Muscle relaxant

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Muscle_relaxant

A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as "centrally acting" muscle relaxant, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxant, the term is commonly used to refer to spasmolytics only.

History

The earliest known use of muscle relaxant drugs was by natives of the Amazon Basin in South America who used poison-tipped arrows that produced death by skeletal muscle paralysis. This was first documented in the 16th century, when European explorers encountered it. This poison, known today as curare, led to some of the earliest scientific studies in pharmacology. Its active ingredient, tubocurarine, as well as many synthetic derivatives, played a significant role in scientific experiments to determine the function of acetylcholine in neuromuscular transmission. By 1943, neuromuscular blocking drugs became established as muscle relaxants in the practice of anesthesia and surgery.

The U.S. Food and Drug Administration (FDA) approved the use of carisoprodol in 1959, metaxalone in August 1962, and cyclobenzaprine in August 1977.

Other skeletal muscle relaxants of that type used around the world come from a number of drug categories and other drugs used primarily for this indication include orphenadrine (anticholinergic), chlorzoxazone, tizanidine (clonidine relative), diazepam, tetrazepam and other benzodiazepines, mephenoxalone, methocarbamol, dantrolene, baclofen, Drugs once but no longer or very rarely used to relax skeletal muscles include meprobamate, barbiturates, methaqualone, glutethimide and the like; some subcategories of opioids have muscle relaxant properties, and some are marketed in combination drugs with skeletal and/or smooth muscle relaxants such as whole opium products, some ketobemidone, piritramide and fentanyl preparations and Equagesic.

Neuromuscular blockers

Detailed view of a neuromuscular junction:

1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine receptor
5. Mitochondrion

Main article: Neuromuscular-blocking drug

Muscle relaxation and paralysis can theoretically occur by interrupting function at several sites, including the central nervous system, myelinated somatic nerves, unmyelinated motor nerve terminals, nicotinic acetylcholine receptors, the motor end plate, and the muscle membrane or contractile apparatus. Most neuromuscular blockers function by blocking transmission at the end plate of the neuromuscular junction. Normally, a nerve impulse arrives at the motor nerve terminal, initiating an influx of calcium ions, which causes the exocytosis of synaptic vesicles containing acetylcholine. Acetylcholine then diffuses across the synaptic cleft. It may be hydrolysed by acetylcholine esterase (AchE) or bind to the nicotinic receptors located on the motor end plate. The binding of two acetylcholine molecules results in a conformational change in the receptor that opens the sodium-potassium channel of the nicotinic receptor. This allows Na⁺
and Ca²⁺
ions to enter the cell and K⁺
ions to leave the cell, causing a depolarization of the end plate, resulting in muscle contraction. Following depolarization, the acetylcholine molecules are then removed from the end plate region and enzymatically hydrolysed by acetylcholinesterase.

Normal end plate function can be blocked by two mechanisms. Nondepolarizing agents, such as tubocurarine, block the agonist, acetylcholine, from binding to nicotinic receptors and activating them, thereby preventing depolarization. Alternatively, depolarizing agents, such as succinylcholine, are nicotinic receptor agonists which mimic Ach, block muscle contraction by depolarizing to such an extent that it desensitizes the receptor and it can no longer initiate an action potential and cause muscle contraction. Both of these classes of neuromuscular blocking drugs are structurally similar to acetylcholine, the endogenous ligand, in many cases containing two acetylcholine molecules linked end-to-end by a rigid carbon ring system, as in pancuronium (a nondepolarizing agent).

Chemical diagram of pancuronium, with red lines indicating the two acetylcholine "molecules" in the structure

Spasmolytics

Main article: antispasmodic

 

A view of the spinal cord and skeletal muscle showing the action of various muscle relaxants – black lines ending in arrowheads represent chemicals or actions that enhance the target of the lines, blue lines ending in squares represent chemicals or actions that inhibit the target of the line

The generation of the neuronal signals in motor neurons that cause muscle contractions is dependent on the balance of synaptic excitation and inhibition the motor neuron receives. Spasmolytic agents generally work by either enhancing the level of inhibition or reducing the level of excitation. Inhibition is enhanced by mimicking or enhancing the actions of endogenous inhibitory substances, such as GABA.

Terminology

Because they may act at the level of the cortex, brain stem, or spinal cord, or all three areas, they have traditionally been referred to as "centrally acting" muscle relaxants. However, it is now known not every agent in this class has CNS activity (e.g. dantrolene), so this name is inaccurate.

Most sources still use the term "centrally acting muscle relaxant". According to MeSH, dantrolene is usually classified as a centrally acting muscle relaxant. The World Health Organization, in its ATC, uses the term "centrally acting agents", but adds a distinct category of "directly acting agents", for dantrolene. Use of this terminology dates back to at least 1973.

The term "spasmolytic" is also considered a synonym for antispasmodic.

Clinical use

Spasmolytics such as carisoprodol, cyclobenzaprine, metaxalone, and methocarbamol are commonly prescribed for low back pain or neck pain, fibromyalgia, tension headaches and myofascial pain syndrome. However, they are not recommended as first-line agents; in acute low back pain, they are not more effective than paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs), and in fibromyalgia they are not more effective than antidepressants. Nevertheless, some (low-quality) evidence suggests muscle relaxants can add benefit to treatment with NSAIDs. In general, no high-quality evidence supports their use. No drug has been shown to be better than another, and all of them have adverse effects, particularly dizziness and drowsiness. Concerns about possible abuse and interaction with other drugs, especially if increased sedation is a risk, further limit their use. A muscle relaxant is chosen based on its adverse-effect profile, tolerability, and cost.

Muscle relaxants (according to one study) were not advised for orthopedic conditions, but rather for neurological conditions such as spasticity in cerebral palsy and multiple sclerosis. Dantrolene, although thought of primarily as a peripherally acting agent, is associated with CNS effects, whereas baclofen activity is strictly associated with the CNS.

Muscle relaxants are thought to be useful in painful disorders based on the theory that pain induces spasm and spasm causes pain. However, considerable evidence contradicts this theory.

