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Wiedemann 1
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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