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Anesthesia

The purpose of general anesthesia is to render surgical patients unconscious, and thus insensitive to pain and oblivious to events occurring during the procedure. For this reason, anesthesia -- like sleep and coma -- often enters into philosophical and scientific discussions of consciousness. How do we know that the patient is unconscious? Appearances to the contrary notwithstanding, are there reasons to think that anesthetized patients are actually conscious after all? Assuming that they are actually unconscious, is it possible for them to acquire and retain unconscious memories of pain and surgical events? What can the biological mechanisms of general anesthesia tell us about the neural correlates of consciousness?

 

The Evolution of General Anesthesia

Up until the middle of the 19th century, anesthesia was not a feature of surgery. Instead, patients were simply required to withstand the pain of the procedure, perhaps with the aid of alcohol, opiates (such as laudanum), a bite-board, and physical restraints. 

In the early 1840s, James Elliotson and James Esdaille, two Scottish surgeons, successfully employed "Mesmerism", otherwise known as "animal magnetism", a forerunner to modern hypnosis, as an anesthetic agent in many surgical operations.  Unfortunately, Mesmerism was in ill repute in scientific medicine.  And their timing was bad: just as they were beginning to publish their results, the first chemical anesthetics were documented.

003Davy.jpg (106228
              bytes) Humphrey Davy (1778-1829), the pioneering electrochemist, discovered the effects of nitrous oxide on headache and dental pain during his research on respiratory physiology; but his report went unnoticed in the medical community and the substance was quickly consigned to use at "laughing gas" parties.  

 

 

In 1845, Horace Wells, an American dentist, successfully used nitrous oxide for anesthesia during a dental extraction.  But when he attempted to repeat the demonstration before an audience of physicians and surgeons, the demonstration failed.

 

Ether Day

005EtherDay.jpg
              (142920 bytes)But on October 16, 1846, William Morton, another dentist, employed ether in the surgical removal of a tumor with no signs or reports of pain in the patient. That event is now celebrated in hospitals and medical schools throughout the world as "Ether Day".  The event is also immortalized in two paintings: the one on the left, by Robert Hinckley (1896), hangs in the Countway Medical Library at Harvard Medical School; the one on the right, by Warren and Lucia Prosperi (2001), hangs in the "Ether Dome", the actual surgical theatre -- complete with audience of physicians and medical students -- where the operation took place.

 

Actually, ether had been used successfully for dental anesthesia as early as 1842, and that same year Crawford Long, a physician in Georgia, actually used ether in surgery.  However, in the 19th century dentistry wasn't considered "real" medicine; and Long did not publish his results until 1849, so Morton got priority for his discovery (still, Morton was a dentist; and Long had the major teaching hospital of Emory University named for him!).

Ether anesthesia quickly crossed the Atlantic to England.  In December 1846, William Squire and Robert Liston, surgeons at University College, London, determined to see Morton's effects for himself.  Squire's uncle Peter, a pharmacist, had fashioned an apparatus for delivering ether, consisting of a glass flask attached to a mask with a rubber tube, and which had already been used successfully for a dental extraction -- but then again, that was mere dentistry, not real surgery.  He coerced a hospital orderly to serve as the demonstration subject, but the man was apparently bothered by the ether fumes and ran from the surgical theatre.  Shortly thereafter, however, a real patient arrived: Frederick Churchill, a butler with an infected leg that required amputation.  The surgery was performed with ether: Churchill was completely unresponsive during the surgery; in fact, when the ether wore off, he asked when the surgery was going to begin.  Lisiton announced to his audience of physicians and medical students (another famous painting, "The Agnew Clinic", by Thomas Eakins, at the Philadelphia Museum of Art, also shows an anesthetist at work): "This Yankee dodge, gentlemen, beats mesmerism hollow!".

A neat historical coincidence: one of the students in Liston's audience that day was Joseph Lister, who would go on to develop antiseptic methods for the control of infections secondary to surgical procedures (Listerine is named for him). 

Morton died in 1868, and his tombstone in Cambridge's Mount Auburn Cemetery carries the following epitaph, composed by Bigelow:

Inventor and Revealer of Inhalation Anesthesia:

Before Whom, in All Time, Surgery was Agony;

By Whom, Pain in Surgery was Averted and Annulled;

Since Whom, Science has Control of Pain.

