The Science of Sleep from the past to the current

How long has the use of anaesthetics during surgical procedures been in existence? What were the pitfalls encountered in finding an ideal anaesthetic? How is an ideal anaesthetic defined? Who were the main scientists and doctors involved in getting anaesthesia to the present level of sophistication? This article throws light on the history of this important medical aid.
 
Introduction
“To trace successfully the evolution of any one of the learned professions would require the hand of a master- of one, who like Darwin, combined a capacity for patient observation with philosophic vision. In the case of medicine, the difficulties are enormously increased by the extraordinary development…. the rate of progress has been too rapid for us to appreciate, and we stand bewildered…” (Sir William Osler, 1849-1919, address to the British Medical Association 1897)

 

On terra firma- what I do and what I am about to do!
All of us have, at one time or the other, been either moved to tears or made to laugh out loud by the actors in a play or a film. When the play is in motion or the film reel rolls, it seems as if only the main characters on stage are there for the performance. Yet each of these performances is actually made real by the tremendous efforts of those who are behind the scene-those who handle the lights or costume, or prompt an actor when he or she forgets, even those who make sure the curtains come off and go on at the right times. The discipline of anaesthesia is akin to these backstage players. While removal of teeth or nails appears simple, surgery can be complicated - such as mending a broken heart.
 
I currently spend the greater part of my working life putting people to a state of painless sleep, particularly when their hearts are repaired. This is in addition to monitoring and maintaining, as close to health as possible, their other organs. I also assist in imaging the heart during the procedure, and finally, have a key role in ending the operation in delinking life support and getting a patient back to his feet in the intensive care unit. In this article, I propose to take you on a journey through modern anaesthetics, a snapshot of its evolution, and through it all, convince you of how interconnected the world of knowledge actually is!
 
From ancient times
The concept of enabling sleep as one went about refashioning an organ is actually ancient. The Bible refers to how the Creator induced a temporary sleep to remove a rib from Adam¹. Sumerian artefacts depict the use of opium poppy in 4000 BC (the use of opioids as analgesics continue to be the mainstay of anaesthesia even to this day) ². Susruta, the pioneer Indian surgeon, refers to the use of wine as a soporific# to induce temporary sleep³. He is also believed to have initiated the use of cannabis² in 600 BC; probably extrapolated from the sleep inducing effects of bhang, consumed on festivals like Holi! The Latin Americans used home grown coca, which is refined to produce modern day cocaine², also one of the first local anaesthetics. Yet others, not as observant, would advise people to chew on lettuce or bite on a stick or used a blow to the head to dull the pain that any surgery would bring forth⁴!
Over time, alcohol and opium became the predominant drugs to be used, but had many problems, among which were the possibility of both inadequate and over dosing (the latter, deadly). Neither was enough to completely ablate the pain of surgery⁵. All in all, the eminent anatomist and surgeon, John Hunter described surgery as a “humiliating spectacle of the futility of science” and that of the practitioner as a “savage with a knife” ⁶.
 
The birth of inhalational anaesthesia
Modern day anaesthetic practice seems largely focused on the administration of medicinal gases via a device into the trachea and from there on the lungs. This began in the mid-18 century when William Morton demonstrated the use of ether at the Massachusetts General Hospital (MGH) in Boston.
However, halogenated alkanes, and not ether, are the main anaesthetic gases in use today. Components of the admixture that have not changed are oxygen and carbon dioxide. Anaesthesiologists have always been preoccupied with the administration, control and composition of these two gases in the breathing mixture since they would inevitably be present at all times.
 
Joseph Priestley⁷ (1742-1786) showed that heating mercuric oxide could keep mice alive longer in a closed space while Robert Hooke managed to keep animals alive by blowing into their lungs⁸. Priestley’s communication across the English Channel to the French chemist Antoine Lavoisier (1743-94) led the latter to suggest that the heating of mercuric oxide released an enigmatic new element which he called ‘oxygen’. It was left to Humphry Davy (1778-1829), a school dropout, to show that the currency of metabolism was the uptake of oxygen and the production of carbon dioxide. John Haldane provided the logical experimental evidence to this theory by designing apparatus that could accurately measure these gases as they made their way in and out of living things; he coined a phrase that an editorialist in the anaesthesia textbook, ‘Miller’s Anaesthesia’, stresses is the primary training of every modern day anaesthesiologist: “anoxemia (an abnormal reduction in the oxygen content in the blood) not only stops the machine but wrecks the machinery”. As the first year doctoral student enters our portals, we teach her that the primary religious duty of anaesthesia is to monitor, correct and maintain adequate supply of oxygen to tissues as our surgical colleagues play challenge to the processes of nature. Failure means cardiac compromise and ominous hypoxic (caused by lack of oxygen) damage to the brain as cells die from failure of cellular respiration. So, even as anaesthesiologists focus on putting people to sleep, they have the important function of maintaining the stability of the cardiovascular and respiratory systems, a theme that we will deal with in some depth later.
 
