resins, insulin in combination with intravenously administered dextrose, intravenously administered bicarbonate and even dialysis.3 Other CKD-related preoperative conditions include acid-base disorders, bleeding, anemia and hypertension, all of which should be controlled before surgery.3 An anesthesiology practitioner can also provide CKD patients with antibiotic prophylaxis to avoid postoperative infection.3 Finally, as cardiovascular disease is the greatest cause of mortality in patients with CKD, preoperative cardiac evaluation—such as exercise testing, radionuclide scanning and stress echocardiography—is crucial to an anesthesiologist’s practice.3,4 In order to prevent intraoperative or postoperative issues, any comorbid disorders should be treated adequately before surgery in a patient with CKD.3

Once surgery is underway, the anesthesia provider should follow strict, standardized guidelines for patients with CKD. A paper by Olivero suggests precautions for anesthesia in patients with renal failure, including not administering large amounts of intravenous (IV) fluids, choosing the proper IV solution according to electrolyte levels, avoiding ACE inhibitors and beta-blockers and lowering calcium levels with citrate administrations.5 Also, according to Tsubokawa, GFR in patients with CKD is correlated with drug or metabolite clearance.6 When drugs such as anesthetics, morphine, muscle relaxants, antibiotics and phosphodiesterase III inhibitors are administered to a CKD patient, drug concentrations are increased and pharmacological effects last longer than in other patients.6 Therefore, dosages of these drugs should be adjusted based on renal function factors, such as creatinine clearance.6 Patients with CKD can also be at higher risk for aspiration due to delayed gastric emptying,7 and their ventilation should be highly controlled to avoid circulatory depression.7 Overall, the anesthesia provider’s foci during the intraoperative period for CKD patients should be fluid management, glucose control and ventilation.4,7,8

Postoperative management is also key in a CKD patient’s care. If morphine or other opioids were used, the patient should be carefully monitored after the procedure for delayed onset respiratory depression.9 Also, because the dose required to maintain a neuromuscular block in CKD patients is lower than normal, these patients are at risk for postoperative residual curarization (PORC; i.e., residual paresis after emergence from anesthesia).9 Additionally, a systematic review found that preoperative renal dysfunction was a common predictor of postoperative renal failure,10 so anesthesia providers should monitor patients for postoperative signs of renal failure. Finally, a study by Ackland et al. found that lower preoperative GFR was associated with more frequent morbidity and longer hospital stay for CKD patients undergoing orthopedic surgery.11 Taken together, these results show that anesthesia providers should account for intraoperative anesthetics and preoperative conditions in CKD patients’ postoperative care.

Anesthesia for patients with CKD can be complex. Before a procedure, an anesthesiologist should assess the patient’s level of CKD with laboratory testing and provide treatment for comorbid conditions. Intraoperative fluid management, glycemic control and ventilation are crucial to avoiding complications. Postoperative management includes close patient monitoring for signs of renal and other issues. Given the potential gravity of CKD, anesthesiology organizations should create standardized care recommendations for patients with CKD based on their disease severity and diagnosis.

1. Levey AS, Coresh J. Chronic kidney disease. The Lancet. 2012;379(9811):165–180.
2. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: Global dimension and perspectives. The Lancet. 2013;382(9888):260–272.
3. Krishnan M. Preoperative care of patients with kidney disease. American Family Physician. 2002;66(8):1471–1476.
4. Meersch M, Schmidt C, Zarbock A. Patient with chronic renal failure undergoing surgery. Current Opinion in Anesthesiology. 2016;29(3):413–420.
5. Olivero JJ, Sr. Administration of Anesthesia to Patients with Renal Failure. Methodist DeBakey Cardiovascular Journal. 2015;11(3):197.
6. Tsubokawa T. Pharmacokinetics of anesthesia related drugs in patients with chronic kidney disease. Masui. 2013;62(11):1293–1303.
7. Butterworth JF, Mackey DC, Wasnick JD. Anesthesia for Patients with Kidney Disease. Morgan and Mikhail’s Clinical Anesthesiology: McGraw-Hill Education; 2013.
8. Campbell JP, Cousins JM. Anesthesia for dialysis patients. In: Jones SB, Berns JS, O’Connor MF, eds. UpToDate November 10, 2018.
9. Craig RG, Hunter JM. Recent developments in the perioperative management of adult patients with chronic kidney disease. British Journal of Anaesthesia. 2008;101(3):296–310.
10. Novis BK, Roizen MF, Aronson S, Thisted RA. Association of preoperative risk factors with postoperative acute renal failure. Anesthesia & Analgesia. 1994;78(1):143–149.
11. Ackland GL, Moran N, Cone S, Grocott MPW, Mythen MG. Chronic Kidney Disease and Postoperative Morbidity After Elective Orthopedic Surgery. Anesthesia & Analgesia. 2011;112(6):1375–1381.