(Photo courtesy of David Gant)

Soon thereafter, in 1847, chloroform was introduced by Simpson as an alternative to ether, which had an unpleasant odor and other side effects.

Anesthesia was also extended from surgery to obstetrics, although some physicians had qualms about dangers to the neonate.  Some religious authorities claimed that anesthesia violated God's will that women give birth in pain (see Genesis).  Queen Victoria essentially ended the debate in 1853 when she received chloroform for the birth of her eighth (!) child, Prince Leopold. The first American woman to give birth under chloroform was Fanny Longfellow, wife of Henry Wadsworth Longfellow.

Nevertheless, some professionals and others continued to debate a "calculus of suffering" by which some individuals, and some conditions, were deemed more worthy of anesthesia than others.  And even in the 20th (and 21st) century, the subjective nature of pain led both healthcare professionals and political policymakers to disparage many claims of "pain and suffering" as mere malingering.

For interesting histories of pain and pain control, see

The story of Morton and Ether Day is told in "The Great Moment" (1944), a biopic directed by Preston Sturges.

 

Further Developments

Debates aside, progress in anesthesia continued.



Freud (and Halsted) on Cocaine

The stories of Freud' and Halsted' relationship to cocaine are told in two books:

  • Genius on the Edge: The Bizarre Double Life of Dr. William Stewart Halsted by Gerald Imber (2010);
  • An Anatomy of Addiction: Sigmund Freud, William Halsted, and the Miracle Drug Cocaine by Howard Merkel (2011).

Both books were reviewed by Frederick Crews in "Physician, Heal Thyself", published in two parts in the New York Review of Books (09/29/2011 and 10/13/2011).  

Halsted became addicted during a program of self-experimentation on the anesthetic properties -- very common in medical research at the time.  He managed to control his addiction, however, engaging in cocaine "binges" during vacations and other free time.  More or less: Halsted was treated for his cocaine addiction with morphine (it was widely believed at the time that the two drugs were antagonists) -- and he promptly became a morphine enthusiast - -if not quite an addict --  as well.

Freud also experimented with cocaine in work leading up to the publication of "On Coca" (Uber Coca, 1884), and other papers that, for some reason, didn't make it into the Standard Edition of the Complete Psychological Works of Sigmund Freud -- perhaps because they were deemed "neurological" in nature.  In a reversal of Halsted's experience, but again based on the belief that morphine and cocaine were physiological antagonists, Freud advocated the use of cocaine for the treatment of morphine addiction!  Despite Freud's advocacy, his principal case, his physician colleague Ernst Fleischl, was a disaster.

  • Freud had first learned about the powers of cocaine from an enthusiastic article in the Therapeutic Gazette -- which was, in fact, the house-organ of the Parke, Davis pharmaceutical company, which was at the time marketing its own brand of cocaine.  Freud's letters to his fiance, Martha Bernays, make it clear that he saw cocaine research as a quick ticket to scientific and professional stardom.  
  • Freud apparently did not understand the distinction between cocaine and coca leaf, which is much less potent.
  • As with Halsted, Fleischl became addicted to both morphine and cocaine, and quickly descended into a psychotic condition from which he never recovered.
  • Nevertheless, as late as 1887, two years after Fleischl descent into madness, Freud was claiming that his treatment had been a success.    

Freud himself was not averse to the recreational use of cocaine. 

  • From 1884 to 1887 he used it frequently to combat fatigue, and even to enhance his sexual ardor.  
  • As late as 1895, under the advice of his colleague Wilhelm Fleiss (now understood to have been a genuine quack), Freud was self-administering cocaine to treat various illnesses, including nasal problems that, most likely, were themselves the result of cocaine abuse.
  • Freud's use of cocaine was controlled and deliberate, not addictive.  Which is a little amazing, when you consider that he was already addicted to another alkaloid substance -- namely, nicotine, in the form of the 20 or so cigars he smoked every day, even in the face of 33 surgeries for cancer that eventually cost him most of his jaw and palate.

