Question: What is general anaesthetic made out of?

General anaesthesia




General anaesthesia or general anesthesia (see spelling differences) is a medically induced coma with loss of protective reflexes, resulting from the administration of one or more general anaesthetic agents. It is carried out to allow medical procedures that would otherwise be intolerably painful for the patient; or where the nature of the procedure itself precludes the patient being awake.
A variety of drugs may be administered, with the overall aim of ensuring unconsciousness, amnesia, analgesia, loss of reflexes of the autonomic nervous system, and in some cases paralysis of skeletal muscles. The optimal combination of drugs for any given patient and procedure is typically selected by an anaesthetist, or another provider such as an operating department practitioner, anaesthetist practitioner, physician assistant or nurse anaesthetist (depending on local practice), in consultation with the patient and the surgeon, dentist, or other practitioner performing the operative procedure.
History


Attempts at producing a state of general anaesthesia can be traced throughout recorded history in the writings of the ancient Sumerians, Babylonians, Assyrians, Egyptians, Greeks, Romans, Indians, and Chinese.  During the Middle Ages, scientists and other scholars made significant advances in the Eastern world, while their European counterparts also made important advances.
The Renaissance saw significant advances in anatomy and surgical technique.  However, despite all this progress, surgery remained a treatment of last resort. Largely because of the associated pain, many patients chose certain death rather than undergo surgery. Although there has been a great deal of debate as to who deserves the most credit for the discovery of general anaesthesia, several scientific discoveries in the late 18th and early 19th centuries were critical to the eventual introduction and development of modern anaesthetic techniques.
Two enormous leaps occurred in the late 19th century, which together allowed the transition to modern surgery. An appreciation of the germ theory of disease led rapidly to the development and application of antiseptic techniques in surgery. Antisepsis, which soon gave way to asepsis, reduced the overall morbidity and mortality of surgery to a far more acceptable rate than in previous eras. Concurrent with these developments were the significant advances in pharmacology and physiology which led to the development of general anaesthesia and the control of pain. On 14 November 1804, Hanaoka Seishū, a Japanese doctor, became the first person to successfully perform surgery using general anaesthesia.
In the 20th century, the safety and efficacy of general anaesthesia was improved by the routine use of tracheal intubation and other advanced airway management techniques. Significant advances in monitoring and new anaesthetic agents with improved pharmacokinetic and pharmacodynamic characteristics also contributed to this trend. Finally, standardized training programs for anaesthesiologists and nurse anaesthetists emerged during this period.
Purpose
General anaesthesia has many purposes, including:
Analgesia (loss of response to pain)
Amnesia (loss of memory)
Immobility (loss of motor reflexes)
Hypnosis (unconsciousness)
Paralysis (skeletal muscle relaxation)
Biochemical mechanism of action
The biochemical mechanism of action of general anaesthetics is not well understood.  Theories need to explain the function of anaesthesia in animals and plants.[1] To induce unconsciousness, anaesthetics have myriad sites of action and affect the central nervous system (CNS) at multiple levels. Common areas of the central nervous system whose functions are interrupted or changed during general anaesthesia include the cerebral cortex, thalamus, reticular activating system, and spinal cord. Current theories on the anaesthetized state identify not only target sites in the CNS but also neural networks and loops whose interruption is linked with unconsciousness.[2] Potential pharmacologic targets of general anaesthetics are GABA, glutamate receptors, voltage-gated ion channels, and glycine and serotonin receptors.
Halothane has been found to be a GABA agonist,[3] and ketamine is an NMDA receptor antagonist.[4]
Preanaesthetic evaluation