Achieving a smooth and rapid emergence from general anesthesia is a primary goal in all surgical cases. Previously, it was assumed that induction and emergence were mirror processes. However, recent findings suggest that the situation is much more complex. For example, different neural circuits govern each process, resulting in an asymmetry – or, hysteresis – in the anesthetic concentration required for induction versus emergence. More precisely, the anesthetic concentration at which consciousness is lost is higher than the anesthetic concentration at which consciousness is regained.

Hysteresis is a property of dynamic systems in which the output is dependent not only on the input, but also on the past input (i.e. path dependency). This results in lagging (where changes in output lag behind changes in input) and rate dependence (where the input-output relationship depends on the value of the input) (1). As an example from physics, the phase transition of water is an asymmetrical process, resulting in different temperatures for melting and freezing points. Of more relevance to anesthesiologists, hysteresis is apparent in anesthetic dose-response loops (2). By generating dose-response data from insects and mammals, for example, Friedman et al showed that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical, i.e. hysteretic (3).

A related phenomenon is neural inertia, proposed by Dr. Max Kelz as a biologically conserved process through which neural circuits resist behavioral state transitions, such as from consciousness to unconsciousness (3). In the context of anesthesia, the area under an anesthetic dose-response loop is a mathematical representation of neural inertia (4). Based on an analysis of such dose-response loops, Friedman et al also showed that hysteresis and, consequently, neural inertia are subject to genetic and pharmacological manipulation. For example, dopamine β- hydroxylase knockout animals demonstrated increased sensitivity to induction, with a disproportionate delay in emergence, indicating a significant increase in neural inertia (3). Based on results from several loss-of-function experiments, Joiner et al further proposed that neural feedback loops account for neural inertia (5). In this model, a bistable switch is hypothesized to regulate the transition between wakefulness to natural sleep, as well as between consciousness and anesthetic-induced unconsciousness (6).

An emerging field, chaos theory, attempts to quantify the depth of anesthesia based on nonlinear dynamics. In nature, there are many examples of nonlinear processes, such as the spread of epidemics, the propagation of flames, and the shifting of sand dunes (7). The brain itself performs computations in both linear and nonlinear fashions. More interestingly, Eaglman et al showed that, relative to standard spectral measures, nonlinear dynamics analyses of EEG signals better predicted states of consciousness in patients anesthetized with propofol (8). Therefore, the transition between consciousness and unconscious may involve nonlinear phenomena, in addition to being hysteretic.

The concept of neural inertia provides some insight into the mechanisms of drug-induced unconsciousness and anesthetic emergence, particularly by shedding light on the path dependency of such behavioral state transitions. More importantly, neural inertia may underlie anesthesia related complications, such as delayed emergence and intraoperative awareness. For example, researchers hypothesize that increased neural inertia accounts for the delayed emergence observed after intracranial surgery under general anesthesia. Similarly, decreased neural inertia – due to polymorphisms affecting neural circuits regulating neural inertia – may explain why some people are at a higher risk for awareness under general anesthesia (9).