Ernest Jones, Freud's biographer (some would say hagiographer), dismisses the whole "cocaine episode" of 1884-1887 as an aberration.  On the other hand, Crews, a vigorous critic of Freud and psychoanalysis, points out that the cocaine episode foreshadowed the problems with Freud's later psychotherapeutic work:

Already by 1886, then, Freud was displaying premature certainty, impatience with methodological safeguards, truculence, and a belief that he was destined for great things.  Those weren't traits that blossomed after he developed psychoanalysis and felt a need to defend it.  They were the very engine of invention.

***

At no point in either campaign did he place the safety and welfare of patients ahead of ambition.  When cocaine was found to be tragically addictive for physicians and patients who had followed his thoughtless advise, he fought back desperately in 1887, bending the truth in order to exculpate himself.  And when, after decades of claiming that psychoanalysis is the sovereign remedy for psychoneuroses, he allowed that he had "never been a therapeutic enthusiast", he didn't apologize; by then his fame as the Columbus of the unconscious was secure.

Freud's triumph in reaching that pinnacle without the aid of any confirmed  discoveries or cures may be the most amazing chapter in the entire history of self-promotion....  Without cocaine, the polite and unhappy young doctor of April 1884 might never have become so reckless, so adamant, so sex preoccupied, and so convinced of his own importance that the contagion was caught by millions.  Cocaine, along with nicotine, was Freud's drug of choice -- but in the century to come, the opiate of the educated classes would be psychoanalysis.

Throughout the 20th century, the techniques for delivering and maintaining anesthesia were improved.

 

Modern Anesthesia

009Balanced.jpg (49320 bytes)Modern anesthetic technique is known as balanced anesthesia, because it employs a "cocktail" of different drugs to achieve the goals of general anesthesia: sedation, loss of consciousness (sometimes referred to as "narcosis" or "hypnosis"), amnesia; and muscle relaxation. 

 

 

 

Alternatives to General Anesthesia

There are also a number of alternatives to general anesthesia:

There's even a turn toward no anesthesia at all.  That is, no general anesthesia, so that the patient is wide awake during even major procedures that, in the past, would have involved general anesthesia.  In awake surgery patients receive local or regional anesthesia to block pain, and conscious sedation to alleviate anxiety, but otherwise they're wide awake during surgery, can watch the proceedings (though it's not clear now much they'll remember, given that they often receive sedatives that are themselves amnestic agents), and interact with the surgical team.  Of course, there are some downsides.  The patient might hear the surgeon comment on some problem encountered during the procedure.  Or, for that matter, the patient might get bored and engage the anesthetist in conversation.  Medical students take courses in doctor-patient communication, but, at least until now, they've not been trained for anything like this.  Still, why "awake" surgery might become more common.  Regional anesthesia is less expensive than general anesthesia, there are fewer complications and side effects, and faster recovery times.  And, of course, general anesthesia is always available if patients change their minds.  See "Going Under the Knife, with Eyes and Ears Wide Open" by Jan Hoffman, New York Times, 03/26/2017).

 

Mechanisms of Anesthesia

Since the 19th century, modern "scientific" medicine has generally disdained purely "empirical" treatments that are known to be efficacious, even though their scientific bases are not known.  Nevertheless, general anesthesia has been universally adopted despite the fact that its underlying mechanisms remain a matter of considerable mystery. 

Based on our understanding of the molecular and cellular bases of neural activity, it seems plausible that general anesthetics could temporarily and reversibly disrupt neural activity in one of several ways:

Beyond that, though, things get murky.

 

Single-Process Theories

To complicate things further, the various classes of anesthetic agents appear to have somewhat different mechanisms of action. For example, many intravenous "hypnotic" drugs -- including propofol, barbiturates such as thiopental, and benzodiazepines such as diazepam -- appear to interact with gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, to increase the time that  chloride ion channels are open, resulting in a hyperpolarization of cell membranes. However, ketamine, another intravenous anesthetic, interacts with excitatory N-methyl-D-aspartate (NMDA) receptors instead. Natural and synthetic opioid anesthetics such as fentanyl, of course, act on opioid receptors, inhibiting presynaptic release of neurotransmitters such as acetylcholine and substance P. However, even in high doses these drugs do not, by themselves, induce loss of consciousness. For this purpose, they are often combined with nitrous oxide and oxygen. Nitrous oxide, for its part, has effects on NMDA receptors similar to those of ketamine. Current evidence is broadly consistent with anesthetic action on both synaptic excitation and inhibition, with the contribution of each process varying from agent to agent.

