Up to this point, we have learned of the incredible evolution of anesthesia since its advent, allowing millions of life-saving, painless, sterile, successful surgeries to take place every day. We have also learned of careful considerations in vulnerable populations. This last blog post will top off the topic of surgery in the brain injured patient.
Surgery can be lifesaving and can also vastly improve quality of life. Over the past decade, however, growing evidence has linked surgery, such as cardiac and orthopedic procedures, to brain pathology similar to that of other neurologic diseases in which the brain is the primary target of injury.
Nature Immunology1
Are the effects of general anesthesia on the brain entirely reversible?
The question of whether the brain reverts entirely to the state it was in preoperatively once the anesthetic agent is removed, remains. Mounting evidence suggests that the effects may be longer lasting than once thought or anticipated due to long-term changes within the brain. Due to the mechanism of these agents acting on receptor targets throughout the brain, the compensating capacity in vulnerable populations is reduced. These populations include developing children and older adults, though focus is emerging towards another group in this population of vulnerability being those with brain injury of any severity as well as other brain diagnoses.
This remains unanswered though some studies suggest the negative effects in attention and memory can languish for days, months or even years.
The stress of surgery: Can we separate the potential long-term effects of general anesthesia from the stress of surgery itself?
Aside from the anesthesia, consider all the different factors that play into surgery. Consider the bright lights in a light-sensitive patient, the various noises of beeping and monitors in a noise-sensitive patient, the blood sugar fluctuations from overnight fasting which may already be erratic, the anxiety and stress associated with the procedure, and the inflammation produced.
There is no doubt that this type of environment could be very triggering to a concussed or post-concussed patient already struggling to be present in such environments. It’s important to note that while this environment can be very triggering to a brain injured patient, if it were solely the culprit those symptoms would likely not languish for months after the exposure. Once removed from the stimuli, the brain should calm depending on the individual within days to a few weeks.
Does the surgical site play a role?
This question emerged from my personal experience following my concussion. It got me thinking that maybe a huge component of my negative outcome after shoulder labrum repair during the early days of my TBI recovery was at least partially a result of the proximity to the neck leading to a favoring of the shoulder and thus further imbalance in the musculature of the neck and surrounding structures.
The surgical site may certainly play a role although there is no clarifying answer on this. In theory, a surgery to the knee or foot may have a more favorable outcome in a concussed patient versus a surgery of the upper body. It’s important to remember that every concussion has neck involvement but every injury to the neck is not accompanied by a concussion. Unfortunately, the neck is often overlooked and left untreated in a good majority of concussed patients. This in combination with a surgical procedure in close proximity may exacerbate the already prevalent issue, though this remains theoretical at this point.
Inflammation and the immune response after surgery
Any trauma to the body produces inflammation, and surgery is a controlled trauma to the body. The link between cognitive impairment from systemic inflammation is not well understood. There is now mounting evidence that the inflammatory cascade can also trigger the brain’s innate immune system leading to long-term cognitive impairment and the development or worsening of other symptoms.
A review article1 addresses neuroinflammation after surgery. The cellular damage that is a result of surgery activates immune cells that are important in restoring homeostasis, but this activation leads to systemic inflammation. If this immune function is impaired or dysregulated, it can drive perioperative neurocognitive disorders (PNDs).
…seemingly harmless interventions like a common surgery to repair a broken limb can overwhelm the immune system and become the driver of further complications such as delirium and other perioperative neurocognitive disorders.
Nature Immunology1
Also triggered by surgical trauma is the coagulation system. This is also necessary for body homeostasis but on the other hand can be a driving force for cognitive deficits. This process could go haywire if fibrinogen, a protein necessary for clotting, enters the brain through the blood brain barrier (BBB). Fibrinogen deposition was found in the brain’s hippocampus just 24 hours after orthopedic surgery. This very deposition has been implicated in traumatic brain injury, Alzheimer’s and MS.
