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Anesthesia and the Effects

Anesthesia is widely used in today’s health care practice. Whether it be for a life-

saving medical procedure, or at the local dentistry office to put a filling on a small cavity.

Anesthesia is defined as a temporary state consisting of unconsciousness, loss of

memory, lack of pain, and/or muscle relaxation. All of these things sound exactly like

what you would want during an invasive medical procedure. However, with the good

always comes the bad, and there are multiple effects that anesthetic drugs have on all

ages that are being brought to surface in today’s day and age.

First, let’s take a look at the monumental history at all of the anesthetic drugs and

how such a broad class was created. Surgery, or medical procedures can be dated back

throughout recorded history in the writings of the ancient Sumerians, Babylonians,

Assyrians, Egyptians, Greeks, Romans, Indians, and Chinese. However, surgery was not

as common back then as it is today. Matter of fact, any invasive procedure, or even mild

surgery was considered to be a last option back in the ancient days. Many people

ultimately chose death, rather than endure the pain associated with the surgical procedure

due to the lack of anesthetic drugs being invented yet. In the 19th century, antiseptic and

asepsis techniques were created to provide for a safer method to perform surgery. These

inventions, along with pharmacology and physiology made significant leaps in the

medical/surgical field, which eventually led to the development of anesthetic drugs

resulting in the control of pain associated with surgical procedures. Medical innovation

didn’t stop here. The first attempts at general anesthesia were most likely herbal

remedies, as folk medicine was the most common practice during these times. The

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opium poppy is widely believed to be used and harvested first by the Sumerians. Opium

poppy contains 12% of the analgesic alkaloid morphine, which undergoes a chemical

transformation to produce synthetic opioids for medicinal use. According to ancient

script, it is said that Hua Tuo, a famous Chinese surgeon of the 2nd century, performed

surgery after putting his patients under general anesthesia using a homemade formula.

Tuo’s homemade formula consisted of a mixture of herbal extracts and wine. Legend has

it that Tuo’s main purpose of adding the wine, was to cause the state of sedation and

unconsciousness in his patients. In 1800, Joseph Priestley discovered nitrous oxide, nitric

oxide, ammonia, hydrogen chloride, and oxygen. It wasn’t until later that Priestley

discovered the significant anesthetic properties of nitrous oxide, widely used in todays

practice as laughing gas. Priestley stated, “As nitrous oxide in its extensive operation

appears capable of destroying physical pain, it may probably be used with advantage

during surgical operations in which no great effusion of blood takes place.” Twenty

years later in 1820, Henry Hill Hickman experimented with the use of carbon dioxide as

an anesthetic drug. During his experiments, he would suffocate the test animals with

carbon dioxide, completely sedating them. Then, he would determine the effectiveness

of the carbon dioxide as an anesthetic agent by amputating one of the animal’s limbs and

observing to see if there was a response to pain stimuli by the test animal during the

procedure. Scottish obstetrician James Young Simpson was the first to use chloroform as

a form of general anesthesia. Shortly after initiating the use of this substance, it rapidly

spread to Europe. After spreading to Europe, Chloroform quickly began to spread

worldwide. A couple of years later, it was adopted by the United States and doctors

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began to use it in practice. Years later, Chloroform was found to cause a profound

number of cases of hepatic and cardiac toxicity, along with multiple cases of cardiac

dysrhythmias. The first intravenous anesthetic drug was Sodium Thiopental, in 1934. In

1939, scientists discovered Meperidine while trying to find a synthetic substitute for

Atropine. During the second half of the 20th century, Paul Janssen made critical

advancements in the science and study of anesthesiology. Janssen developed over 80

pharmaceutical compounds, of which contained nearly all of the Butyrophenone class of

antipsychotic drugs such as Haloperidol and Droperidol (PubMed 2). These drugs

continue to be implanted in today’s medical practice.