In general, muscle relaxants are not approved by FDA for long-term use. However, rheumatologists often prescribe cyclobenzaprine nightly on a daily basis to increase stage 4 sleep. By increasing this sleep stage, patients feel more refreshed in the morning. Improving sleep is also beneficial for patients who have fibromyalgia.

Muscle relaxants such as tizanidine are prescribed in the treatment of tension headaches.

Diazepam and carisoprodol are not recommended for older adults, pregnant women, or people who have depression or for those with a history of drug or alcohol addiction.

Mechanism

Because of the enhancement of inhibition in the CNS, most spasmolytic agents have the side effects of sedation and drowsiness and may cause dependence with long-term use. Several of these agents also have abuse potential, and their prescription is strictly controlled.

The benzodiazepines, such as diazepam, interact with the GABA_A receptor in the central nervous system. While it can be used in patients with muscle spasm of almost any origin, it produces sedation in most individuals at the doses required to reduce muscle tone.

Baclofen is considered to be at least as effective as diazepam in reducing spasticity, and causes much less sedation. It acts as a GABA agonist at GABA_B receptors in the brain and spinal cord, resulting in hyperpolarization of neurons expressing this receptor, most likely due to increased potassium ion conductance. Baclofen also inhibits neural function presynaptically, by reducing calcium ion influx, and thereby reducing the release of excitatory neurotransmitters in both the brain and spinal cord. It may also reduce pain in patients by inhibiting the release of substance P in the spinal cord, as well.

Clonidine and other imidazoline compounds have also been shown to reduce muscle spasms by their central nervous system activity. Tizanidine is perhaps the most thoroughly studied clonidine analog, and is an agonist at α₂-adrenergic receptors, but reduces spasticity at doses that result in significantly less hypotension than clonidine. Neurophysiologic studies show that it depresses excitatory feedback from muscles that would normally increase muscle tone, therefore minimizing spasticity. Furthermore, several clinical trials indicate that tizanidine has a similar efficacy to other spasmolytic agents, such as diazepam and baclofen, with a different spectrum of adverse effects.

The hydantoin derivative dantrolene is a spasmolytic agent with a unique mechanism of action outside of the CNS. It reduces skeletal muscle strength by inhibiting the excitation-contraction coupling in the muscle fiber. In normal muscle contraction, calcium is released from the sarcoplasmic reticulum through the ryanodine receptor channel, which causes the tension-generating interaction of actin and myosin. Dantrolene interferes with the release of calcium by binding to the ryanodine receptor and blocking the endogenous ligand ryanodine by competitive inhibition. Muscle that contracts more rapidly is more sensitive to dantrolene than muscle that contracts slowly, although cardiac muscle and smooth muscle are depressed only slightly, most likely because the release of calcium by their sarcoplasmic reticulum involves a slightly different process. Major adverse effects of dantrolene include general muscle weakness, sedation, and occasionally hepatitis.

Other common spasmolytic agents include: methocarbamol, carisoprodol, chlorzoxazone, cyclobenzaprine, gabapentin, metaxalone, and orphenadrine.

Thiocolchicoside is a muscle relaxant with anti-inflammatory and analgesic effects and an unknown mechanism of action. It acts as a competitive antagonist at GABA_A and glycine receptors with similar potencies, as well as at nicotinic acetylcholine receptors, albeit to a much lesser extent. It has powerful proconvulsant activity and should not be used in seizure-prone individuals.

Side effects

Patients most commonly report sedation as the main adverse effect of muscle relaxants. Usually, people become less alert when they are under the effects of these drugs. People are normally advised not to drive vehicles or operate heavy machinery while under muscle relaxants' effects.

Cyclobenzaprine produces confusion and lethargy, as well as anticholinergic side effects. When taken in excess or in combination with other substances, it may also be toxic. While the body adjusts to this medication, it is possible for patients to experience dry mouth, fatigue, lightheadedness, constipation or blurred vision. Some serious but unlikely side effects may be experienced, including mental or mood changes, possible confusion and hallucinations, and difficulty urinating. In a very few cases, very serious but rare side effects may be experienced: irregular heartbeat, yellowing of eyes or skin, fainting, abdominal pain including stomach ache, nausea or vomiting, lack of appetite, seizures, dark urine or loss of coordination.

Patients taking carisoprodol for a prolonged time have reported dependence, withdrawal and abuse, although most of these cases were reported by patients with addiction history. These effects were also reported by patients who took it in combination with other drugs with abuse potential, and in fewer cases, reports of carisoprodol-associated abuse appeared when used without other drugs with abuse potential.

Common side effects eventually caused by metaxalone include dizziness, headache, drowsiness, nausea, irritability, nervousness, upset stomach and vomiting. Severe side effects may be experienced when consuming metaxalone, such as severe allergic reactions (rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue), chills, fever, and sore throat, may require medical attention. Other severe side effects include unusual or severe tiredness or weakness, as well as yellowing of the skin or the eyes. When baclofen is administered intrathecally, it may cause CNS depression accompanied with cardiovascular collapse and respiratory failure. Tizanidine may lower blood pressure. This effect can be controlled by administering a low dose at the beginning and increasing it gradually.

Anesthesia awareness

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Anesthesia_awareness

Awareness under anesthesia, also referred to as intraoperative awareness or accidental awareness during general anesthesia (AAGA), is a rare complication of general anesthesia where patients regain varying levels of consciousness during their surgical procedures. While anesthesia awareness is possible without resulting in any long-term memory, it is also possible for the victim to have awareness with explicit recall, where victims can remember the events related to their surgery (intraoperative awareness with explicit recall).