The molecular and cellular mechanisms by which inhaled anesthetics such as isoflurane achieve their effects have been subject of intense investigation and debate. According to the Myer-Overton rule known since the late 19th century, there is a strong correlation between the potency of an anesthetic gas and its solubility in lipids.  One early suggestion was that the expansion of nerve cell membranes effectively closed the ion channels by which sodium enters the cell to induce an action potential. 

However, It is now believed that the inhalants bind directly to specific pockets of relevant proteins rather than altering the lipid bilayer itself. In this way, they might create a dynamic block of the "lock and key" channels involved in synaptic excitation; some anesthetics also intensify synaptic inhibition. Although the general view is that anesthetics act on the postsynaptic side, there are some indications that they inhibit presynaptic neurotransmitter release as well.

The concept of balanced anesthesia implies that there are likely to be a number of separate mechanisms working together to produce analgesia (lack of pain), a sleep-like loss of consciousness (sometimes referred to as "hypnosis"), immobility (voluntary responses to surgical stimuli, as opposed to the spinal reflexes suppressed by muscle relaxants such as vecuronium), and amnesia (lack of memory for surgical events). According to one proposal, inhalants such as isoflurane, which induce both immobility and amnesia, achieve these effects by different routes: immobility by acting on GABA receptors in the spinal cord, and amnesia by suppressing activity in the hippocampus.

As it happens, the specific proteins affected by inhaled anesthetics are receptors for GABA, among other neurotransmitters. Thus, the inhaled anesthetics may share a mechanism with the intravenous anesthetics after all. Along the same lines, the inhaled anesthetics share some pharmacological properties, such as tolerance, withdrawal, and cross-tolerance, with alcohol and sedative hypnotics such as barbiturates; this suggests that there may be a common mechanism uniting the inhaled and the intravenous anesthetics as well. On the other hand, there are now a number of anesthetic agents that violate the Meyer-Overton rule, and it is known some gases can bind to the proteins implicated in anesthesia yet not cause anesthesia. Although much attention has focused on GABA, Hans Flohr has implicated NMDA instead. Both nitrous oxide and ketamine act as antagonists on NMDA receptors, blocking glutamate, an excitatory neurotransmitter -- as does xenon, a newly developed anesthetic. Even if the intravenous anesthetics share a final common pathway with some inhaled anesthetics, other inhalants may achieve the same effects by rather different means.

 

Dual-Process Theories

These considerations suggest a "dual-process" theory, in which general anesthesia occurs by virtue of one or another of two general processes:

Of course, it is also likely that the various kinds of anesthesia work by means of quite different mechanisms:


A "Quantum" Theory of Consciousness-- and Anesthesia

020Quantum.jpg (88887 bytes)Some theorists have sought to solve the mystery of anesthesia by invoking another mystery, namely quantum theory. Roger Penrose, a British mathematical physicist, and Stuart Hameroff, an American anesthesiologist, have famously speculated that consciousness is a product of certain processes described by quantum theory. 

 

Briefly:

As stated, it should be understood that the quantum theory is really little more than a metaphor for consciousness.  It is far from an empirically based scientific theory.  With some justification, some critics have dismissed the Penrose-Hameroff theory as explaining one mystery by invoking another.

Anyway, within the context of the quantum theory, Hameroff has proposed that these processes take place in microtubules -- proteins found in the walls of neurons that are shaped like hollow tubes.  Although the conventional view is that microtubules serve a structural function, supporting the structure of the cell, it is also true that they are built out of proteins -- and certain proteins are known to be the site of anesthetic activity. Penrose and Hameroff contend that consciousness is actually a product of processes occurring in this microtubular cytoskeleton, which are in turn magnified by the neuron itself.