The BBB protects and regulates what goes in and out of the brain. A consideration is that the BBB is often damaged after brain trauma leaving it exceptionally vulnerable. This may be an important mechanism for systemic inflammation to cause inflammation within the brain. Preclinical models demonstrated surgery and anesthesia can lead to increased permeability of the BBB, allowing inflammatory cells into the hippocampus which plays a huge role in learning and memory. A good majority of TBI patients already have a leaky BBB so this combination may be bad news.
Researchers discovered the two proteins associated with Alzheimer’s went from normal levels pre-surgery to increased levels associated with mild cognitive impairment six months post-surgery in human patients. This has also been seen in other studies to increase just 48 hours post-surgery.2 A separate study3 looking at the immune response before and after surgery showed interesting results. The researchers used brain PET scans to image this response and found a significant decrease in brain glial activity early post-operatively and also months after. This study demonstrates an association between the immune response and cognitive impairment. The more dysregulated the immune response, the worse the cognitive impairment.
“The Immune Response of the Human Brain to Abdominal Surgery”3
Certain anesthetics may strengthen areas in the brain
Researchers have looked into whether anesthetics can help protect or benefit the brain as well. Ketamine has been used for its anti-depressant effects and may strengthen neural connections and reset the brain’s award and disappointment centers. It may reduce post-operative cognitive impairment and is theorized it does this by modifying the immune response. Other anesthetics such as propofol and isoflurane in certain doses have also been used as antidepressant therapy.
Bottom line: The negative effects from surgery are likely multifactorial
Is general anesthesia the culprit for decline in cognition and other symptoms after surgery? Is it the inflammation produced? Is this due to a leaky blood brain barrier or dysregulated immune response? Is it a combination of all of the above?
While many questions remain unanswered, it seems most plausible to be a combination of all of the above – systemic inflammation, the hospital setting, an already vulnerable brain with pre-existing cognitive deficiencies, leaky blood brain barrier, dysfunctional immune response. Elective surgery should be carefully considered in the concussed and post-concussed patient and the risks and benefits should be discussed thoroughly before proceeding. Careful consideration should also be placed on anesthesia and a conversation with the anesthesiologist can be helpful.
How can we better protect the brain when going under the knife?
Support the immune system
Optimize nutrition
Protect the blood brain barrier
Curcumin, resveratrol, vitamin D, B vitamins, magnesium, omega 3
Discuss the possibility of using EEG to fine-tune anesthesia dosing with your anesthesiologist
Discuss the risks and benefits of the surgery with your physician and surgeon before proceeding
If time slowly steals our memories, let us at least ensure that interventions like surgery do not accelerate the natural course of time, especially on an already vulnerable brain
The advent of general anesthesia completely altered the course of surgery from a barbaric, hazardous, Frankenstein-like horror to a humane and often life-saving intervention. Thanks to general anesthesia, the trauma associated with the surgery to both the medical staff and patients due to horrific screams, pain, terror and death was eliminated.
Some of the first substances attempted to minimize pain associated with surgery were wine and opium. For hundreds of years, various herbs were used. Ether was first synthesized from alcohol in 1540 followed by the discovery of nitrous oxide (laughing gas) in 1722. Both ether and laughing gas were used solely for entertainment purposes and ether follies became a popular gathering. People would gather, sniff ether together and get high. It wasn’t until the mid-19th century when these entertaining intoxicants were considered for medical use.
William Morton, dentist, was experimenting ways in which he could perform dental procedures pain-free on his patients and first considered laughing gas. At one of the ether follies, Harvard chemist, Charles Jackson, witnessed a man who sustained a significant leg injury while high on ether and he did not show any evidence of pain. He advised Morton to use ether for his procedures.
Morton proceeded with the use of ether in several dental procedures. He then got in contact with surgeon, John Warren, who gave him permission to anesthetize his patient with ether. Together, they proceeded with the first public demonstration of surgery using ether-induced general anesthesia on October 16, 1846, now called Ether Day. In just a few short months following, the world of surgery took a drastic change as ether-induced anesthesia was used in surgeries across the globe.1 Today, we have various anesthetic agents to choose from for surgery.