With such a broad spectrum of anesthetic drugs, it must be broken down into

subcategories. There are two broad classes of anesthesia; local and general. Local

Anesthesia is any technique used to induce the absence of sensation in a particular part of

the body. It works by blocking the nerve transmission to pain centers in the central

nervous system by binding to sodium channels. The sodium channel is an ion channel

found inside of the cell membrane of nerve cells. Therefore, the local anesthetic agent

inhibits the channel, temporarily obstructing the movement of nerve impulses near the

site of injection and surgical procedure (Oltra 1). With this type of anesthesia, there is no

change in awareness, level of consciousness, or sense of perception in other areas of the

body. Examples of when local anesthesia would be used is topical anesthesia,

infiltration, Plexus Block, Epidurals, and Subarachnoid Blocks (Oltra 3). Certain

contraindications to the use of local anesthesia include: any history of allergy to local

anesthetic agents, fear/apprehension, presence of acute inflammation or infection at site

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of insertion, use in infants and small children, mentally ill patients, hypertension, certain

developmental defects, renal dysfunction, and congenital Methemoglobinemia or any

other syndrome with reduced oxygen carrying capacity of blood. Local anesthesia also is

contraindicated in patients with hepatic dysfunction, due to the anesthetic drug not being

able to be metabolized by the liver. Patients with restricted mouth openings such as

complete Ankylosis of the temperomandibular joint are contraindicated as well (Oltra 3).

Also, patients with cardiovascular disease should not be given anesthetic drugs that

contain high concentrations of vasoconstrictors.

General Anesthesia is when a patient is sedated to an unconscious level by

anesthetic drugs. The patients vital physiologic functions such as, breathing, maintaining

blood pressure, and heart rate all continue to function properly, but are monitored closely

throughout the procedure. General anesthetic drugs are most commonly administered by

breathing a potent anesthetic gas, known as volatile anesthetics. These work by primarily

acting on the central nervous system by inhibiting nerve transmission. The inhibition of

nerve transmission occurs at synapses, where neurotransmitters are released and exert

their initial action in the body. These volatile anesthetics bind very weakly to the site of

action, which results in a weak onset of the anesthetic drug. Therefore, in order to

achieve a true anesthetic effect and sedation of the patient, a high concentration of the

drug is needed. General Anesthesia is divided into four planes. Plane one is light

anesthesia, where most reflexes are still present. Plane two is known as medium

anesthesia, most surgeries are conducted at this level. In medium anesthesia, muscles are

very relaxed, and most reflexes are absent. In plane three, deep anesthesia, intercostal

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muscles are relaxed. The patient’s ability to maintain respirations is endangered, and

his/her pupillary light reflex may be slow or absent. Plane four is called too deep of

anesthesia. In this plane, all muscles, including the diaphragm and intercostal muscles

are paralyzed leading to a medical emergency and the need of immediate resuscitation

efforts. Contraindications to the use of general anesthesia include; ingested food/liquid in

the past eight hours, esophageal problems, previous anaphylactic/allergic reactions to

general anesthesia, and difficulty of maintaining a patent airway.

Due to such a broad class of anesthetic drugs, there are many potential side effects

of anesthesia. Nausea and vomiting is a very common side effect experienced by patients

of all ages. Hypothermia is also a common side effect experienced from anesthesia. A

slight drop in body temperature is a very common side effect with the use of general

anesthesia. Certain preventive measures are taken during the operation to assure the

patient’s body temperature does not drop to a dangerously low level. Another common

side effect is impaired coordination and judgement due to the effects of anesthetic drugs

on the central nervous system. Patients experiencing impaired coordination and

judgement may experience drowsiness, lethargy, and weakness for several days

(Sheffield 2). It is also common for patients to experience blurred vision and fuzzy

thinking as well.