The actual birth of modern day anaesthesia has a longer history than in the public imagination, and like other momentous events in general history, not free of controversy. If one were to cite a figure who was the most apt to be the father of anaesthetics, it would probably be Humphry Davy⁹ (1778-1829), and not Horace Wells (1815- 48) or William Thomas Green Morton (1819-68). It is however, Morton’s demonstration at the MGH on October 16, 1846 that is celebrated all over the globe as World Anaesthesia Day. Davy was not an ordinary person - at 15 years when the death of his father had left him and his family in extreme poverty, he decided to commence a life of selflearning. His study plans at that time detail that he wanted to be a chemist, physician, geographer, mathematician, astronomer and logician - all at the same time! Davy did contribute to each of these fields through the discovery of six elements in the periodic table; or through inventions to facilitate mining, improve agriculture, and art conservation⁹. It is his study of biologic gases as a physician at the Bristol Pneumatic Institute that set the ball rolling for anaesthesia. As a preliminary step, Davy set out to study on himself which gases were safe to inhale without causing serious injury - some were truly risky, such as, his experiments to inhale carbon monoxide, which he described as an agent that would cause his pulse to become ‘rapid and thread like’, nearly killing him. We all know that this gas is deadly¹⁰, as it is colourless and odourless and inhibits the oxygen transport function of haemoglobin (Hb) (its affinity for Hb is 200 times greater than that of oxygen), besides inhibiting cellular respiration¹¹. His efforts to use carbon dioxide to dull the senses were funnier - it does (and his was one of the first descriptions of this effect)¹² in patients with chronic lung disease causing them to lose full consciousness. It is his adventures with nitrous oxide, however, that are of direct consequence for anaesthesia. Breathing pure nitrous oxide, as he demonstrated to himself, completely abolished his toothache. It was incremental to suggest its potential use in surgery¹³. He was all of 21 years old, and the psychotropic# effects of that gas were demonstrated by his writing poetry under the influence of nitrous oxide.
“Gentlemen, this is no humbug”
Across the Atlantic, another entirely different agent was being used in country fairs to produce a similar transformed state, which was entirely reversed when one stopped breathing the vapour that caused this. These were in the form of ‘ether frolics’, and the agent was diethyl ether. At the forefront of these endeavours were a motley crowd of physicians, chemists and dentists - Gardner Quincy Colton, Horace Wells, Crawford Long, Charles Jackson and William Thomas Green Morton. In as much as their efforts, singly and together, laid the foundations of the whole science of inhalational anaesthesia, they undid much of their effort in attempting to gain individual fame and money over any sense of collective scientific achievement. If there was going to be a ‘first’ person to have used a true anaesthetic (which nitrous oxide was not) in the form of ‘etherisation’, it is near certain that it was Crawford Long (1815-78)¹⁴. Long, a physician, noted that injuries sustained during the ether frolics were often associated with painlessness. In 1842, he successfully used diethyl ether as an anaesthetic to remove a cyst from the neck; his second attempt was only part successful. Unsure of  reproducibility, he put off any publicity till he himself was sure that anaesthesia was produced by the ether and “not the  effect of the imagination”. 
 