As a topic that continues to be brought to light, I felt it best to address it again. Many concussed patients might find themselves in a similar situation – deciding to proceed with a surgery or not. The risks in relation to brain injury recovery and the potential for worsening preoperative symptoms and even causing a prolonging of concussion symptoms are not typically discussed at length prior to proceeding.
Thankfully, with the evolution from literally no sedation or anesthesia, to wine and opium, to laughing gas and ether follies, and now to a wide variety of anesthetic agents, we can undergo surgery without the unspeakable and unfathomable agony experienced in the past. Only, underneath the surface, long-lasting lingering effects of general anesthesia may still continue to haunt patients. With the evidence currently available, can we really blame anesthesia for such outcomes?
I have connected with several people who wanted to gain more insight and discuss moving forward with a surgery during their own respective brain injury recoveries. Faced again with a similar predicament recently, I was reminded of my blog post entailing an elective surgery that occurred within three months of my TBI. While awareness has heightened regarding this very topic, more research is required. I reviewed some of the literature discussed in my previous blog post which will be re-visited but also pose new questions and concerns regarding surgical outcomes in the concussed patient.
I was astounded by the percentage of concussed patients that are faced with this same predicament. Within one year of concussion, typically in the first month, about 8-12% of these patients will present for surgery.2 Another study showed 5% of recently concussed patients underwent elective surgeries unrelated to the concussion within one week of injury.3 The significant percentage of concussed patients faced with the prospect of going under the knife could simply be due to the increased risk of musculoskeletal injury they face due to changes in attention, cognition, hand eye coordination, reaction time, etc. In reality, these percentages may be higher due to the fact that there are no concussion screening tests implemented preoperatively. With such a prevalence of concussion patients presenting for surgery, the outcomes should be considered.
There are some questions that come to mind when considering surgery during TBI recovery:
How will surgery itself affect the brain and specifically how will it affect brain recovery?
How will general anesthesia affect the brain and specifically how will it affect brain recovery?
How likely is it that surgery will worsen preoperative concussion symptoms?
Are the effects of general anesthesia on the brain entirely reversible?
How will the inflammation produced from surgery affect the brain?
How will surgery recovery in combination with concussion recovery affect quality of life?
Does the specific surgical site play a part in recovery of the brain?
Here’s what we do know:
Surgery itself is stressful and multifactorial!
General anesthesia can negatively affect the brain.
All surgeries and trauma to any part of the body produces inflammation.
Inflammation can negatively affect the brain.
The general consensus from surveyed anesthesiologists is that elective surgery should be postponed until patient concussion symptoms are stable or have completely abated. Keep in mind, the brain continues to heal long after symptoms disappear. Symptom disappearance does NOT mean the brain is fully healed.
Advice to the concussed patient considering or undergoing surgery:
My best advice to any patient with brain trauma who is in a predicament because they are recommended surgery during brain injury recovery and to those who are unable to postpone the surgery is to read the science and literature that is available. It is best to empower yourself with this information and bring it to your provider for discussion. Consider your current quality of life and think about how the recovery of another part of the body would affect your quality of life which includes your mental health. Consider your current symptoms and the risk involved with worsening of those very symptoms postoperatively.