With such invasive procedures required for today’s advance medical diagnoses,

there are numerous potential adverse effects from anesthesia in younger adults, and older

adults. These adverse effects are more common among general anesthetic drugs, rather

than local anesthetic drugs. Injuries to the teeth, vocal cords, arteries, veins and nerves

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are a possibility with anesthesia. One of the hallmark adverse effects of anesthesia is

severe hypotension, or a dropping of the blood pressure. With this, the patient may also

experience cardiac dysrhythmias. While under anesthesia, vomiting is a risk to the

patient. If the patient were to vomit, they run the risk of breathing in their own vomit

leading to aspiration and inflammation of the lungs (Sheffield 3). Another adverse effect

noted with the use of anesthesia is cerebral anoxia, where the patient receives no oxygen

to their brain. Below is a table of certain anesthetic drugs known to cause certain

complications and adverse effects:

Drug Name Adverse Effect

Ether Liver toxicity

Methoxyflurane Nephrotoxicity

Halothane Hepatotoxicity

Nitrous Oxide Hepatotoxicity

The occurrence of anesthesia related complications tends to be higher in the aging

population rather than in the younger population (Vutskits 5). This is due to the older

patients having prior medical conditions such as cardiac disease, congestive heart failure,

and patients with severely impaired functional capacity due to heart and lung disease.

However, there are two prominent complications that are most feared by elderly patients

who are undergoing anesthesia. The first prominent complication feared is postoperative

delirium. Delirium is the most common anesthesia related complication, occurring in 10-

40% or more of older patients following surgery. In return, the older patients are at a

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greater risk for experiencing prolonged hospitalizations, leading to a worsened prognosis.

The other major complication that is feared among the elderly is postoperative cognitive

dysfunction. However, true postoperative cognitive dysfunction can only be diagnosed

through neuropsychological testing.

Scientist have researched the potential adverse effects of anesthesia for years.

Recently, they have found that general anesthesia may be a gateway to modulate synapse

formation and cause neural plasticity, especially in younger children (Todorovic 12). In

order for a person to maintain a homeostatic state of neuronal activity, there must be a

balance between excitatory and inhibitory neural activity. This balance depends on many

variables, such as averaging across time or population of neurons that is involved; the

relevant timescale; whether the synaptic activity is sustained or transient, spontaneous or

evoked (Todorovic 14). This balance is reached if the ratio between the two inputs of

excitatory and inhibitory is constant. General Anesthesia has been found to interfere with

this particular balance, resulting in temporary loss of consciousness, but it also has the

potential to cause long-term changes in brain function. Although these harmful adverse

effects have been found, research has found probable cause that under specific conditions

general anesthetics may eventually improve neural function by modulating

synaptogenesis and neural plasticity during developmental stages in childhood, and later

in adulthood. Synaptogenesis, the formation of synapses within the cerebral network, is

highly dependent on the balance of homeostasis of neuronal activity, and the fine balance

of excitatory and inhibitory neural activity. A synapsis acts as a pathway for brain cells

to communicate with one another. It is defined as, “a place where two neurons join in

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such a way that signal can be transmitted from one to another,” (Vutskits 8). Each

synapse within this network contains a variety of receptor proteins that are responsible

for altering the firing pattern of a neuron, known as neural oscillation. The human brain

contains billions of neurons, and within each neuron is a large amount of synaptic

connections to other neurons within the brain. So, when general anesthesia acts on the

balance of excitatory and inhibitory neural activity, it is also affecting the synaptogenesis

and network formation during the brain growth spurt. Synaptogenesis in the central

nervous system occurs over a protracted period of development from early childhood, to

late adulthood. The most intense phase of synaptogenesis is during the brains “growth

spurt”. This growth spurt usually occurs between the second and fourth postnatal weeks.

A study was done with monkeys about this theory, and scientist found that the monkeys

had up to a 17 fold increase in the number of synapses within a few months during the

perinatal period (Todorovic 18). In comparison, humans have a comparable number of

synaptogenesis reactions occur in the central nervous system as the monkeys do,

primarily in the third trimester of pregnancy and the first few years of postnatal life.

However, even with this many synapses, we as humans don’t use all of them. Between

puberty and adolescents, we have a natural selective pruning process of certain synaptic

channels that we will retain throughout our lives.