Horace Wells, a dentist, was the next in this line of daring men. He successfully used nitrous oxide in dental extraction, but his attempts to seek public recognition at a demonstration at Massachusetts General Hospital (MGH) in early 1845 was met with some moans and groans from the patient (a feature of this anaesthetic though not proof of its total lack of efficacy) and scepticism from the audience. A pupil, Morton, in the audience now jumped into the fray and set out to better his teacher’s effort. Morton was sure it would work, but wished to be the high priest at a new ritual - he would refuse to share the composition of his “Letheon” (it was diethyl ether mixed with a dye and some additional scents to make it feel and seem an invention that he alone owned) but successfully used it at the MGH on October 16, 1846. In hindsight he was very lucky - he used a contraption that would resemble a modern day teapot (the nature of the exact device used is mired in controversy) to anaesthetise a young male with a large, vascular tumour of the neck, to be excised by John Warren, the chief surgeon at MGH. A modern day anaesthesiologist would be cautious - blood loss, loss of airway control, air embolism… but for Morton, fortune favoured the brave. At the heart of his success were the very different physical-chemical properties of ether as compared to nitrous oxide. The offset of actions of ether would be much more gradual than nitrous oxide. Thus, in the days of approximate action, when small errors such as disconnection, dosing, and premature cessation could mean that the patient suddenly woke up in the middle of surgery, to his horror and that of his  treating physicians, these errors were more likely of this dramatic kind, when the agent was nitrous oxide than ether. Morton, however, never really lived to enjoy his success: the mad fallout of who should get credit for this success (his as  against the claims of Wells, Long and the others) coupled with his passionate desire to promote himself, ensured that he died very young, at 49 years of age, unhappy and insolvent! 
 
Recollections from a long while ago
What determines how gas delivered into a patient’s lung will cross the alveolar membrane into the bloodstream and then be carried by the cardiovascular system via the left heart to the brain and spinal cord to exert its actions in anaesthesia? In mixtures of gases, the relative contribution of each gas to the whole pressure exerted by the gaseous mix is in proportion to their presence in the gas (Dalton’s law of partial pressures). Thus, if the atmospheric pressure at sea level is 760 mm Hg, nitrogen (which makes up about 78% of this mix we call “air”) contributes 78/100 X (760), i.e. 592.8 mm Hg of the total pressure of 760 mm Hg exerted by this mixture. 
Just as we think of the diffusion of water into the root of a plant from the soil as a result of the higher concentration of water (when we pour it into a flower pot) in the soil relative to the root, we can think of gaseous exchange being determined by the relative partial pressures of a gas. These diffusion processes govern the transfer of oxygen across the alveolar membrane from atmospheric air to the haemoglobin in our blood: the venous blood has low oxygen tensions relative to the air in the breathing mixture and passive transfer occurs across the alveolar capillaries which are designed to be thin and ready to allow this. What complicates the picture, somewhat, is the presence of two different states of  matter: liquid and gas - blood as liquid and atmospheric air as gas. Apart from partial pressure, the transfer of gas from a gaseous phase across a membrane into a liquid is also influenced by its solubility in that liquid.
Now the δ value of diethyl ether which Morgan used is 12 whereas that of poor Wells’ nitrous oxide is only 0.47; at any given time there is about 12/0.47 = 25 X as much ether dissolved in blood as nitrous oxide at the same partial pressure. Suppose Mr Wells were to suddenly stop or run out of nitrous oxide, there is very little nitrous oxide to well out of the blood to sustain the partial pressure of nitrous oxide needed to maintain anaesthesia; Mr Morgan however, even if he were to fall asleep, has a huge volume of diethyl ether within the patient’s bloodstream. This can diffuse out as gas even if her physician were to stop administration and this diffused gas would continue to keep the patient asleep for a while, 
explaining the two different courses of those historical anaesthetics.
 
However, there is a flip side to the diethyl ether (it has virtually no place in modern anaesthesia). Imagine attempting to put a hypothetical patient to sleep using the ether - now what acts on the brain to cause anaesthesia is the undissolved ‘free’ gas in blood that crosses the blood brain barrier. When a very soluble gas like ether is used, a whole lot of it is just guzzled by the large blood volume in the patients as dissolved (and hence of no utility) ether, before any significant undissolved concentration is achieved for reaching and dulling the patient. Etherisation, therefore, while offering a large safety margin in keeping patients asleep once they are anaesthetised, takes a long while to achieve - enough to give hospitals, anaesthesiologists and surgeons the funny smell that many of us associate with hospitals (this is historical, since the era of etherisation is virtually over). Further, in a busy world like today, where hospital facilities are vastly outpaced by patients needing to use them, it would be a big  waste of time waiting for them to wake up from the dissolved ether in their body. 
 