Discuss these concerns with your surgeon and also ask to discuss these concerns with the anesthesiologist that will be in the surgery with you. There are now intraoperative goals specifically for TBI patients. As this is still an issue on the rise, it is wise to discuss these established goals5 with both your surgeon but more importantly, your anesthesiologist:
Cerebral blood flow autoregulation is likely impaired after TBI so even mild hypotension should be avoided to reduce the risk of cerebral hypoperfusion
Maintenance of mean arterial pressure at the patient’s baseline value or higher is therefore appropriate
Hypovolemia should be treated using isotonic normal saline rather than hypotonic fluids, which could cause cerebral edema, or colloids, which have been associated with poor outcomes in TBI
Since hypocarbia (reduced carbon dioxide in the blood) in the face of impaired pressure autoregulation may lead to cerebral ischemia, mechanical ventilation should be adjusted to maintain normocarbia during surgery
In my next post, I will discuss the specific questions posed in this post in detail and review studies available on this front. Is general anesthesia the culprit or are the compounding factors surrounding surgery itself to blame for poor outcomes and worsening of preoperative symptoms?
Prior to my concussion, I was undergoing a work up for a hockey related shoulder injury. I was diagnosed with a torn labrum. I actually received my MRI results the day after my concussion. I saw the orthopedic surgeon who recommended I have surgery to repair it. There was no rush on having the repair; prolonging it just meant I would have to experience the pain and periodic subluxation (partial dislocation) in the shoulder a bit longer. I wasn’t even planning on having the surgery until after that hockey season so then I could rehab it and be ready by the time the next season was due to start.
Because of my concussion recovery and the prospect of being out of the season for the shoulder injury, I thought I would put this surgery off until I was fully recovered. I thought I would be fully recovered from the concussion fairly quickly and the hockey season would be ending mid-April so I booked the surgery for the first week of May. This way, I could play and finish the season before going forward with the operation. The thought of having this surgery during my concussion recovery didn’t even cross my mind.
I was at an appointment with my concussion specialist and he just happened to see this surgery scheduled in my chart. The doctor said, “Why not have the surgery done now while you are out of work?” I didn’t think through how this might affect my concussion recovery but thought if the concussion specialist is recommending it and doesn’t see an issue with it, I should trust his advice. No potential negative outcomes were discussed regarding the impact it could have on my concussion recovery and I didn’t stop to think about it.
I scheduled the surgery for January of 2019, not even three months after my concussion. Going under (anesthesia) was great – it was the first time I had slept deeply in months. I woke up back to reality and was thinking, can someone just put me back to sleep? Unfortunately, this deep sleep wasn’t worth it and I was in for a brutal awakening.
The shoulder surgery was successful and everything went as planned. I was in a sling for six weeks. About three weeks following the surgery, I started physical therapy. The first step of physical therapy was to increase mobility in the shoulder with passive movements (they moved my arm for me). This seemed to be going okay until we had to start the strengthening phase of physical therapy.
At that point, I had already started to struggle mentally and physically. Prior to the surgery, I had struggled with losing my routine and normal activity level. My quality of life was drifting to the poor category. The surgery added to the physical restrictions I had been dealing with that further challenged my mental bounds. The combination of the concussion recovery and shoulder recovery left me feeling so disabled and I started to feel even more down about it with every day that had passed. My daily headaches worsened and episodic migraines became chronic, daily migraines. My brain fog and neurological fatigue became difficult to manage.
The strengthening phase of physical therapy was disheartening, frustrating and belittling. I was unable to add any weight to the strengthening activities because every time we added a resistance band or even one pound, my neck would flare up so badly causing my headaches to become so debilitating that I had to lie in bed for days at a time. This was the first time I realized just how messed up my neck was and that it wasn’t addressed at all.
I was struggling to understand my body. I was struggling to understand why one pound could cause me to be completely incapacitated. I was losing hope in both recoveries and my spirits began to wither. After trying to strengthen the shoulder in physical therapy for about three months, they decided to abandon that plan and attempt to loosen my neck. This continued through the month of May without any improvement.
My headaches continued to worsen among other symptoms – neck pain, insomnia, dizziness, dysautonomia, memory, focus, attention, mental clarity. It became so bad that I was collapsing on the floor and experiencing syncopal episodes quite frequently along with chest pain, shortness of breath and extreme fatigue. It seemed like they didn’t really know what to do with me at that point and I didn’t know what to do with me either.