Intraoperative awareness with explicit recall is an infrequent condition with potentially devastating psychological consequences. While it has gained popular recognition in media, research shows that it only occurs at an incidence rate of 0.1-0.2%. Patients report a variety of experiences ranging from vague, dreamlike states to being fully awake, immobilized, and in pain from the surgery. This is usually caused by the delivery of inadequate anesthetics relative to the patient's requirements. Risk factors for intraoperative awareness include anesthetic factors (i.e. use of neuromuscular blockade drugs, use of intravenous anesthetics, technical/mechanical errors), surgical factors (i.e. cardiac surgery, trauma/emergency, C-sections), and patient factors (i.e. reduced cardiovascular reserve, history of substance use, history of awareness under anesthesia).

Currently, the mechanism behind consciousness and memory as related to anesthesia is unknown, although there are many working hypotheses. However, intraoperative monitoring of anesthetic level with bispectral index (BIS) or end-tidal anesthetic concentration (ETAC) can help to reduce the incidence of intraoperative awareness. There are also many preventative techniques considered for high-risk patients, such as pre-medicating with benzodiazepines, avoiding complete muscle paralysis, and managing patients' expectations. Diagnosis is made postoperatively by asking patients about potential awareness episodes and can be aided by the modified Brice interview questionnaire. A common but devastating complication of intraoperative awareness with recall is the development of post-traumatic stress disorder (PTSD) from the events experienced during surgery. Prompt diagnosis and referral to counseling and psychiatric treatment are crucial to the treatment of intraoperative awareness and the prevention of PTSD.

Signs and symptoms

Intraoperative awareness can present with a variety of signs and symptoms. A large proportion of patients report vague, dreamlike experiences, while others report specific intraoperative events, such as:

• hearing noises or conversations in the operating room
• remembering details of the operation
• sensing pain associated with intubation or surgery
• having weakness or muscle paralysis
• feeling anxiety, helplessness, or an impending sense of doom

Intraoperative signs that may indicate patient awareness include:

• hypertension (high blood pressure)
• tachycardia (high heart rate)
• patient movement
• tachypnea
• intravenous anesthesia line infiltrated or occluded

Patients under anesthesia are paralyzed if a neuromuscular blockade drug, a type of muscle relaxant, has been given as part of general anesthesia. When paralyzed, patients may not be able to communicate their distress or alert the operating room staff of their consciousness until the paralytic wears off. After surgery, recognition of the symptoms of an awareness event may be delayed. One review showed that only about 35% of patients are able to report an awareness event immediately after the surgery, with the rest remembering the experience weeks to months afterward. Depending on the awareness experience, patients may have postoperative psychological problems that range from mild anxiety to post-traumatic stress disorder (PTSD). PTSD is characterized by recurrent anxiety, irritability, flashbacks or nightmares, avoidance of triggers related to the trauma, and sleep disturbances.

Causes

Paralytic and muscle relaxant use

The biggest risk factor is anesthesia performed by unsupervised trainees and the use of a medication that induces muscle paralysis, such as suxamethonium (succinylcholine) or non-depolarising neuromuscular blocking drugs (muscle relaxants). During general anesthesia, the patient's muscles may be paralyzed in order to facilitate tracheal intubation or surgical exposure (abdominal and thoracic surgery can only be performed with adequate muscle relaxation). Because the patient cannot breathe for themselves mechanical ventilation must be used. The paralysing agent does not cause unconsciousness or take away the patient's ability to feel pain, but does prevent the patient from breathing so their airway (trachea) must be protected and their lungs ventilated to ensure adequate oxygenation of the blood and removal of carbon dioxide.

A fully paralyzed patient is unable to move, speak, blink the eyes, or otherwise respond to the pain. If neuromuscular blocking drugs are used this causes skeletal muscle paralysis but does not interfere with cardiac or smooth muscle or the functioning of the autonomic nervous system so heart rate, blood pressure, intestinal peristalsis, sweating and lacrimation are unaffected. The patient cannot signal their distress and they may not exhibit the signs of awareness that would be expected to be detectable by clinical vigilance because other drugs used during anaesthesia may block or obtund these.

Many types of surgery do not require the patient to be paralyzed. A patient who is anesthetized but not paralyzed can move in response to a painful stimulus if the analgesia is inadequate. This may serve as a warning sign that the anesthetic depth is inadequate. Movement under general anesthesia does not imply full awareness but is a sign that the anesthesia is light. Even without the use of neuromuscular blocking drugs the absence of movement does not necessarily imply amnesia.

Light anesthesia

For certain operations, such as Caesarean section, or in hypovolemic patients or patients with minimal cardiac reserve, the anesthesia provider may aim to provide "light anesthesia" and should discuss this with the patient to warn them. During such circumstances, consciousness and recall may occur because judgments of depth of anesthesia are not precise. The anesthesia provider must weigh the need to keep the patient safe and stable with the goal of preventing awareness. Sometimes, it is necessary to provide lighter anesthesia in order to preserve the life of the patient. "Light" anesthesia means less drugs by the intravenous route or via inhalational means, leading to less cardiovascular depression (hypotension), but causing "awareness" in the anesthetized subject.

Anesthesiologist error

Human errors include repeated attempts at intubation during which the short-acting anesthetic may wear off but the paralysing drug has not, oesophageal intubation, inadequate drug dose, drug given by the wrong route or wrong drug given, drugs given in the wrong sequence, inadequate monitoring, patient abandonment, disconnections and kinks in tubes from the ventilator, and failure to refill the anesthetic machine's vaporizers with volatile anesthetic. Other causes of awareness include unfamiliarity with techniques used, e.g. ⁠intravenous anesthetic regimes, or inexperience. Most cases of awareness are caused by inexperience and poor anesthetic technique, which can be any of the above, but also includes techniques that could be described as outside the boundaries of "normal" practice. The American Society of Anesthesiologists in 2007 released a Practice Advisory outlining the steps that anesthesia professionals and hospitals should take to minimize these risks. Other societies have released their own versions of these guidelines, including the Australian and New Zealand College of Anaesthetists.

To reduce the likelihood of awareness, anesthetists must be adequately trained and supervised while still in training. Equipment that monitors depth of anesthesia, such as bispectral index monitoring, should not be used in isolation.