Prior to a planned procedure, the anesthesiologist reviews medical records and/or interviews the patient to determine the best combination of drugs and dosages and the degree to which monitoring will be required to ensure a safe and effective procedure. Key factors in this evaluation are the patient's age, body mass index, medical and surgical history, current medications, and fasting time. Thorough and accurate answering of the questions is important so that the anaesthetist can select the proper drugs and procedures. For example, a patient who consumes significant quantities of alcohol or illicit drugs could be undermedicated if they fail to disclose this fact, and this could lead to anaesthesia awareness or intraoperative hypertension. Commonly used medications can interact with anaesthetics, and failure to disclose such usage can increase the risk to the patient.
An important aspect of pre-anaesthetic evaluation is an assessment of the patient's airway, involving inspection of the mouth opening and visualisation of the soft tissues of the pharynx. The condition of teeth and location of dental crowns are checked, and neck flexibility and head extension are observed.
Premedication
Prior to administration of a general anaesthetic, the anaesthetist may administer one or more drugs that complement or improve the quality or safety of the anaesthetic.
One commonly used premedication is clonidine, an alpha-2 adrenergic agonist.[5][6] Clonidine premedication reduces the need for anaesthetic induction agents, for volatile agents to maintain general anaesthesia, and for postoperative analgesics. It also reduces postoperative shivering, postoperative nausea and vomiting, and emergence delirium. In children, clonidine premedication is at least as effective as benzodiazepines and has less serious side effects. However, oral clonidine can take up to 45 minutes to take full effect,[7] and drawbacks include hypotension and bradycardia.
Midazolam, a benzodiazepine characterized by a rapid onset and short duration, is effective in reducing preoperative anxiety, including separation anxiety in children.[8] Dexmedetomidine and certain atypical antipsychotic agents may be used in uncooperative children.[9]
Melatonin has been found to be effective as an anaesthetic premedication in both adults and children because of its hypnotic, anxiolytic, sedative, antinociceptive, and anticonvulsant properties. Unlike midazolam, melatonin does not impair psychomotor skills or hinder recovery. Recovery is more rapid after premedication with melatonin than with midazolam, and there is also a reduced incidence of post-operative agitation and delirium.[10] Melatonin premedication also reduces the required induction dose of propofol and sodium thiopental.[10]
Another example of anaesthetic premedication is the preoperative administration of beta adrenergic antagonists to reduce the incidence of postoperative hypertension, cardiac dysrhythmia, or myocardial infarction. Anaesthesiologists may administer an antiemetic agent such as ondansetron, droperidol, or dexamethasone to prevent postoperative nausea and vomiting, or subcutaneous heparin or enoxaparin to reduce the incidence of deep vein thrombosis. Other commonly used premedication agents include opioids such as fentanyl or sufentanil, gastrokinetic agents such as metoclopramide, and histamine antagonists such as famotidine.
Non-pharmacologic preanaesthetic interventions include playing relaxing music, massage, and reducing ambient light and noise levels in order to maintain the sleep-wake cycle.[11] These techniques are particularly useful for children and patients with intellectual disabilities. Minimizing sensory stimulation or distraction by video games may help to reduce anxiety prior to or during induction of general anaesthesia. Larger high-quality studies are needed to confirm the most effective non-pharmacological approaches for reducing this type of anxiety.[12] Parental presence during premedication and induction of anaesthesia has not been shown to reduce anxiety in children.[12] It is suggested that parents who wish to attend should not be actively discouraged, and parents who prefer not to be present should not be actively encouraged to attend.[12]
Stages of anaesthesia
Guedel's classification, introduced by Arthur Ernest Guedel in 1937,[13] describes four stages of anaesthesia. Despite newer anaesthetic agents and delivery techniques, which have led to more rapid onset of—and recovery from—anaesthesia (in some cases bypassing some of the stages entirely), the principles remain.
Stage 1Stage 1, also known as induction, is the period between the administration of induction agents and loss of consciousness. During this stage, the patient progresses from analgesia without amnesia to analgesia with amnesia. Patients can carry on a conversation at this time.
Stage 2Stage 2, also known as the excitement stage, is the period following loss of consciousness and marked by excited and delirious activity. During this stage, the patient's respiration and heart rate may become irregular. In addition, there may be uncontrolled movements, vomiting, suspension of breathing, and pupillary dilation. Because the combination of spastic movements, vomiting, and irregular respiration may compromise the patient's airway, rapidly acting drugs are used to minimize time in this stage and reach Stage 3 as fast as possible.