Good rest following a concussion is absolutely necessary for the brain to heal. After any surgery, sleep and rest is hard to come by. It is typically broken sleep and not restorative. And in my case, sleeping with a sling on every night was nearly impossible. Prior to this, I was already struggling with severe insomnia so this was not a good addition to my recovery.
Physical therapy for my shoulder was abandoned in May of 2019. I persisted to have a lot of pain and stiffness in the shoulder because I never completed the strengthening phase and proper rehab. My shoulder was so weak, my arm felt like a useless, dangling appendage. It seemed like good health was drifting further and further away from me. It wasn’t until starting physical therapy at a new center (The PT Center) the beginning of 2020 where they fully addressed the shoulder and neck. It took about six months to get to a point where we could add weight without wrecking my neck and head.
If you are suffering through a complicated recovery and you are not progressing, you often search to find solutions and learn more about your condition to ultimately achieve relief. This is often how someone becomes knowledgeable in their prospective diagnosis and this is how patients become experts in their diagnoses. Even after all of my education and work as a physician assistant, I did not have the knowledge that I do now about concussions and TBI. I have spent a great deal of time learning more and more in order to find solutions.
I took my doctor’s word for it that going ahead with the surgery would be completely fine at that point in time. In no way am I saying never trust your doctors, but rather, take the time to weigh the options and maybe even get a second opinion before proceeding. I never stopped to truly weigh the risks and benefits and how it might affect my brain recovery which was my top priority. This process has taught me that being your own advocate is so important.
My important takeaway: Avoid surgery unless absolutely necessary while recovering from a brain injury or the aftermath.
What happens following brain trauma that might make one susceptible to worsened outcomes with surgery? What does the research say?
The Cascade That Follows Brain Trauma
Immediately following a brain injury, the brain goes into a state of neuro-inflammation propagated by complex changes at the cellular level. This process has been referred to as the neurometabolic cascade. I wanted to touch on this cascade in order to paint you a picture of the vulnerable state of the brain and how surgery might affect it. This is an extremely condensed version of it, not even scratching the surface.
Definitions:
Neurons: Basic working units of the brain forming a communication network, connecting every part of the body. Each neuron consists of a cell body and an axon.
Axon: electrical signaling tail which I like to call the communication highway. Myelin sheath is the insulation of the axon aiding in communication and speeding up signals
Ions: calcium, potassium, sodium, chloride. Flow in and out of the neuronal cell body and travel down the axons as signaling molecules
Mitochondria: powerhouse of the cell that produces energy
ATP: energy for our cells, made from glucose. Glucose from food -> reaches brain -> enters neurons -> mitochondria turns glucose into ATP for energy
Glutamate: excitatory chemical messenger that in excess causes damage and even cell death
Free radicals: unstable molecules that contain oxygen and easily react with other molecules (opposite of antioxidants)
Blood brain barrier: close knit group of blood vessels and cells that regulate what passes into the brain
Glial cells: Support neurons by supplying oxygen, nutrients and insulate axons. Serve as part of the immune system by aiding in removal of cellular debris, dead neurons and toxins.
Let’s break it down:
Brain trauma occurs: brain jolts hitting the skull causing tearing or shearing of nerve tissue and axons
Axons stretch, becoming porous with holes or break completely, allowing leakage of ions (excess sodium and calcium in, excess potassium out). Broken axons release damaging products and toxins
Excess calcium damages the cell and disrupts cellular transmission. Mitochondria is poisoned. Communication highway (axon) severed.