“In sorrow thou shalt bring forth children”
A parallel drama was being enacted in Britain just about the same time that Morgan et al. were playing it out in the United States. At the heart of this enactment was James Young Simpson; primarily an obstetrician, but a very clever and versatile one. Simpson (1811-90) was also acutely interested in drugs that would abolish pain. When etherisation was described in the US, he was quick to obtain a sample, and use it in a complicated childbirth in preference to mesmerism. A witness was to remark “this Yankee dodge beats mesmerism hollow”. Meanwhile, organic chemists had started to synthesise many more compounds, and chloroform arrived in the 1830s. It had a slightly lower blood gas partition 
coefficient than ether (which was already getting on everyone’s nerves given its ‘volatility’) and was also not as inflammable. Simpson used it first on himself, then on his niece, and gradually on women to abolish the pain of childbirth¹⁴. Simpson apparently encountered opposition to its use as theologians suggested that child birth was meant to be painful as punishment for the original sin (as stated in the Bible); it is currently believed that this theologic opposition was mild¹⁴. Another key figure in Britain was the legendary John Snow - the father of modern epidemiology (the statistics of modern medicine, and its foundation of using experiments to decide what is right instead of the whim of a caregiver) who would define the stages of a typical anaesthetic and warn of the hazards of excess. However, chloroform and ether, their historical importance notwithstanding, would probably never have stood the test of time: low potency, long times to effect and wearing off, inflammability (since the use of oxygen as also the cauterisation of surgical wounds using electrical energy can make a dangerous mix to set off fires in operating rooms) would be their is advantages. The demand for pure agents, and the neighbouring revolution in chemical synthesis in the early 20th century would mean their replacement by potent, relatively non-toxic agents such as the fluorinated hydrocarbons in use today. The latter have much better blood gas partition coefficients (with 0.42 being that of desflurane, the newest, which is the fastest to act and disappear and 1.15 that of isoflurane which is among the most commonly used today), do not support combustion, are quick to act, and also fast in wearing off, such that most people could have an operation in the morning in hospital, and help make dinner at home in the evening¹⁵! 
 
The Hindi film discourse and real being different from reel
Most depictions of anaesthesia on television and in the theatrics surrounding accident or childbirth in our films are far from real. They usually begin with a masked man or woman stuffing the victim’s nose and mouth with a gas and as she thrashes about in pain from the original trauma or from being so restrained, she dulls to sleep. Whether or not she will wake up is usually decided by the plot - there is either dramatic recovery as we approach the end or an agonising wait for the missing hero who would then wave his magic wand. In contrast, most anaesthesia commencements today are made using intravenous drugs, in the quiet of hundreds of operating rooms all over the world.
 
Unlike gas, there were several impediments to the development of intravenous anaesthesia - some of which were the disastrous effects of inadvertent microbial contamination (leading to sepsis), the complicated apparatus required, in the form of needles and syringes, and the dependence on metabolism by organs for termination of action (unlike gas which could just be breathed out). The first recorded intravenous anaesthetic was the injection of alcohol using a contraption of dog bladder and goose quill into a dog who went to sleep and yet managed to awake and survive the onslaught; the hero in question was Christopher Wren, founder of the Royal Society in Britain in 1656¹⁶. The development
of injectable apparatus in the form of needles (Francis Rynd 19 to still be the most commonly used - easy administration, non-dependence on metabolism, elimination in those who have diseased livers or kidneys (the main sites for all drug metabolism), faster offset because of these properties - all these gives it an edge. Since like all diffusion, this ends with a state of equilibrium, measuring the  concentration of these gases in the breathing mixture is an estimate of their  concentration in the brain where they act. This measurement can aid in correcting both over and under-dosing.
New arms in the inventory: local anaesthesia
It was known in the mid18th century that cocaine applied to the tongue would numb it. However it was the psychedelic experimentation of Sigmund Freud and his colleague, Carl Koller at the Vienna General Hospital that would bring anaesthesia a new set of arms. Koller’s colleague, who accidentally licked cocaine off a pen knife, found his tongue numbed. His account to Koller, immediately prompted instillation of cocaine into the eyes of a frog and a guinea pig (Koller was an aspirational ophthalmologist), which made the conjunctiva and cornea insensate. A presentation to the Heidelberg Ophthalmological Society in 1884 started a new train - injection into nerves (Halsted, the great surgeon) or into the spinal canal (Bier 1897). The latter approach would lead to numbing of a whole set of nerves at one go. Local anaesthesia was once believed to be safer and superior to general anaesthesia. Whilst there are many limitations on the complexity and anatomic extent of surgical work that can be accomplished with local or regional anaesthesia, this tool has come to stay - from offering superior pain relief than achieved with intravenous drugs¹⁸, to enabling faster surgical  recovery¹⁹, preventing persistent pain after surgery²⁰, or preventing lung complications from breathing and coughing better when the lung or regions nearby are operated upon²¹.  
 