Stage 3In Stage 3, also known as surgical anaesthesia, the skeletal muscles relax, vomiting stops, respiratory depression occurs, and eye movements slow and then stop. The patient is unconscious and ready for surgery. This stage is divided into four planes:
The eyes roll, then become fixed;
Corneal and laryngeal reflexes are lost;
The pupils dilate and light reflex is lost;
Intercostal paralysis and shallow abdominal respiration occur.
Stage 4Stage 4, also known as overdose, occurs when too much anaesthetic medication is given relative to the amount of surgical stimulation and the patient has severe brainstem or medullary depression, resulting in a cessation of respiration and potential cardiovascular collapse. This stage is lethal without cardiovascular and respiratory support.
Induction
General anaesthesia is usually induced in a medical facility, most commonly in an operating theatre or in a dedicated anaesthetic room adjacent to the theatre. However, it may also be conducted in other locations, such as an endoscopy suite, radiology or cardiology department, emergency department, or ambulance, or at the site of a disaster where extrication of the patient may be impossible or impractical.
Anaesthetic agents may be administered by various routes, including inhalation, injection (intravenous, intramuscular, or subcutaneous), oral, and rectal. Once they enter the circulatory system, the agents are transported to their biochemical sites of action in the central and autonomic nervous systems.
Most general anaesthetics are induced either intravenously or by inhalation. Intravenous injection works faster than inhalation, taking about 10–20 seconds to induce total unconsciousness. This minimizes the excitatory phase (Stage 2) and thus reduces complications related to the induction of anaesthesia. Commonly used intravenous induction agents include propofol, sodium thiopental, etomidate, methohexital, and ketamine. Inhalational anaesthesia may be chosen when intravenous access is difficult to obtain (e.g., children), when difficulty maintaining the airway is anticipated, or when the patient prefers it. Sevoflurane is the most commonly used agent for inhalational induction, because it is less irritating to the tracheobronchial tree than other agents.
As an example sequence of induction drugs:
Pre-oxygenation to fill lungs with oxygen to permit a longer period of apnea during intubation without affecting blood oxygen levels
Lidocaine for sedation and systemic analgesia for intubation
Fentanyl for systemic analgesia for intubation
Propofol for sedation for intubation
Switching from oxygen to a mixture of oxygen and inhalational anesthetic
Laryngoscopy and intubation are both very stimulating and induction blunts the response to these maneuvers while simultaneously inducing a near-coma state to prevent awareness.
Physiologic monitoring
Several monitoring technologies allow for a controlled induction of, maintenance of, and emergence from general anaesthesia.
Continuous electrocardiography (ECG or EKG): Electrodes are placed on the patient's skin to monitor heart rate and rhythm. This may also help the anaesthesiologist to identify early signs of heart ischaemia. Typically lead II and V5 are monitored for arrhythmias and ischemia, respectively.
Continuous pulse oximetry (SpO2): A device is placed, usually on a finger, to allow for early detection of a fall in a patient's haemoglobin saturation with oxygen (hypoxaemia).
Blood pressure monitoring: There are two methods of measuring the patient's blood pressure. The first, and most common, is non-invasive blood pressure (NIBP) monitoring. This involves placing a blood pressure cuff around the patient's arm, forearm, or leg. A machine takes blood pressure readings at regular, preset intervals throughout the surgery. The second method is invasive blood pressure (IBP) monitoring. This method is reserved for patients with significant heart or lung disease, the critically ill, and those undergoing major procedures such as cardiac or transplant surgery, or when large blood loss is expected. It involves placing a special type of plastic cannula in an artery, usually in the wrist (radial artery) or groin (femoral artery).
Agent concentration measurement: anaesthetic machines typically have monitors to measure the percentage of inhalational anaesthetic agents used as well as exhalation concentrations. These monitors include measuring oxygen, carbon dioxide, and inhalational anaesthetics (e.g., nitrous oxide, isoflurane).
Oxygen measurement: Almost all circuits have an alarm in case oxygen delivery to the patient is compromised. The alarm goes off if the fraction of inspired oxygen drops below a set threshold.
A circuit disconnect alarm or low pressure alarm indicates failure of the circuit to achieve a given pressure during mechanical ventilation.
Capnography measures the amount of carbon dioxide exhaled by the patient in percent or mmHg, allowing the anaesthesiologist to assess the adequacy of ventilation. MmHg is usually used to allow the provider to see more subtle changes.
Temperature measurement to discern hypothermia or fever, and to allow early detection of malignant hyperthermia.
Electroencephalography, entropy monitoring, or other systems may be used to verify the depth of anaesthesia. This reduces the likelihood of anaesthesia awareness and of overdose.
Airway management