Neurons begin to rapid fire = dysfunctional communication
Snowball Effect: surrounding cell damage and cell death secondary to toxins
Energy Crisis: Ion pump works frantically to attempt to re-establish a balance
No energy to clear abnormal proteins and toxins from in and outside the cell. Cells starve
Inflammation: Buildup of toxins and inflammatory proteins attacks myelin sheath and cell. Glutamate released causing further damage and excitotoxicity
Decreased blood flow = decreased ATP to brain = worsening energy depletion
Impaired ability to regulate blood flow, impaired response to changes in blood pressure
Free radical accumulation: more inflammation
Blood brain barrier permeability: stuff that shouldn’t be allowed in the brain comes in
Glial cells and axons damaged…inflammation continues
Photo Credit: Toronto Star Graphic
The pathophysiological changes that occur in the brain following trauma is a very complex cascade. Some of the changes are still not completely understood. I have questioned whether these changes can increase the risk of anesthesia and contribute to worsened concussion symptoms to the already vulnerable brain as I experienced following my surgery.
Blood Pressure Alterations and Inflammation in Surgery
Sometimes during surgery, you can experience low blood pressure. Even a mild change in blood pressure could affect the blood flow to the brain which has already been compromised by the injury. The brain after such an injury is already under a great deal of stress and has an impaired ability to regulate blood flow as well as an impaired response to changes in blood pressure. If the brain is already experiencing a deficit in oxygen, even a slight drop during surgery could potentially worsen the vulnerable state that the brain is already in.
Surgery not only has an effect on blood pressure but also glucose regulation and autonomic function. The brain after trauma already experiences impairment in glucose regulation. Autonomic dysfunction is quite common following a head injury and I was already diagnosed with it, so it is not inconceivable that surgery can worsen this process. There have been many cases of patients with a new diagnosis of autonomic dysfunction following a surgery even without head trauma! Sounds like the perfect storm.
Following any surgery, your body produces an inflammatory response. This response is necessary because it sets the stage for the healing process to occur. Every surgery causes stress to the body. When I had my surgery, my body was already under stress from the high inflammatory state sustained from the TBI which I had not fully recovered from yet. I already likely had inefficient communicating cells and altered blood flow. The surgery was trauma on top of trauma or inflammation on top of inflammation.
I still question if this further inflammation added to my complicated and prolonged recovery. I don’t think it’s a coincidence that my concussion symptoms worsened dramatically after the surgery. It felt like it opened up yet another negative cascade in my body.
What Does the Research Say?
I have spent some time looking into studies on post-concussion patients undergoing surgery and the outcomes. My concerns are validated in several different published articles. Unfortunately, no randomized, controlled trials on the outcomes of anesthesia and surgery on post-concussion patients exist. Given that it is quite common for patients with concussive symptoms to present for surgery, with estimates ranging from 6-7%, it seems this should be something to consider for these patients.4
Within one year of concussion, typically in the first month, about 8-12% of these patients will present for surgery.4Another study showed 5% of recently concussed patients underwent elective surgeries unrelated to the concussion within one week of injury.1 In reality, these percentages may be higher due to the fact that there are no concussion screening tests implemented preoperatively. With such a prevalence of concussion patients presenting for surgery, the outcomes should be considered.
In a panel session for the International Anesthesia Research Society, it was concluded that future studies are needed for more data but until that is available, the perioperative period of patients with recent concussion should be considered as a potential time period for secondary brain injury. Interestingly, anesthesiologists were surveyed on this matter and most said they would delay elective surgeries until full resolution of concussion symptoms.4
Similarly, in a review published in Current Opinion in Anaesthesiology, the consensus is that both acute and chronic repeated concussion may put the brain at risk for secondary injury due to its already vulnerable state. They go on to suggest further research is needed but that it seems reasonable to delay elective procedures until resolution of clinical symptoms.8
An interesting quote from a published scientific review in the Korean Journal of Anesthesiology: “It is possible that the use of anesthesia may create a neurocognitive exacerbation worsening pre-surgical symptoms such as headache, dizziness, postural instability, sleep disturbances, memory impairment, decreased processing speed, attention deficit, fatigue, depression, and anxiety. This concern again suggests that it may be safest to postpone elective surgery until the patient is ready to return to school or normal daily activities if possible.”9 This is particularly interesting to me because I experienced worsening of all of these symptoms post-op.