Current research attributes the incidence of AAGA to a combination of the risks mentioned above, together with ineffective practice from ODPs, anesthetic nurses, HCAs and anesthetists. The main failures include:

• Inattention or judgement errors related to drugs and volatile agents
• Termination of anesthesia too soon before surgery has finished due to poor communication
• Lack of understanding of offset times of volatile agents
• Backflow of induction agent up a giving set
• Failure to fill vaporizers (which is the cause of 19% of the cases of AAGA)
• Under-dosing of induction agent during difficult intubation
• Failure to monitor MAC (minimum alveolar concentration of inhaled anaesthetic required to prevent movement in 50% of patients in response to surgical incision)
• Syringe swaps
• Rushing caused by organizational or individual circumstances (bringing attention to staff shortage and stressful work environment)
• Distractions caused by another member of staff

Equipment failure

Machine malfunction or misuse may result in an inadequate delivery of anesthetic. Many Boyle's machines used in many hospitals have the oxygen regulator serving as a slave to the pressure in the nitrous oxide regulator, to enable the nitrous oxide cut-off safety feature. If nitrous oxide delivery suffers due to a leak in its regulator or tubing, an 'inadequate' mixture can be delivered to the patient, causing awareness. Many World War II vintage Boyle 'F' models are still functional and used in UK hospitals. Their emergency oxygen flush valves have a tendency to release oxygen into the breathing system, which when added to the mixture set by the anesthesiologist, can lead to awareness. This may also be caused by an empty vaporizer (or nitrous oxide cylinder) or a malfunctioning intravenous pump or disconnection of its delivery tubing. Patient abandonment (when the anesthesiologist is no longer present) causes some cases of awareness and death.

Patient physiology

Very rare causes of awareness include drug tolerance, or a tolerance induced by the interaction of other drugs. Some patients may be more resistant to the effects of anesthetics than others; factors such as younger age, obesity, tobacco smoking, or long-term use of certain drugs (alcohol, opiates, or amphetamines) may increase the anesthetic dose needed to produce unconsciousness. There may be genetic variations that cause differences in how quickly patients clear anesthetics, and there may be differences in how the sexes react to anesthetics as well. In addition, anesthetic requirement is increased in persons with naturally red hair. Marked anxiety prior to the surgery can increase the amount of anesthesia required to prevent recall.

Conscious sedation

See also: Sedoanalgesia

There are various levels of consciousness. Wakefulness and general anesthesia are two extremes of the spectrum. Conscious sedation and monitored anesthesia care (MAC) refer to an awareness somewhere in the middle of the spectrum depending on the degree to which a patient is sedated. Monitored anesthesia care involves titration of local anesthesia along with sedation and analgesia. Awareness/wakefulness does not necessarily imply pain or discomfort. The aim of conscious sedation or monitored anesthetic care is to provide a safe and comfortable anesthetic while maintaining the patient's ability to follow commands.

Under certain circumstances, a general anesthetic, whereby the patient is completely unconscious, may be unnecessary or undesirable. For instance, with a cesarean delivery, the goal is to provide comfort with neuraxial anesthetic yet maintain consciousness so that the mother can participate in the birth of the child. Other circumstances may include, but are not limited to, procedures that are minimally invasive or purely diagnostic (and thus not uncomfortable). Sometimes, the patient's health may not tolerate the stress of general anesthesia. The decision to provide monitored anesthesia care versus general anesthesia can be complex involving careful consideration of individual circumstances and after discussion with the patient as to their preferences.

Patients who undergo conscious sedation or monitored anesthesia care are never meant to be without recall. Whether or not a patient remembers the procedure depends on the type of anesthetic, dosages, patient physiology, and other factors. Many patients undergoing monitored anesthesia go through profound amnesia depending on the amount of anesthetic used.

Some patients undergo sedation for smaller procedures such as biopsies and colonoscopies and are told they will be asleep, although in fact they are getting a sedation that may allow some level of awareness as opposed to a general anesthetic.

Memory

New research has been carried out to test what people can remember after a general anesthetic in an effort to more clearly understand anesthesia awareness and help to protect patients from experiencing it. A memory is not one simple entity; it is a system of many intricate details and networks.

Memory is currently classified under two main subsections.

• First there is explicit or conscious memory, which refers to the conscious recollection of previous experiences. An example of explicit memory is remembering what you did last weekend. When it comes to an anesthetized patient, a doctor may ask the patient after undergoing general anesthesia if he or she could remember hearing any distinct sounds or words while under anesthesia. This approach is called a "recall test" because patients are asked to recall any memories they had during surgery.
• The second main type of memory is implicit memory or unconscious memory, which refers to the changes in performance or behavior that are produced by previous experiences but without any conscious recollection of those experiences. An example of this is a recognition test, where patients are asked to determine, after surgery, which of a selection of words could be heard to during the surgery. The following scenario is an example. Patients were exposed during anesthesia to a list of words containing the word "pension". Postoperatively, when they were presented with the three-letter word stem PEN___ and were asked to supply the first word that came to their minds beginning with those letters, they gave the word "pension" more often than "pencil" or "peninsula" or others.

Some researchers are now formally interviewing patients postoperatively to calculate the incidence of anesthesia awareness. It is good practice for the anesthesiologist to visit the patient after the operation and check that the patient was not aware. Most patients who were not unduly disturbed by their experiences do not necessarily report cases of awareness unless directly asked. Many who are greatly disturbed report their awareness but anesthesiologists and hospitals deny it has happened. It has been found that some patients may not recall experiencing awareness until one to two weeks after undergoing surgery. It was also found that some patients require a more detailed interview to jog their memories for intraoperative experiences but these are only untraumatic cases. Some researchers have found that while anesthesia awareness does not commonly occur in minor surgeries, it may occur more frequently in more serious surgeries, and that it is good practice to warn of the possibility of awareness in those cases where it may be more likely.