As opposed to conventional theories of anesthesia, which focus on processes operating at the synapse, the Hameroff-Penrose theory shifts attention to processes operating inside the neural cell itself. 

The Penrose-Hameroff theory of both consciousness and anesthesia has attracted a great deal of interest, and something like it has been endorsed by Eccles, but at this stage it remains highly speculative, and has been criticized on both logical and empirical grounds.

The quantum theory of consciousness has been criticized as excessively speculative, but its status might actually be worse than that -- an instance of what the Nobel physics laureate Murray Gell-Mann has called "quantum flapdoodle".  The basic problem  is that there is no reason to think that the "micro" (really, subatomic) world of quantum mechanics has anything to do with the "macro" world of classical physics -- that is, the real world in which human experience, thought, and action actually take place.  For example, in the Unconscious Quantum (1995), Victor Stenger calculated that quantum mechanics operates only when a system's mass (m), speed (v), and distance (d) are on the order of Planck's constant (h).  Because the properties of neurotransmitters exceed this limit, Stenger argues that quantum mechanics cannot provide a useful description of what is going on in the nervous system.  

Or, as I like to put it, whether the strings of string theory vibrate in 10 or 11 or 26 dimensions, apples still fall, planets still revolve around their suns, the universe still expands -- and people still think and behave.

 

Anesthesia and Awareness

Clinically, the success of general anesthesia is marked by three criteria:

Information relevant to these issues is typically gleaned from a brief post-operative interview in which the patient is asked such questions as "What was the last thing you remember before you went to sleep? What was the first thing you remember when you woke up? Can you remember anything in between these two periods? Did you dream during your operation?". 

Evaluated in these terms, anesthesia is almost always successful, with far fewer than 1% of surgical patients report any awareness during surgery. 

Occasionally, the incident is so serious as to result in post-traumatic stress disorder; but more commonly, the patient is left with only vague -- and non-distressing -- memories of intraoperative events. 

In general surgery, intraoperative awareness and postoperative recall are usually attributable to light anesthesia, machine malfunction, errors of anesthetic technique, and increased anesthetic requirements -- for example, on the part of patients who are obese or abuse alcohol or drugs. The incidence of surgical recall arises in special circumstances, such as trauma, cardiac, or obstetrical surgery, where cardiovascular circumstances dictate lighter planes of anesthesia. Even then, the incidence of surgical recall is remarkably low -- in part because even in the absence of anesthesia, the benzodiazepines often used for sedation are themselves amnestic agents. 

In fact, modern anesthetic practice may underestimate the incidence of intraoperative awareness by interfering with postoperative memory. That is to say, an inadequately anesthetized patient may be aware of surgical events at the time they occur, but be unable to remember them later because of sedative-induced anterograde amnesia.

However low, the possibility of surgical awareness means that, in addition to monitoring various aspects of vital function during the operation, the anesthetist must also monitor the patient's state of consciousness, or anesthetic depth. This task would be made easier if psychology and cognitive science could reach consensus on the neural or behavioral correlates of consciousness. In the absence of such criteria, anesthesiologists have often been forced to improvise. 

 

MAC and MAC-Aware

One set of standards simply relies on measures of anesthetic potency. Research has determined the minimum alveolar concentration (MAC) of inhalant which prevents movement in response to surgical stimulation in 50% of patients; MAC-aware is the concentration required to eliminate awareness of the stimulation. As a rule, MAC-aware is roughly half of MAC, suggesting that some of the movement in response to surgical stimulation is mediated by subcortical structures, and does not necessarily reflect conscious awareness. Similar standards for adequate anesthesia, based on blood plasma levels, have been worked out for intravenous drugs such as propofol.

It should be noted that the operational definition of MAC-Aware means that 50% of patients will be aware of surgical events despite the presence of anesthetic -- although a dose amounting to about 1.3 MAC does seem to do the trick. 

Nevertheless, it is important to supplement knowledge of dose-response levels with more direct evaluations of the patient's conscious awareness. Unfortunately, many obvious clinical signs of consciousness -- such as talking or muscle movement in response to surgical stimulation are obviated by the use of muscle relaxants. 