Trail blazing science in the middle of war
The 20th century was a violent epoch, with two world wars scarring its first half. With these events in the background, the demand for complicated surgery surged more than ever before. In addition to attending to casualties of war, surgeons were now attempting to remove complicated organs such as the lungs during peacetime or performing palliative surgery for life threatening heart conditions²². Precise control over the cardiac and respiratory systems in the interim period of surgery meant demand for sophisticated machines that could deliver exact concentrations of gas, accurate volumes of air at just the right composition, instruments akin to weather gauges predicting an impending crisis and so on. The immediate periods of the Wars often meant a standstill for peace - time science (economic squeeze and conscription in the War for scientists and physicians alike), but the birth of quantum mechanics during this period, describing the behaviour of subatomic particles would spurn a revolution in the development of devices and technologies that lie at the heart of our modern lives: transistors, computers, the electron microscope and magnetic resonance imaging. Anaesthesia is among those disciplines in medicine that are most heavily reliant on these technological revolutions. 
 
Modern ventilators use microprocessors to time the onset of a ventilator cycle or end a mechanical breath. The science of spectrophotometry lies at the heart of the continuous measurement of blood oxygen (thus warning anaesthesiologists of low levels well before their ominous effects on the central nervous system can occur), sophisticated monitors mean providers can focus on other tasks, such as detecting cyanosis (appearance of blue colour on the skin due to lack of oxygen) with the naked eye, or provide minute to minute data on the prevailing blood pressure or filling and emptying of the human heart.
 
Anaesthesia and technology: the harmony is proven by our report card 
Anaesthesiologists would first recognise low oxygen levels from the colour of the tongue or mucous membranes, or the blue colour of eoxygenated blood. During surgery, this could, often, be a little late in the day for meaningful action. Today a pulse oximeter analyses the relative concentrations of oxygenated and deoxygenated blood non-invasively from the finger tip on a beat- to- beat basis; the instrument uses spectrophotometric principles to deduce this value and alert the physician to quick action. Infrared spectrophotometry identifies whether or not a tube is placed correctly in the trachea instead of the oesophagus (anaesthesia trainees and experts can accidentally intubate the food pipe instead of the trachea - thus the stomach gets ventilated, instead of the lungs).
 
Electrocardiograms are generated from surface electrodes on the chest; blood pressure measurements are automatic using the principles of oscillometry; and the anaesthesia provider can also use a number to quantify consciousness (allowing him to titrate the quantity of anaesthetic to be delivered). There are various indices used today to quantify conciousness²³. These indices are developed using the raw electroencephalogram data (EEG, akin to the ECG these are surface waves reflecting electrical activity within the human cortical cells of the brain). They are a measure of the order in the brain²⁴, which increases with deepening anaesthesia. A research group I have worked with has developed a computer based system that automatically increases or reduces the amount of anaesthesia, without requiring the anaesthesiologist to do this manually²⁵. 
 
However, if one were to be driven to think that anaesthesia is inherently safe, the Russian army experience in 2002 would caution us. In 2002, a hostage crisis confronted the army in Moscow in an opera house; it sprayed fentanyl, an analgesic opioid (besides causing analgesia it also causes sleep and potent dose dependent respiratory depression) to end the impasse. A good 129 attendees (15% of the total attendance) – including the innocent as well as terrorists, died²⁶.
 