In summation, neural inertia creates resistance to the behavioral state transition between consciousness and unconsciousness. Because distinct neurochemical systems regulate each process, there is an asymmetry, or hysteresis, in the anesthetic concentration required for induction versus emergence (4). Furthermore, the drug-induced transition from consciousness to unconsciousness may involve nonlinear processes, based on recent mathematical models of EEG activity. An improved understanding of neural inertia and its clinical implications may allow anesthesiologists to tailor their techniques and drugs to individual phenotypes (4). In turn, anesthesiologists can minimize morbidities (e.g. delayed emergence, intraoperative awareness, postoperative confusion, and delirium) that contribute to stress disorders, prolonged hospital stays, and high healthcare costs (4).

References

1) Morris KA. What is Hysteresis? Appl Mech Rev. 2011;64:050801–14.

2) Escolar JD, Escolar A. Lung hysteresis: a morphological view. Histol Histopathol. 2004;19:159–66.

3) Friedman EB, Sun Y, Moore JT, et al. A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia. PLoS One. 2010;5:e11903.

4) Tarnal V, Vlisides PE, Mashour GA. The Neurobiology of Anesthetic Emergence. J Neurosurg Anesthesiol. 2016;28(3):250–255.

5) Joiner WJ, Friedman EB, Hung HT, et al. Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness. PLoS Genet. 2013;9:e1003605.

6) Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257–63.

7) Stam CJJ. Nonlinear dynamical analysis of EEG and MEG: Review of an emerging field. Clin Neurophysiol. 2005;116(10):2266–301.

8) Eagleman SL, Chander D, Reynolds C, Ouellette NT, MacIver MB. Nonlinear dynamics captures brain states at different levels of consciousness in patients anesthetized with propofol. PLoS One. 2019;14(10):e0223921.

9) Aranake A, Gradwohl S, Ben-Abdallah A, et al. Increased risk of intraoperative awareness in patients with a history of awareness. Anesthesiology. 2013;119:1275–83.

A growing body of evidence suggests that neuroinflammation plays a role in the development of neurodegeneration in patients with Alzheimer’s disease. Modulation of neuroinflammation may be possible early in the pathogenesis, though less so once cognitive symptoms appear. In particular, events during the perioperative period can modulate neuroinflammatory pathways and thereby impact the pathogenesis of Alzheimer’s disease. Such perioperative events include the anesthetic, surgery, pain, and sepsis (1).

Inflammation in the central nervous system (CNS) is mediated by cellular and humoral mechanisms which primarily involve the microglial cell. Derived from myeloid precursors in the bone marrow, microglia evenly distribute throughout the brain and perform several age-dependent functions, including brain development, synaptic plasticity, immune surveillance, and repair (2). In response to stressors – such as ischemia, trauma, and pathogens – microglia become activated and migrate to the affected areas. Subsequently, microglia undergo morphological changes that cause them to resemble macrophages, the phagocytic cells of the immune system (2). This morphological change heralds the production of cytokines, chemokines, growth factors, and reactive oxygen species, as well as the initiation of phagocytosis.

Migroglia activation during a neuroinflammatory response can be both beneficial and harmful (3). On the one hand, microglia clear apoptotic cells, dysfunctional synapses, and amyloid-β plaque, as well as promote repair by secreting neurotrophic factors and producing anti-inflammatory cytokines, such as interleukin-10. On the other hand, microglia activation is accompanied by a pro-inflammatory response mediated by interleukin-beta, interleukin-6, tumor necrosis factor, and reactive oxygen species, resulting in synaptic, neuronal, and ultimately cognitive dysfunction. Although the precise mechanisms remain unclear, neuroinflammation is a hallmark of Alzheimer’s disease. For example, researchers observed that patients taking anti-inflammatory drugs, e.g. for arthritis, displayed a lower incidence and later onset of Alzheimer symptoms (4). Based on such observations, randomized trials were performed, which confirmed the protective effects of anti-inflammatory drugs, such as ibuprofen, on the development of Alzheimer’s disease (5). Additional studies show increased levels of activated microglia and pro-inflammatory proteins (e.g. interleukin-6 and tumor necrosis factor) in patients with neurodegenerative diseases (6). That said, it remains unclear whether Alzheimer’s disease is primarily due to amyloidopathy (i.e. accumulation of amyloid), the brain’s inflammatory response, or dysfunctional microglial responses.