Anaesthetized patients lose protective airway reflexes (such as coughing), airway patency, and sometimes a regular breathing pattern due to the effects of anaesthetics, opioids, or muscle relaxants.
To maintain an open airway and regulate breathing, some form of breathing tube is inserted after the patient is unconscious.
To enable mechanical ventilation, an endotracheal tube is often used, although there are alternative devices that can assist respiration, such as face masks or laryngeal mask airways.
Generally, full mechanical ventilation is only used if a very deep state of general anaesthesia is to be induced for a major procedure, and/or with a profoundly ill or injured patient.
That said, induction of general anaesthesia usually results in apnea and requires ventilation until the drugs wear off and spontaneous breathing starts.
In other words, ventilation may be required for both induction and maintenance of general anaesthesia or just during the induction.
However, mechanical ventilation can provide ventilatory support during spontaneous breathing to ensure adequate gas exchange.
General anaesthesia can also be induced with the patient spontaneously breathing and therefore maintaining their own oxygenation which can be beneficial in certain scenarios (e.g. difficult airway or tubeless surgery). Spontaneous ventilation has been traditionally maintained with inhalational agents (i.e. halothane or sevoflurane) which is called a gas or inhalational induction. Spontaneous ventilation can also be maintained using intravenous anaesthesia (e.g. propofol). Intravenous anaesthesia to maintain spontaneous respiration has certain advantages over inhalational agents (i.e. suppressed laryngeal reflexes) however it requires careful titration. SponTaneous Respiration using IntraVEnous anaesthesia and High-flow nasal oxygen (STRIVE Hi) is a technique that has been used in difficult and obstructed airways.[14]
Eye management

General anaesthesia reduces the tonic contraction of the orbicularis oculi muscle, causing lagophthalmos, or incomplete eye closure, in 59% of patients.[15] In addition, tear production and tear-film stability are reduced, resulting in corneal epithelial drying and reduced lysosomal protection. The protection afforded by Bell's phenomenon (in which the eyeball turns upward during sleep, protecting the cornea) is also lost. Careful management is required to reduce the likelihood of eye injuries during general anaesthesia.[16]
Neuromuscular blockade

Paralysis, or temporary muscle relaxation with a neuromuscular blocker, is an integral part of modern anaesthesia. The first drug used for this purpose was curare, introduced in the 1940s, which has now been superseded by drugs with fewer side effects and, generally, shorter duration of action. Muscle relaxation allows surgery within major body cavities, such as the abdomen and thorax, without the need for very deep anaesthesia, and also facilitates endotracheal intubation.
Acetylcholine, the natural neurotransmitter at the neuromuscular junction, causes muscles to contract when it is released from nerve endings. Muscle relaxants work by preventing acetylcholine from attaching to its receptor. Paralysis of the muscles of respiration—the diaphragm and intercostal muscles of the chest—requires that some form of artificial respiration be implemented. Because the muscles of the larynx are also paralysed, the airway usually needs to be protected by means of an endotracheal tube.
Paralysis is most easily monitored by means of a peripheral nerve stimulator. This device intermittently sends short electrical pulses through the skin over a peripheral nerve while the contraction of a muscle supplied by that nerve is observed. The effects of muscle relaxants are commonly reversed at the end of surgery by anticholinesterase drugs, which are administered in combination with muscarinic anticholinergic drugs to minimize side effects. Novel neuromuscular blockade reversal agents such as sugammadex may also be used. Examples of skeletal muscle relaxants in use today are pancuronium, rocuronium, vecuronium, cisatracurium, atracurium, mivacurium, and succinylcholine.
Maintenance

The duration of action of intravenous induction agents is generally 5 to 10 minutes, after which spontaneous recovery of consciousness will occur. In order to prolong unconsciousness for the required duration (usually the duration of surgery), anaesthesia must be maintained. This is achieved by allowing the patient to breathe a carefully controlled mixture of oxygen, sometimes nitrous oxide, and a volatile anaesthetic agent, or by administering medication (usually propofol) through an intravenous catheter. Inhaled agents are frequently supplemented by intravenous anaesthetics, such as opioids (usually fentanyl or a fentanyl derivative) and sedatives (usually propofol or midazolam). With propofol-based anaesthetics, however, supplementation by inhalation agents is not required.
At the end of surgery, administration of anaesthetic agents is discontinued. Recovery of consciousness occurs when the concentration of anaesthetic in the brain drops below a certain level (usually within 1 to 30 minutes, depending on the duration of surgery). 