Henry Beecher and Donald Todd were the first to systematically assess the risks of anaesthesia; their study determined that about 1:2000 deaths in the operation theatre were directly related to anaesthesia management. If a particular technique (muscle relaxation to facilitate surgery) was used, the number was 1:370²⁷. Neuromuscular blocking drugs (that work at the nerve terminal with muscles, like botulinum toxin or nerve gas) can be deadly, if their residual action is not detected. This study proved that if one was more careful and monitored the effects of these drugs, it could lead to more anaesthesia safety. In a large country, such as the United States of America, 2,211 patients died from an anaesthesia
related cause in the period 1999-2005; the study estimated that the risk of anaesthesia was of the order of 1.1 per million population per year, probably lower than that of a terrorist strike!²⁸. Similar impressive numbers are reported from Australia²⁹. In our country, roughly 12 people per 100,000 population die of a road accident per year³⁰! Thus travelling in a bus or a car may be more unsafe than being put to sleep for surgery. The synthesis of human skill and technology has made anaesthesia a safe specialty, and this success story is evidence of the potential of good science in human life. We might, however, end this section with caution: while anaesthesia related mortality has steeply fallen all over the world, there is a big divergence between countries in the developed world and the underdeveloped or emerging economy status countries like ours³¹. This may be due to a combination of poor technology use, bad science (and by extension inadequate science education by educators) and poor economic spending on healthcare. 
Beyond anaesthesia: from an enabling specialty to a therapeutic partner
Anaesthesia is an enabling specialty: it helps perform surgery safely, but the actual therapeutic benefit is that of the surgical procedure itself, not the anaesthetic. It thus behoves us to be as safe as possible. However anaesthesia can also have therapeutic effects. Curare, a dangerous drug has been used to abolish the excruciatingly painful spasms associated with tetanus³². Anaesthetics have been shown to prepare the heart for disaster - a term called pre-conditioning, just like how we save money in a bank to prepare for tough times in the future³³. A polio epidemic in  Denmark was the impetus for an  anaesthesiologist Bjork Ibsen to keep children with respiratory failure alive (secondary to the paralysis induced by polio virus) by use of positive pressure ventilation³⁴. In the spirit of our highest traditions as doctors whose sole aim is to cure and help others in need, this ventilation was provided by hundreds of volunteer anaesthesia trainees, anaesthesiologists and other medical doctors round the clock manually! In Ibsen’s action lay the nucleus for founding our modern day intensive care units³⁴. Virginia Apgar, an anaesthesiologist formulated the first score³⁵ to sort newborns into those who would need further attention and those who could manage alone - her score continues to be in use to this day, and is taught to all doctors during their first paediatric rotation. Anaesthesiologists,  driven by their own need to accurately measure oxygen tension in blood, have contributed substantially to the  development of technologies, such as electrodes for the measurement of arterial oxygen³⁶. Anaesthesia management can affect the rates of tumour recurrence after cancer surgery³⁷, or the rate of heart attacks in patients with cardiac disease after non-heart surgery³⁸. 

 

Extending the knowledge frontier: can being asleep teach you about what it is to be awake?
The quantum mechanics era, and the giant steps made in medical imaging as a result of these studies, has already been referred to; today, it is possible to use appropriate tools, such as functional Magnetic Resonance Imaging (fMRI) or Positron Emission tomograms (PET), to correlate brain function with anatomic areas - in health or in disease³⁹, ⁴⁰. Imagine an anesthetised patient who is undergoing fMRI – his visual cortex is active during the drug induced hypnotic state. Does it not tell us that the visual cortex activity has no correlation with the awake or asleep state? Likewise, anaesthesia appears to be associated with functional uncoupling of the parietal-frontal cortical loop. What this means literally is that, although, these individual areas may or may not be active, their cross talk is what causes cognition (simplistically the parietal area is the sensor, the frontal the interpreter of sensation). Cognition is broadly the way we see, think, feel or hear the world around us. All of these sensations are abolished with anaesthesia. Anaesthetic drugs do not impact the activity of individual regions but abolish their cross talk. Thus, anaesthesia processes provide an insight into how the brain works when awake.
 
Ahoy ! Ahead.
Our quest to understand the natural world within and outside ourselves continues in an unbroken tradition from pre-historic times. This quest asks us to forever persevere in furthering the frontiers of knowledge; today anaesthesiologists guide heart repair during surgery, use ultrasound to inject local anaesthetic in the proximity of nerves etc. Anesthesiology is a super-specialised branch with sub- specialties in paediatrics, cardiology, neurology, pain and intensive care. There is only one way forward - to be constantly awake and alive in the primeval spirit that science is all about.
 