Prevention

The risk of awareness is reduced by avoidance of paralytics unless necessary; careful checking of drugs, doses and equipment; good monitoring, and careful vigilance during the case. The Isolated Forearm Technique (IFT) can be used to monitor consciousness; the technique involves applying a tourniquet to the patient's upper arm before the administration of muscle relaxants, so that the forearm can still be moved consciously. The technique is considered a reference standard by which other means of assessing consciousness can be assessed.

Because the medical staff may not know if a person is unconscious or not, it has been suggested that the staff maintain the professional conduct that would be appropriate for a conscious patient.

Monitors

Recent advances have led to the manufacture of monitors of awareness. Typically these monitor the EEG, which represents the electrical activity of the cerebral cortex, which is active when awake but quiescent when anesthetized (or in natural sleep). The monitors usually process the EEG signal down to a single number, where 100 corresponds to a patient who is fully alert, and zero corresponds to electrical silence. General anesthesia is usually signified by a number between 60 and 40 (this varies with the specific system used). There are several monitors now commercially available. These newer technologies include the bispectral index (BIS), EEG entropy monitoring, auditory evoked potentials, and several other systems such as the SNAP monitor and the Narcotrend monitor.

None of these systems are perfect. For example, they are unreliable at extremes of age (e.g. neonates, infants or the very elderly). Secondly, certain agents, such as nitrous oxide, may produce anesthesia without reducing the value of the depth monitor. This is because the molecular action of these agents (NMDA receptor antagonists) differs from that of more conventional agents, and they suppress cortical EEG activity less. Thirdly, they are prone to interference from other biological potentials (such as EMG), or external electrical signals (such as electrosurgery). This means that the technology that will reliably monitor depth of anesthesia for every patient and every anesthetic does not yet exist. This may in part explain why a 2016 systematic review and meta analysis concluded depth of anaesthesia monitors had a similar effect to standard clinical monitoring on the risk of awareness during surgery

Incidence

The incidence of this anesthesia complication is variable and seems to affect 0.2% to 0.4% of patients according to the surgical setting carried out. This variation reflects the surgical setting as well as the physiological state of the patient. Thus, the incidence is 0.2% in general surgery, about 0.4% during caesarean section, between 1 and 2% during cardiac surgery and between 10% and 40% for anesthesia of the traumatized. The majority of these do not feel pain although around one third did, in a range of experience from a sore throat due to the endotracheal tube, to traumatic pain at the incision site. The incidence is halved in the absence of neuro-muscular blockade.

The quoted incidences are controversial as many cases of "awareness" are open to interpretation.

The incidence of anesthesia awareness is higher and has more serious sequelae when muscle relaxants or neuromuscular-blocking drugs are used. This is because without relaxant the patient will move and the anesthesiologist will deepen the anesthesia.

One study has indicated this phenomenon occurs in about 1 or 2 per 1000 patients or 0.13%. There are conflicting data however as another study suggested it is a rare phenomenon, with an incidence of 0.0068% after review of their data from a patient population of 211,842 patients.

Post operative interview by an anesthetist is common practice to elucidate if awareness occurred in the case. If awareness is reported a case review is immediately performed to identify machine, medication, or operator error.

Outcomes

Patients who experience full awareness with explicit recall may have suffered an enormous trauma due to the extreme pain of surgery. Some patients experience post traumatic stress disorder (PTSD), leading to long-lasting after-effects such as nightmares, night terrors, flashbacks, insomnia, and in some cases even suicide. Some cases of awareness alert the patient to intra-operative errors.^{[citation needed]}

A study from Sweden in 2002 attempted to follow up 18 patients for approximately 2 years after having been previously diagnosed with awareness under anesthesia. Four of the nine interviewed patients were still severely disabled due to psychiatric/psychological after-effects. All of these patients had experienced anxiety during the period of awareness, but only one had stated feeling pain. Another three patients had less severe, transient mental symptoms, although they could cope with these in daily life. Two patients denied any lasting effects from their awareness episode.

Anaxagoras

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Anaxagoras

 

Anaxagoras
Anaxagoras; part of a fresco in the portico of the National University of Athens.
Born	c. 500 BC Clazomenae, Ionia, Persian Empire (now Urla, İzmir, Turkey)
Died	c. 428 BC Lampsacus (now Lapseki, Çanakkale, Turkey)
Era	Ancient philosophy
Region	Western philosophy
School	Ionian school
Main interests	Natural philosophy
Notable ideas	Nous, or Mind ordering all things

Anaxagoras (/ˌænækˈsæɡərəs/; Greek: Ἀναξαγόρας, Anaxagóras, "lord of the assembly"; c. 500 – c. 428 BC) was a Pre-Socratic Greek philosopher. Born in Clazomenae at a time when Asia Minor was under the control of the Persian Empire, Anaxagoras came to Athens. According to Diogenes Laërtius and Plutarch, in later life he was charged with impiety and went into exile in Lampsacus; the charges may have been political, owing to his association with Pericles, if they were not fabricated by later ancient biographers.

Anaxagoras (1636) by Jusepe de Ribera

Responding to the claims of Parmenides on the impossibility of change, Anaxagoras introduced the concept of Nous (Cosmic Mind) as an ordering force. He also gave several novel scientific accounts of natural phenomena, including the notion of panspermia, that life exists throughout the universe and could be distributed everywhere. He deduced a correct explanation for eclipses and described the Sun as a fiery mass larger than the Peloponnese, as well as attempting to explain rainbows and meteors.

Biography

Anaxagoras was born in the town of Clazomenae in the early 5th century BCE, where he may have been born into an aristocratic family. He arrived at Athens, either shortly after the Persian war, which he may have fought in on the Persian side, or sometimes when he was a bit older, around 456 BCE. While at Athens, he became close with the Athenian statesman Pericles According to Diogenes Laërtius and Plutarch, in later life he was charged with impiety and went into exile in Lampsacus; the charges may have been political, owing to his association with Pericles, if they were not fabricated by later ancient biographers. According to Laërtius, Pericles spoke in defense of Anaxagoras at his trial, c. 450 Even so, Anaxagoras was forced to retire from Athens to Lampsacus in Troad (c. 434 – 433). He died there in around the year 428. Citizens of Lampsacus erected an altar to Mind and Truth in his memory and observed the anniversary of his death for many years. They placed over his grave the following inscription:

Here Anaxagoras, who in his quest of truth scaled heaven itself, is laid to rest.