Scientist have pondered general anesthesia and synaptogenesis, but continue to

research extensively on the exact impact that general anesthesia has on this process

during the brains growth spurt and rapid central nervous system development, whether it

be positive or negative. Extensive research has been done on the subject of

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environmental exposure of pregnant women who worked in the hospital operating rooms

to common anesthesia gasses such as Halothane, and the potential complications. In

order to examine this theory, scientists used rats that were chronically exposed to low

concentrations of Halothane in utero, or during the early postnatal period. Research

revealed that the exposure of the Halothane to pregnant women during fetal central

nervous system development would in fact “permanently impair dendritic arbor

development, decrease synaptic density, and induce significant functional cognitive

deficits in learning and behavior,” (Todorovic 13). This wasn’t enough proof for

scientists, they wanted to further study the effect of anesthetic drugs on synaptogenesis

during the brain growth spurt. Therefore, they exposed rodents to Midazolam-Nitrous

Oxide- Isoflurane anesthesia for six hours straight. Evidence from this experiment

showed that long term exposure to this drug induced nueropil scarcity, mitochondrial

degeneration, and a 30-40% decrease in synaptic generation in the developing subiculum

when evaluated one week after exposure. Nueropil’s are dense networks of

interconnected nerve fibers and their branches and synapses fused together by glial

filaments. Mitochondria are known as the powerhouse of the cell, so degeneration of

mitochondria plays a big role in the adverse effects of this anesthetic drug on the central

nervous system. Mitochondria make adenosine triphosphate (ATP) which is used in

cellular cycles, cellular growth and cellular death. Mitochondria also play an important

role in fueling synaptogenesis and maintaining synaptic plasticity, which is the ability of

synapses to strengthen or weaken over an extended period of time. Degenerative

mitochondria leads to reduced ATP production, and increased generation of reactive

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oxygen species. These reactive oxygen species are known to play an important role in

the progression of neurodegenerative diseases, such as Huntington’s Disease, Parkinson’s

Disease, and Friedreich’s Ataxia. A seminal series of recent works provided further

insights into the molecular mechanisms involved in general anesthesia induced synaptic

loss and mitochondrial degeneration during the early stages of the brain growth spurt

(Vutskits 21). These works were done on 5-7 day old neuronal cultures that were isolated

form neonatal rodent brains in the laboratory. Research found that general anesthesia

induced cultures by Isoflurane and Propofol caused a decreased presynaptic release of

tissue plasminogen activator. This plasminogen activator is responsible for converting

plasminogen to plasmin, which in return is required to convert pro-BDNF to BDNF.

Mature BDNF cells act to promote cellular survival and synaptic plasticity. This

evidence concludes and supports the hypothesis that there is an experimental link

between early anesthesia exposure and impaired cognitive functioning. How these

changes are related to impaired neural circuitry development remains to be explored, but

late research has showed that a growing body of human evidence has indicated that many

psychiatric and neurological disorders ranging from mental retardation to severe

Alzheimers, are accompanied by significant alterations in synaptic density and structure

(PubMed 17). Therefore one can say that it is more than enough data to at most speculate

that anesthetic induced alterations in synaptic density and synaptogenesis could very well

be a contributing factor to impaired neurocognitive performance in humans.

Research didn’t stop once scientists found the potential complications that

anesthesia can cause on synaptogenesis and neural plasticity. As pediatric specialists

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become increasingly aware that surgical anesthesia may have lasting effects on the

developing brains of young children, new research suggests the threat may also apply to

adult brains as well (Vutskits 24). Researchers report that testing in laboratory mice

shows anesthesia’s neurotoxic effects depend on the age of brain neurons—not the age of

the animal undergoing anesthesia, as it was once believed. Researches from Cincinnati

Children’s Hospital conducted an experiment to investigate this hypothesis. For the

experiment, researchers exposed three classes of mice; newborn, juvenile, and young

adult to Isoflurane to doses comparable to those used in surgical procedures. The

newborn mice exhibited widespread neuronal loss in their forebrain structures, however

had no significant damage to the dentate gyurs. Dentate gyurs are the part of the brain

that help control learning and memory. However, the effect of the Isoflurane in juvenile

mice was opposite that of the newborn mice. The juvenile mice had minimal neuronal

impact in the forebrain, but had significant cellular death in the dentate gyrus, resulting in

severe learning and memory impairments. Similar results were found in the young adult

mice. This is what led researches to believe that older brains were just as vulnerable to

anesthesia induced cognitive impairment as young brains were.