In the 1990s, a novel method of maintaining anaesthesia was developed in Glasgow, Scotland. Called target controlled infusion (TCI), it involves using a computer-controlled syringe driver (pump) to infuse propofol throughout the duration of surgery, removing the need for a volatile anaesthetic and allowing pharmacologic principles to more precisely guide the amount of the drug used by setting the desired drug concentration. Advantages include faster recovery from anaesthesia, reduced incidence of postoperative nausea and vomiting, and absence of a trigger for malignant hyperthermia. At present, TCI is not permitted in the United States, but a syringe pump delivering a specific rate of medication is commonly used instead.
Other medications are occasionally used to treat side effects or prevent complications. They include antihypertensives to treat high blood pressure; ephedrine or phenylephrine to treat low blood pressure; salbutamol to treat asthma, laryngospasm, or bronchospasm; and epinephrine or diphenhydramine to treat allergic reactions. Glucocorticoids or antibiotics are sometimes given to prevent inflammation and infection, respectively.
Emergence
Emergence is the return to baseline physiologic function of all organ systems after the cessation of general anaesthetics. This stage may be accompanied by temporary neurologic phenomena, such as agitated emergence (acute mental confusion), aphasia (impaired production or comprehension of speech), or focal impairment in sensory or motor function. Shivering is also fairly common and can be clinically significant because it causes an increase in oxygen consumption, carbon dioxide production, cardiac output, heart rate, and systemic blood pressure. The proposed mechanism is based on the observation that the spinal cord recovers at a faster rate than the brain. This results in uninhibited spinal reflexes manifested as clonic activity (shivering). This theory is supported by the fact that doxapram, a CNS stimulant, is somewhat effective in abolishing postoperative shivering.[17] Cardiovascular events such as increased or decreased blood pressure, rapid heart rate, or other cardiac dysrhythmias are also common during emergence from general anaesthesia, as are respiratory symptoms such as dyspnoea.
Postoperative care


Anaesthesia should conclude with a pain-free awakening and a management plan for postoperative pain relief. This may be in the form of regional analgesia or oral, transdermal, or parenteral medication. Minor surgical procedures are amenable to oral pain relief medications such as paracetamol and NSAIDs (e.g., ibuprofen). Moderate levels of pain require the addition of mild opiates such as tramadol. Major surgical procedures may require a combination of modalities to confer adequate pain relief. Parenteral methods include patient-controlled analgesia (PCA) involving a strong opioid such as morphine, fentanyl, or oxycodone. The patient presses a button to activate a syringe device and receive a preset dose or "bolus" of the drug (e.g., one milligram of morphine). The PCA device then "locks out" for a preset period to allow the drug to take effect. If the patient becomes too sleepy or sedated, he or she makes no more requests. This confers a fail-safe aspect that is lacking in continuous-infusion techniques.
Postanesthetic shivering is common. Apart from causing discomfort and exacerbating pain, shivering has been shown to increase oxygen consumption, catecholamine release, cardiac output, heart rate, blood pressure, and intraocular pressure. A number of techniques are used to reduce shivering, such as increased ambient temperature, conventional or forced warm air blankets, and warmed intravenous fluids.[18]
In many cases, opioids used in general anaesthesia can cause postoperative ileus, even after non-abdominal surgery. Administration of a μ-opioid antagonist such as alvimopan immediately after surgery can help reduce the severity and duration of ileus.[19]
Perioperative mortality

Most perioperative mortality is attributable to complications from the operation, such as haemorrhage, sepsis, and failure of vital organs. Current estimates of perioperative mortality in procedures involving general anaesthesia range from one in 53 to one in 5,417.[20][21] However, a 1997 Canadian retrospective review of 2,830,000 oral surgical procedures in Ontario between 1973 and 1995 reported only four deaths in cases in which an oral and maxillofacial surgeon or a dentist with specialized training in anaesthesia administered the general anaesthetic or deep sedation. The authors calculated an overall mortality rate of 1.4 per 1,000,000.[22]
Mortality directly related to anaesthetic management is very uncommon but may be caused by pulmonary aspiration of gastric contents,[23] asphyxiation,[24] or anaphylaxis.[25] These in turn may result from malfunction of anaesthesia-related equipment or, more commonly, human error. A 1978 study found that 82% of preventable anaesthesia mishaps were the result of human error.[26] In a 1954 review of 599,548 surgical procedures at 10 hospitals in the United States between 1948 and 1952, 384 deaths were attributed to anaesthesia, for an overall mortality rate of 0.064%.[27] In 1984, after a television programme highlighting anaesthesia mishaps aired in the United States, American anaesthesiologist Ellison C. Pierce appointed the Anesthesia Patient Safety and Risk Management Committee within the American Society of Anesthesiologists.[28] This committee was tasked with determining and reducing the causes of anaesthesia-related morbidity and mortality.[28] An outgrowth of this committee, the Anesthesia Patient Safety Foundation, was created in 1985 as an independent, nonprofit corporation with the goal "that no patient shall be harmed by anesthesia".[29]
As with perioperative mortality rates in general, mortality attributable to the management of general anaesthesia is controversial.[30] Estimates of the incidence of perioperative mortality directly attributable to anaesthesia range from one in 6,795 to one in 200,200.[20]
See also
Local anaesthesia



 An article at University of Bristol providing interesting facts about chloroform.
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