Philosophy

Responding to the claims of Parmenides on the impossibility of change, Anaxagoras described the world as a mixture of primary imperishable ingredients, where material variation was never caused by an absolute presence of a particular ingredient, but rather by its relative preponderance over the other ingredients; in his words, "each one is... most manifestly those things of which there are the most in it". He introduced the concept of Nous (Cosmic Mind) as an ordering force, which moved and separated the original mixture, which was homogeneous, or nearly so.

Anaxagoras brought philosophy and the spirit of scientific inquiry from Ionia to Athens. According to Anaxagoras, all things have existed in some way from the beginning, but originally they existed in infinitesimally small fragments of themselves, endless in number and inextricably combined throughout the universe. All things existed in this mass but in a confused and indistinguishable form. There was an infinite number of homogeneous parts (ὁμοιομερῆ) as well as heterogeneous ones.

The work of arrangement, the segregation of like from unlike, and the summation of the whole into totals of the same name, was the work of Mind or Reason (νοῦς). Mind is no less unlimited than the chaotic mass, but it stood pure and independent, a thing of finer texture, alike in all its manifestations and everywhere the same. This subtle agent, possessed of all knowledge and power, is especially seen ruling all life forms. Its first appearance, and the only manifestation of it which Anaxagoras describes, is Motion. It gave distinctness and reality to the aggregates of like parts. 

Decrease and growth represent a new aggregation (σὐγκρισις) and disruption (διάκρισις). However, the original intermixture of things is never wholly overcome. Each thing contains parts of other things or heterogeneous elements and is what it is, only on account of the preponderance of certain homogeneous parts which constitute its character. Out of this process arise the things we see in this world.

Astronomy

Plutarch says "Anaxagoras is said to have predicted that if the heavenly bodies should be loosened by some slip or shake, one of them might be torn away, and might plunge and fall to earth."

His observations of the celestial bodies and the fall of meteorites led him to form new theories of the universal order, and to the prediction of the impact of meteorites. According to Pliny, he was credited with predicting the fall of the meteorite in 467. He was the first to give a correct explanation of eclipses, and was both famous and notorious for his scientific theories, including the claims that the Sun is a mass of red-hot metal, that the Moon is earthy, and that the stars are fiery stones. He thought the Earth was flat and floated supported by 'strong' air under it and disturbances in this air sometimes caused earthquakes. He introduced the notion of panspermia, that life exists throughout the universe and could be distributed everywhere.

He attempted to give a scientific account of eclipses, meteors, rainbows, and the Sun, which he described as a mass of blazing metal, larger than the Peloponnese; He also said that the Moon had mountains and believed that it was inhabited. The heavenly bodies, he asserted, were masses of stone torn from the Earth and ignited by rapid rotation. His theories about eclipses, the Sun, and Moon may well have been based on observations of the eclipse of 463 BCE, which was visible in Greece.

Mathematics

According to Plutarch in his work On exile, Anaxagoras is the first Greek to attempt the problem of squaring the circle, a problem he worked on while in prison.

Legacy

Anaxagoras wrote a book of philosophy, but only fragments of the first part of this have survived, through preservation in the work of Simplicius of Cilicia in the 6th century AD.

Anaxagoras' book was reportedly available for a drachma in the Athenian marketplace. It was certainly known to Sophocles, Euripides, and Aristophanes based on the contents of their surviving plays, and possibly to Aeschylus as well, based on the testimony of Seneca. However, although Anaxagoras almost certainly lived in Athens during the lifetime of Socrates (born 470 BCE), there is no evidence that they ever met. In the Phaedo, Plato portrays Socrates saying of Anaxagoras as a young man: 'I eagerly acquired his books and read them as quickly as I could'. However, Socrates goes on to describe his later disillusionment with his philosophy. Anaxagoras is also mentioned by Socrates during his trial in Plato's Apology.

He is also mentioned in Seneca's Natural Questions (Book 4B, originally Book 3: On Clouds, Hail, Snow) It reads: "Why should I too allow myself the same liberty as Anaxagoras allowed himself?"

The Roman author Valerius Maximus preserves a different tradition: Anaxagoras, coming home from a long voyage, found his property in ruin, and said: "If this had not perished, I would have"—a sentence described by Valerius as being "possessed of sought-after wisdom"

Dante Alighieri places Anaxagoras in the First Circle of Hell (Limbo) in his Divine Comedy (Inferno, Canto IV, line 137).

Chapter 5 in Book II of De Docta Ignorantia (1440) by Nicholas of Cusa is dedicated to the truth of the sentence "Each thing is in each thing" which he attributes to Anaxagoras.

Anaxagoras appears as a character in the second Act of Faust, Part II by Johann Wolfgang von Goethe.

Parmenides

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Anaxagoras

Parmenides
Bust of Parmenides discovered at Velia, thought to have been partially modeled on a Metrodorus bust.
Born	c. late 6th century BC Elea, Magna Graecia
Died	c. 5th century BC
Era	Pre-Socratic philosophy
Region	Western philosophy
School	Eleatic school
Main interests	Ontology, poetry, cosmology
Notable ideas	Monism, truth/opinion distinction

Parmenides of Elea (/pɑːrˈmɛnɪdiːz ... ˈɛliə/; Greek: Παρμενίδης ὁ Ἐλεάτης; fl. late sixth or early fifth century BC) was a pre-Socratic Greek philosopher from Elea in Magna Graecia.

Parmenides was born in the Greek colony of Elea, from a wealthy and illustrious family. His dates are uncertain; according to doxographer Diogenes Laërtius, he flourished just before 500 BC, which would put his year of birth near 540 BC, but in the dialogue Parmenides Plato has him visiting Athens at the age of 65, when Socrates was a young man, c. 450 BC, which, if true, suggests a year of birth of c. 515 BC. He is thought to have been in his prime (or "floruit") around 475 BC.