The field of anesthesia is rapidly growing. However, it seems that the list of

potential adverse effects and anesthetic induced complications may be growing too. It is

clear that anesthetic drugs can cause common side effects in both young and elder

patients, these are to be expected. In contrast, we have learned that instead of anesthetic

drugs inducing complications on a certain age group of patients more so than others, they

are instead inducing complications on a certain age group of neurons. This causes major

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difficulty to the health field today as we are forced to use anesthetic drugs for certain

procedures. This issue will continue to be researched and developed, and hopefully will

just be another milestone in the advancement of safe practice of anesthesia.

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Personal Reflection

This particular research paper was very interesting to me. My goal is to become a

Certified Registered Nurse Anesthetist (CRNA) after I complete my BSN and gain

experience in the critical care settings. The most interesting thing to me was probably the

depth of problems in synaptogenesis that general anesthesia can cause. I knew that

anesthesia in general has the potential to cause side effects and more severe adverse

effects in some patients. However, the fact that it had the ability to modulate the

formations of synapses in our cerebral network, such an integral part to our cognitive

functioning. I found it interesting that they linked this complication to the advancement

of Alzheimer’s disease. My grandma has Alzheimer’s, and had many neck surgeries

when she was younger. During these surgeries, General Anesthesia was used so it really

makes me ponder the thought if the anesthesia had an effect on her synaptogenesis

process and caused the advancement of her Alzheimer’s. I also had no idea of the rich

history of anesthetic drugs before this research paper. The most interesting part was

when I read about the scientist who tested the anesthetic drugs by inducing the animals

and then amputating a limb and watching for a reaction to pain stimuli. I was astonished

by this technique as it seems there could have been a more humane way to test the drugs,

but maybe not in such early history. The most difficult part of this research paper was

probably trying to understand the research that I gathered. I was reading about the nueral

plasticity and synaptogenesis, and had no idea what those two words even meant.

However, after researching about both topics and learning the processes behind each, it

was easier to understand the true effect anesthesia had on them. All in all, this paper was

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a great learning process for me and really taught me a lot about not only anesthesia, but

its adverse effects and potential long term complications associated with it. It made me

only more anxious to become a CRNA, and maybe one day contribute to the extensive

research being done on anesthetic drugs.

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Works Cited

Vutskits, Laszlo. "General Anesthesia: A Gateway to Modulate Synapse Formation Neural Plasticity."

PubMed 2nd ser. 115.5 (2012): 1-25. 2 Aug. 2012. Web. 13 Mar. 2015.

Todorovic, Vesna. "Developmental Synaptogenesis and General Anesthesia: A Kiss of Death?" Research

Gate. PubMed, 1 July 2012. Web. 10 Mar. 2015.

"The History of Local Anesthesia." National Center for Biotechnology Information. U.S. National Library

of Medicine, 1 Apr. 2009. Web. 30 Apr. 2015.

<http://www.ncbi.nlm.nih.gov/pubmed/17612366>.

Peñarrocha-Oltra, David, Javier Ata-Ali, María J. Oltra-Moscardó, and María Peñarrocha-Diago. "Side

Effects and Complications of Intraosseous Anesthesia and Conventional Oral Anesthesia."

Medicina Oral, Patología Oral Y Cirugía Bucal. Medicina Oral S.L., 17 May 2012. Web. 30

Apr. 2015. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476103/>.

"Result Filters." National Center for Biotechnology Information. U.S. National Library of Medicine, 3 Nov.

1992. Web. 30 Apr. 2015. <http://www.ncbi.nlm.nih.gov/pubmed/1418699>.

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