References
  1. “And the LORD God caused a deep sleep to fall upon Adam, and he slept: and he took one of his ribs, and closed up the flesh instead thereof”. Genesis 2.21- 2.23, King James Bible "Authorized Version", Cambridge Edition. URL: http://www.kingjamesbibleonline.org/Genesis-2-21/
  2. The History of Anesthesia Timeline. Wood Library-Museum of Anesthesiology. URL: http://www.woodlibrarymuseum.org/history-ofanesthesia. Accessed March 2015.
  3. Sushrutha- our proud heritage. Bhattacharya S. Ind J Plast Surg 2009; 42:223-25.
  4. Bite down on a stick: the history of anesthesia. Inglis- Arkell E. URL: http://io9.com/5787069/bitedown-on-a-stick-the-history-of-anesthesia. Accessed March 29, 2015.
  5. Surgery before anesthesia. Sullivan JT. ASA Newsletter Sept 1996; 60:9:8-10.
  6. Dentistry’s answer to “the humiliating spectacle”. Jacobson PH. J Am Dental Assoc 1994; 1576.
  7. A history of medicine. Major R. Springfield IL, CC Thomas 1954.
  8. An account of an experiment made by Mr Hooke, of preserving animals alive by blowing through their lungs with bellows. Hooke R. Phil Trans 1666-67; 2: 539-40.
  9. Humphry Davy: his life, works and contribution to anesthesiology. Riegels N, Richards MJ. Anesthesiology 2011; 114:1282-8. 
  10. Carbon monoxide poisoning – Causes. National Health Services, UK. URL:http://www.nhs.uk/Conditions/Carbon-monoxidepoisoning/ Pages/Causes.aspx. Accessed last on March 29 2015.
  11. Carbon monoxide poisoning. Weaver LK. New Engl J Med 2009; 360:1217-25.
  12. Researches Chemical and philosophical chiefly concerning nitrous oxide. Davy H. Bristol, Biggs and Cottle, 1800.
  13. Nitrous oxide revisited, evidence for potent antihyperalgesic properties. Richebe P, Rivat C, Creton C, Laulin J-P, Maurette P, Lemaire M et al. Anesthesiology 2005; 103: 845-54.
  14. Early experiments with inhalation anaesthesia: Morton and the ether controversy. Coley NG. Proceedings of the History of Anaesthesia Society 2000; 28: 10-18.
  15. Meta- analysis of average and variability of time to extubation comparing isoflurane with desflurane or isoflurane with sevoflurane. Agoliati A, Dexter F, Jason L, Danielle M, Muhammad S, Stuart S et al. Anesth Analg 2010; 110:1433-39.
  16. A history of intravenous anaesthesia. White PF. Eger EI, Saidman L, Westhorpe RN eds, The Wondrous Story of Anaesthesia. Springer New York 2014. 
  17. "Adolf von Baeyer - Biographical". Nobelprize.org. Nobel Media AB 2014. URL: http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1905/baeyer-b.... Accessed last on March 29, 2015.
  18. Epidural anaesthesia and outcome of major surgery: a randomised trial. Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ et al. Lancet 2002; 359:1276-82.
  19. Prolonged epidural infusion improves functional outcomes following kee arthroscopy in patients with arthrofibrosis after total knee arthroplasty: a retrospective evaluation. Saltzmann BM, Dave A, Ahuja M, Amin SD, Bush- Joseph CA. J Knee Surg 2014; DOI: 10.1055/s-0034-1394163. 
  20. A systematic review of therapeutic interventions to reduce acute and chronic post surgical pain after amputation, thoracotomy or mastectomy. Humble SR, Dalton AJ, Li L. Eur J Pain 2015; 19: 451-65.
  21. Influence of pain on postoperative ventilator disturbances: management and expected benefits. Beaussier M, Genty T, Lescot T, Aissou M. Ann Fr Anesth Reamin 2014; 33:484-6.
  22. 1910-50: Anesthesia before, during and after two world wars. Eger EI II, Westhorpe RN, Saidman LJ. In Eger EI, Saidman L, Westhorpe RN eds, The Wondrous Story of Anaesthesia. Springer, New York, 2014.
  23. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. Gan TJ, Glass PS, Windor A, et al. BIS Utility Study Group. Anesthesiology. 1997;87(4):808-815.