In an article published in the Journal of Neurosurgical Anesthesiology, patients with pre-op cognitive deficits had an increased risk for worsening post-op cognitive symptoms.10 This study was not dedicated to concussion patients, so is only suggestive of this risk.In another review from Current Opinion in Anaesthesiology, the conclusion is that those suffering post-concussion syndrome may be particularly clinically susceptible to worsening outcomes due to physiologic instability.11
The data from a retrospective study on patients from July 1, 2005, to June 30, 2015, who underwent surgery after concussion suggests clinicians should have an increased awareness for concussion in patients who have recently sustained trauma including those without a formal diagnosis of such because of the vulnerable state of the brain. It is again suggested that clinicians consider postponing elective surgery until resolution of concussion symptoms.2
While there isn’t much research on post-concussion patients and surgical outcomes, it is something that should 100% be considered and something clinicians should have an increased awareness of. At the very least, risk and benefit should be considered. Even the theoretical risk of exacerbating post-concussion symptoms with surgery should be discussed with patients.
This is definitely something I would consider if discussing elective surgery with my own recently concussed patients. It seems most reasonable to delay elective surgery until concussion symptoms have completely abated, and something I wish I had researched prior to my surgery.
If I had known what I know now about brain trauma and the cascade that follows, I would have never had this surgery during the recovery of my vulnerable, post-concussed brain.
Sources
1. Abcejo, A. and Pasternak, J., 2018. Is a Concussed Brain a Vulnerable Brain? Anesthesia after Concussion – Anesthesia Patient Safety Foundation.
2. Abcejo, A. S., Savica, R., Lanier, W. L., & Pasternak, J. J. (2017). Exposure to Surgery and Anesthesia After Concussion Due to Mild Traumatic Brain Injury. Mayo Clinic Proceedings, 92(7), 1042–1052.doi:10.1016/j.mayocp.2017.03.012.
3. Büki, A., & Povlishock, J. T. (2005). All roads lead to disconnection? – Traumatic axonal injury revisited. Acta Neurochirurgica, 148(2), 181–194.doi:10.1007/s00701-005-0674-4.
4. Guay, Christian A., 2018. Concussion in the Perioperative Period: A Common Condition Requiring More Investigation. International Anesthesia Research Society. IARS Annual Meeting.
5. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014;75 Suppl 4(0 4):S24-S33. doi:10.1227/NEU.0000000000000505.
6. Katayama, Y., Becker, D. P., Tamura, T., & Hovda, D. A. (1990). Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. Journal of Neurosurgery, 73(6), 889–900.doi:10.3171/jns.1990.73.6.0889.
7. Mele C, Pingue V, Caputo M, Zavattaro M, Pagano L, Prodam F, Nardone A, Aimaretti G, Marzullo P. Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury. International Journal of Molecular Sciences. 2021; 22(5):2686. doi:10.3390/ijms22052686.
8. Pasternak, Jeffrey J.; Abcejo, Arnoley S. Anesthesia and the brain after concussion, Current Opinion in Anaesthesiology: October 2020 – Volume 33 – Issue 5 – p 639-645. doi: 10.1097/ACO.0000000000000906.
9. Rasouli MR, Kavin M, Stache S, Mahla ME, Schwenk ES. Anesthesia for the patient with a recently diagnosed concussion: think about the brain!. Korean J Anesthesiol. 2020;73(1):3-7. doi:10.4097/kja.19272.
10. Sheshadri, V., Manninen, P., & Venkatraghavan, L. (2017). Anesthesia in Patients With Postconcussion Syndrome. Journal of Neurosurgical Anesthesiology, 29(2), 185. doi:10.1097/ana.0000000000000269.
11. Tasker, R. C. (2017). Anesthesia and concussion. Current Opinion in Anaesthesiology, 30(3), 343–348.doi:10.1097/aco.0000000000000459.