In the perioperative period, both anesthesia and surgery can modulate inflammation and cognition. For example, there is substantial evidence for the anti-inflammatory properties of local anesthetics, namely lidocaine (7). Furthermore, some studies demonstrate that isoflurane attenuates peripheral and central inflammatory markers (e.g. interleukin-beta, interleukin-6, tumor necrosis factor, and microglia), albeit other studies provide conflicting data (8-9). The possible mechanisms for anesthetic effects on inflammation include alterations in the blood brain barrier permeability (10), alterations in monocyte recruitment (11), and direct interactions with signaling molecules, such as integrins (12).

It is also well established that surgery plays a role in the inflammatory response, with the magnitude of inflammation roughly proportional to the amount of tissue damage (13). However, robust peripheral responses attenuate before manifesting in the CNS, likely due to the short-lived nature of humoral factors, as well as the blood brain barrier. Nevertheless, cytokines may enter the CNS in the event of blood brain barrier damage or by active transport across epithelial cells (14). Upon entering the CNS, these signals may activate microglia and initiate the neuroinflammatory response – though administration of a variety of anti-inflammatory drugs can prevent such events.

Much of the evidence supporting an interaction between surgery, inflammation, postoperative cognitive dysfunction, and Alzheimer’s disease comes from animal studies. For example, in young WT mice, surgery but not anesthesia led to neuroinflammation and acute cognitive losses (15). Overall, the current literature suggests that anesthesia alone causes only a modest neuroinflammatory response, while surgery causes a robust peripheral inflammatory response that is attenuated in the CNS. However, few studies examine the long term consequences of anesthesia and surgery on the pathology of Alzeihmer’s disease. Considering that many patients with cognitive complaints undergo surgery each year, there is ample opportunity to further study this complex issue in humans.

References

1) Tang J et al. Anesthetic modulation of neuroinflammation in Alzheimer’s disease. Current opinion in anaesthesiology. 2011;24: 389-94.

2) Prinz M, Mildner A. Microglia in the CNS: immigrants from another world. Glia. 2011;59:177–187.

3) Schlachetzki JC, Hull M. Microglial activation in Alzheimer’s disease. Curr Alzheimer Res. 2009;6:554–563.

4) Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer’s disease or mild cognitive impairment? Front Aging Neurosci. 2010;2:article 19, 1–14.

5) lad SC, Miller DR, Kowall NW, et al. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008;70:1672–1677.

6) Agostinho P, Cunha RA, Oliveira C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des. 2010;16:2766–2778. Current review of the interaction between neuroinflammation and Alzheimer’s disease.

7) Cassuto J, Sinclair R, Bonderovic M. Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiol Scand. 2006;50:265–282.

8) Adams SD, Radhakrishnan RS, Helmer KS, et al. Effects of anesthesia on lipopolysaccharide-induced changes in serum cytokines. J Trauma. 2008;65:170–174.

9) Xu X, Kim JA, Zuo Z. Isoflurane preconditioning reduces mouse microglial activation and injury induced by lipopolysaccharide and interferon-gamma. Neuroscience. 2008;154:1002–1008. Isoflurane exposure can enhance pro-inflammatory influences in the brain.

10) Tetrault S, Chever O, Sik A, et al. Opening of the blood-brain barrier during isoflurane anaesthesia. Eur J Neurosci. 2008;28:1330–1341.

11) Lehmberg J, Waldner M, Baethmann A, et al. Inflammatory response to nitrous oxide in the central nervous system. Brain Res. 2008;1246:88–95.

12) Zhang H, Astrof NS, Liu JH, et al. Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems. FASEB J. 2009;23:2735–2740.

13) Kohl BA, Deutschman CS. The inflammatory response to surgery and trauma. Curr Opin Crit Care. 2006;12:325–332.

14) Banks WA, Erickson MA. The blood-brain barrier and immune function and dysfunction. Neurobiol Dis. 2010;37:26–32.

15) Wan Y, Xu J, Ma D, et al. Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology. 2007;106:436–443.