  24. Closed-loop anaesthesia delivery system (CLADS) using bispectral index: a performance assessment study. Puri GD, Kumar B, Aveek J. Anaesth Intensive Care 2007; 35: 357-62.
  25. The Moscow Theater Hostage Crisis: The Perpetrators, their Tactics, and the Russian Response. Adam Dolnik and Richard Pilch. International Negotiation, 8:577–611, 2003. URL: http://www.academia.edu/1498225/the_moscow_theater_hostage_crisis_their_... ponse. Accessed Apr 06, 2015.
  26. A study of the deaths associated with anaesthesia and surgery. Beecher HK, Todd DP. In 599,548 anaesthesias in ten institutions 1948-52, inclusive. Ann Surg 1954; 140:2-35.
  27. Epidemiology of Anaestheisa related mortality in the United States, 1999-2005. Li G, Warner M, Lang BH, Huang L, Sun LS. Anesthesiology 2009; 110:759-65.
  28. Report of the Committee convened under the auspices of the Australian and New Zealand College of Anaesthetists. Melbourne: Australian and New Zealand College of Anaesthetists; 2006. Gibbs N, Borton C. Safety of Anaesthesia in Australia: A review of anaesthesia related mortality, 2000–2002.
  29. Road accidents in India, 2013. Government of India - Ministry of Road Transport & Highways Transport Research Wing, New Delhi. URL: http://morth.nic.in/writereaddata/mainlinkFile/File1465.pdf Accessed 06 Apr, 2015.
  30. Perioperative and anaesthetic related mortality in developed and developing countries: a systematic review and meta- analysis. Bainbridge D, Martin J, Arango M, Cheng D. Lancet 2012; 380:1075-81.
  31. Tetanus treated with tubocurarine and intermittent positive pressure ventilation. Honey GE, Dwyer BE, Smith AC, Spalding JM. Br Med J. 1954 Aug 21; 2(4885): 442–443.
  32. Enflurane enhances post- ischemic functional recovery in the isolated rat heart. Freedman BM, Hamm DP, Everson CT, Wechsler AS. Anesthesiology 1985; 62:29-33.
  33. The first intensive care unit in the world: Copenhagen, 1953. Berthelsen PG, Cronqvist M. Acta Anesthesiol Scand 2003l 47:1190-5.
  34. A proposal for a new method of evaluation of the newborn. Apgar V. Infant. Curr Res Anesth Analg 1953; 32:260-7.
  35. Electrodes for blood and gas PCO2, PO2 pH. Severinghaus JW. Acta Anaesthesiol Scand 1962; 11:207-20.
  36. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? Heaney A, Buggy DJ. Br J Anaesth 2012; 109 (suppl 1): i17-i28. 
  37. Effects of extended release metoprolol succinate in patients undergoing non cardiac surgery: a randomised controlled trial. POISE study group. Lancet 2008; 371: 1839-47.
  38. Types of Brain Imaging Techniques. Michael Demitri, M.D. Psych Central (2013). URL:  http://psychcentral.com/lib/types-of-brainimaging-techniques/. Accessed on 06 April, 2015. 
  39. Functional imaging of memory processes in humans: positron emission tomography and magnetic resonance imaging. Poeppel TD, Krause BJ. Methods 2008; 44:315-28.
  40. What is fMRI? UC San Diego Center for Functional MRI. URL: http://fmri.ucsd.edu/Research/whatisfmri.html.Accessed on 06 April, 2015.
  41. Integrating the science of consciousness and anesthesia. Mashour GA. Anesth Analg 2006;103: 975-82.

Aveek Jayant (MD DM) is on the faculty of the Postgraduate Institute of Medical Education and Research, Chandigarh. He obtained the Indian School Certificate from the Rishi Valley School in 1995; and a graduate degree in Medicine from the Tamil Nadu Dr MGR Medical University, Chennai in 2000. He was awarded a doctoral degree in Anaesthesiology by the PGIMER, Chandigarh in 2005; and a postdoctoral degree in Cardiac Anaesthesiology by the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram in 2009. Besides attending to his clinical duties, he is a researcher and writes occasionally for newspapers such as The Hindu and The Tribune.
 

 

18472 registered users
7227 resources