The single known work by Parmenides is a poem whose original title is unknown but which is often referred to as On Nature. Only fragments of it survive. In his poem, Parmenides prescribes two views of reality. The first, the Way of "Aletheia" or truth, describes how all reality is one, change is impossible, and existence is timeless and uniform. The second view, the way of "Doxa", or opinion, describes the world of appearances, in which one's sensory faculties lead to conceptions which are false and deceitful.

Parmenides has been considered the founder of ontology and has, through his influence on Plato, influenced the whole history of Western philosophy. He is also considered to be the founder of the Eleatic school of philosophy, which also included Zeno of Elea and Melissus of Samos. Zeno's paradoxes of motion were developed to defend Parmenides' views. In contemporary philosophy, Parmenides' work has remained relevant in debates about the philosophy of time.

Biography

Parmenides was born in Elea (called Velia in Roman times), a city located in Magna Graecia. Diogenes Laertius says that his father was Pires, and that he belonged to a rich and noble family. Laertius transmits two divergent sources regarding the teacher of the philosopher. One, dependent on Sotion, indicates that he was first a student of Xenophanes, but did not follow him, and later became associated with a Pythagorean, Aminias, whom he preferred as his teacher. Another tradition, dependent on Theophrastus, indicates that he was a disciple of Anaximander.

Chronology

Everything related to the chronology of Parmenides—the dates of his birth and death, and the period of his philosophical activity—is uncertain.

Date of birth

All conjectures regarding Parmenides' date of birth are based on two ancient sources. One comes from Apollodorus and is transmitted to us by Diogenes Laertius: this source marks the Olympiad 69th (between 504 BC and 500 BC) as the moment of maturity, placing his birth 40 years earlier (544 BC – 540 BC). The other is Plato, in his dialogue Parmenides. There Plato composes a situation in which Parmenides, 65, and Zeno, 40, travel to Athens to attend the Panathenaic Games. On that occasion they meet Socrates, who was still very young according to the Platonic text.

The inaccuracy of the dating from Apollodorus is well known, who chooses the date of a historical event to make it coincide with the maturity (the floruit) of a philosopher, a maturity that he invariably reached at forty years of age. He tries to always match the maturity of a philosopher with the birth of his alleged disciple. In this case Apollodorus, according to Burnet, based his date of the foundation of Elea (540 BC) to chronologically locate the maturity of Xenophanes and thus the birth of his supposed disciple, Parmenides. Knowing this, Burnet and later classicists like Cornford, Raven, Guthrie, and Schofield preferred to base the calculations on the Platonic dialogue. According to the latter, the fact that Plato adds so much detail regarding ages in his text is a sign that he writes with chronological precision. Plato says that Socrates was very young, and this is interpreted to mean that he was less than twenty years old. We know the year of Socrates' death (399 BC) and his age—he was about seventy years old–making the date of his birth 469 BC. The Panathenaic games were held every four years, and of those held during Socrates' youth (454, 450, 446), the most likely is that of 450 BC, when Socrates was nineteen years old. Thus, if at this meeting Parmenides was about sixty-five years old, his birth occurred around 515 BC.

However, neither Raven nor Schofield, who follows the former, finds a dating based on a late Platonic dialogue entirely satisfactory. Other scholars directly prefer not to use the Platonic testimony and propose other dates. According to a scholar of the Platonic dialogues, R. Hirzel, Conrado Eggers Lan indicates that the historical has no value for Plato. The fact that the meeting between Socrates and Parmenides is mentioned in the dialogues Theaetetus (183e) and Sophist (217c) only indicates that it is referring to the same fictional event, and this is possible because both the Theaetetus and the Sophist are considered after the Parmenides. In Soph. 217c the dialectic procedure of Socrates is attributed to Parmenides, which would confirm that this is nothing more than a reference to the fictitious dramatic situation of the dialogue. Eggers Lan proposes a correction of the traditional date of the foundation of Elea. Based on Herodotus I, 163–167, which indicates that the Phocians, after defeating the Carthaginians in naval battle, founded Elea, and adding the reference to Thucydides I, 13, where it is indicated that such a battle occurred in the time of Cambyses II, the foundation of Elea can be placed between 530 BC and 522 BC So Parmenides could not have been born before 530 BC or after 520 BC, given that it predates Empedocles. This last dating procedure is not infallible either, because it has been questioned that the fact that links the passages of Herodotus and Thucydides is the same. Nestor Luis Cordero also rejects the chronology based on the Platonic text, and the historical reality of the encounter, in favor of the traditional date of Apollodorus. He follows the traditional datum of the founding of Elea in 545 BC, pointing to it not only as terminus post quem, but as a possible date of Parmenides' birth, from which he concludes that his parents were part of the founding contingent of the city and that he was a contemporary of Heraclitus. The evidence suggests that Parmenides could not have written much after the death of Heraclitus.

Timeline relative to other Presocratics

Beyond the speculations and inaccuracies about his date of birth, some specialists have turned their attention to certain passages of his work to specify the relationship of Parmenides with other thinkers. It was thought to find in his poem certain controversial allusions to the doctrine of Anaximenes and the Pythagoreans (fragment B 8, verse 24, and frag. B 4), and also against Heraclitus (frag .B 6, vv.8–9), while Empedocles and Anaxagoras frequently refer to Parmenides.

The reference to Heraclitus has been debated. Bernays's thesis that Parmenides attacks Heraclitus, to which Diels, Kranz, Gomperz, Burnet and others adhered, was discussed by Reinhardt, whom Jaeger followed.

Guthrie finds it surprising that Heraclitus would not have censured Parmenides if he had known him, as he did with Xenophanes and Pythagoras. His conclusion, however, does not arise from this consideration, but points out that, due to the importance of his thought, Parmenides splits the history of pre-Socratic philosophy in two; therefore his position with respect to other thinkers is easy to determine. From this point of view, the philosophy of Heraclitus seems to him pre-Parmenidean, while those of Empedocles, Anaxagoras and Democritus are post-Parmenidean.

Anecdotes

Plutarch, Strabo and Diogenes—following the testimony of Speusippus—agree that Parmenides participated in the government of his city, organizing it and giving it a code of admirable laws.

Detail of the pedestal found in Velia. Greek inscriptions were made only in capital letters, and without spaces. Read as follows: ΠΑ[ ]ΜΕΝΕΙΔΗΣ ΠΥΡΗΤΟΣ ΟΥΛΙΑΔΗΣ ΦΥΣΙΚΟΣ

Archaeological discovery

In 1969, the plinth of a statue dated to the 1st century AD was excavated in Velia. On the plinth were four words: ΠΑ[Ρ]ΜΕΝΕΙΔΗΣ ΠΥΡΗΤΟΣ ΟΥΛΙΑΔΗΣ ΦΥΣΙΚΟΣ. The first two clearly read "Parmenides, son of Pires." The fourth word φυσικός (fysikós, "physicist") was commonly used to designate philosophers who devoted themselves to the observation of nature. On the other hand, there is no agreement on the meaning of the third (οὐλιάδης, ouliadēs): it can simply mean "a native of Elea" (the name "Velia" is in Greek Οὐέλια), or "belonging to the Οὐλιος" (Ulios), that is, to a medical school ( the patron of which was Apollo Ulius). If this last hypothesis were true, then Parmenides would be, in addition to being a legislator, a doctor. The hypothesis is reinforced by the ideas contained in fragment 18 of his poem, which contains anatomical and physiological observations. However, other specialists believe that the only certainty we can extract from the discovery is that of the social importance of Parmenides in the life of his city, already indicated by the testimonies that indicate his activity as a legislator.

Visit to Athens

Plato, in his dialogue Parmenides, relates that, accompanied by his disciple Zeno of Elea, Parmenides visited Athens when he was approximately sixty-five years old and that, on that occasion, Socrates, then a young man, conversed with him. Athenaeus of Naucratis had noted that, although the ages make a dialogue between Parmenides and Socrates hardly possible, the fact that Parmenides has sustained arguments similar to those sustained in the Platonic dialogue is something that seems impossible. Most modern classicists consider the visit to Athens and the meeting and conversation with Socrates to be fictitious. Allusions to this visit in other Platonic works are only references to the same fictitious dialogue and not to a historical fact.

On Nature

Parmenides' sole work, which has only survived in fragments, is a poem in dactylic hexameter, later titled On Nature. Approximately 160 verses remain today from an original total that was probably near 800. The poem was originally divided into three parts: an introductory proem that contains an allegorical narrative which explains the purpose of the work, a former section known as "The Way of Truth" (aletheia, ἀλήθεια), and a latter section known as "The Way of Appearance/Opinion" (doxa, δόξα). Despite the poem's fragmentary nature, the general plan of both the proem and the first part, "The Way of Truth" have been ascertained by modern scholars, thanks to large excerpts made by Sextus Empiricus and Simplicius of Cilicia. Unfortunately, the second part, "The Way of Opinion", which is supposed to have been much longer than the first, only survives in small fragments and prose paraphrases.

Introduction

The introductory proem describes the narrator's journey to receive a revelation from an unnamed goddess on the nature of reality. The remainder of the work is then presented as the spoken revelation of the goddess without any accompanying narrative.

The narrative of the poet's journey includes a variety of allegorical symbols, such as a speeding chariot with glowing axles, horses, the House of Night, Gates of the paths of Night and Day, and maidens who are "the daughters of the Sun" who escort the poet from the ordinary daytime world to a strange destination, outside our human paths. The allegorical themes in the poem have attracted a variety of different interpretations, including comparisons to Homer and Hesiod, and attempts to relate the journey towards either enlightenment or darkness, but there is little scholarly consensus about any interpretation, and the surviving evidence from the poem itself, as well as any other literary use of allegory from the same time period, may be too sparse to ever determine any of the intended symbolism with certainty.

The Way of Truth

In the Way of Truth, an estimated 90% of which has survived, Parmenides distinguishes between the unity of nature and its variety, insisting in the Way of Truth upon the reality of its unity, which is therefore the object of knowledge, and upon the unreality of its variety, which is therefore the object, not of knowledge, but of opinion. This contrasts with the argument in the section called "the way of opinion", which discusses that which is illusory.

The Way of Opinion

In the significantly longer, but far worse preserved latter section of the poem, Way of Opinion, Parmenides propounds a theory of the world of seeming and its development, pointing out, however, that, in accordance with the principles already laid down, these cosmological speculations do not pretend to anything more than mere appearance. The structure of the cosmos is a fundamental binary principle that governs the manifestations of all the particulars: "the aether fire of flame" (B 8.56), which is gentle, mild, soft, thin and clear, and self-identical, and the other is "ignorant night", body thick and heavy. Cosmology originally comprised the greater part of his poem, explaining the world's origins and operations. Some idea of the sphericity of the Earth also seems to have been known to Parmenides.

Legacy

As the first of the Eleatics, Parmenides is generally credited with being the philosopher who first defined ontology as a separate discipline distinct from theology. His most important pupil was Zeno, who appears alongside him in Plato's Parmenides where they debate dialectic with Socrates. The pluralist theories of Empedocles and Anaxagoras and the atomist Leucippus, and Democritus have also been seen as a potential response to Parmenides' arguments and conclusions. Parmenides is also mentioned in Plato's Sophist and Theaetetus. Later Hellenistic doxographers also considered Parmenides to have been a pupil of Xenophanes. Eusebius, quoting Aristocles of Messene, says that Parmenides was part of a line of skeptical philosophy that culminated in Pyrrhonism for he, by the root, rejects the validity of perception through the senses whilst, at any rate, it is first through our five forms of senses that we become aware of things and then by faculty of reasoning. Parmenides' proto-monism of the One also influenced Plotinus and Neoplatonism.