 

The Isolated Forearm Test

046Harlan.jpg (109848 bytes) To make things worse, the use of muscle relaxants in balanced anesthesia makes it possible to perform surgery under lighter doses of anesthetic agents -- increasing the risk of intraoperative awareness and postoperative recall at the same time as they decrease the risk of anesthetic morbidity. In fact, it was recognized early on that the use of muscle relaxants increased the risks further, by preventing inadequately anesthetized patients from communicating their intraoperative awareness to the surgical team -- a situation reminiscent of Harlan Ellison's science-fiction classic, I Have No Mouth and I Must Scream (1967).

Of course, the simple fact that anesthesia impairs conscious recall does not mean that anesthetized patients lack on-line awareness of what is going on around them. In principle, at least, they could experience an anterograde amnesia for surgical events similar to that which occurs in conscious sedation.  Or, perhaps, a retrograde amnesia.  In either case, the possibility remains open that the patient is aware during surgery, but forgets it completely thereafter.

In the absence of a reliable and valid physiological index of conscious awareness -- something that is not likely to be available any time soon -- what is needed is some kind of direct behavioral measure of awareness, such as the patient's self-report. In balanced anesthesia, of course, such reports are precluded by the use of muscle relaxants. 

But a variant on balanced anesthesia known as the isolated forearm technique (IFT), developed by Tunstall (1977), actually permits surgical patients to directly report their level of awareness in response to commands and queries. Because muscle relaxants tend to bind relatively quickly to receptors in the skeletal musculature, if the flow of blood is temporarily restricted to one forearm by means of a tourniquet, the muscles in that part of the body will not be paralyzed. And therefore, the patient can respond to the anesthetist's instruction to squeeze his or her hand, or raise their fingers -- that is, if they are aware of the command in the first place.

048Caesarian.jpg (43884 bytes)Interestingly, response to the IFT is not highly correlated with ostensible clinical signs of consciousness. Nor does it predict postoperative recollection of intraoperative events. In one study (King et al., 1993), more than 40% of patients receiving general anesthesia for caesarian section responded positively to commands; yet only about 2% had even fragmentary recollections of the procedure. On the assumption that a patient who responds discriminatively to verbal commands is clearly conscious to some extent, the IFT indicates that intraoperative awareness is somewhat greater than has previously been believed. On the other hand, discriminative behavior also occurs in the absence of perceptual awareness, as in cases of "subliminal" perception, masked priming, and blindsight. Estimates of intraoperative awareness may indeed be suppressed by an anterograde amnesia, which effectively prevents patients from remembering, and thus reporting, any awareness that they experienced during surgery.

The IFT is a useful tool for the anesthesiologist, but there are other, less direct, ways of monitoring surgical awareness that are more popular.

 

Monitoring the Autonomic Nervous System

ANS.JPG
                              (86233 bytes)Traditionally, some anesthesiologists have relied on presumed autonomic signs of conscious pain and stress, such as the PRST score based on four factors:

 

 

 

Monitoring the Central Nervous System

In modern practice, most methods for monitoring the depth of anesthesia involve the central nervous system. 

026ERP.jpg (99885 bytes)One common monitoring technique employs event-related potentials (ERPs, also known as evoked potentials, or EPs) elicited in the EEG by weak somatosensory, auditory, or even visual stimulation. The ERP, which is obtained by averaging the brain's response to repeated stimulation, consists of three components:

 


For example, the P300 response, a positive spike occurring about 300 msec after the stimulus, is enhanced by presentation of a novel stimulus -- for example, a series of "beeps" followed by a "boop". The N400 response, a negative spike occurring about 400 msec after the stimulus, is enhanced by presentation of a semantically incongruent stimulus -- for example, the last word in the sentence I take my coffee with salt.

Adequate anesthesia reduces the amplitude of the various peaks and troughs in the ERP, as well as the latency of various components representing brainstem response and early and late cortical responses. Of course, the late "cognitive" components of the ERP would be expected to disappear entirely during adequate anesthesia. An AEP index of consciousness reflects the degree to which the late "cognitive" components of the ERP are suppressed, and the three "mid-latency" components of are delayed with respect to their normal occurrence between 20 and 45 milliseconds after the stimulus.

PowerSpectrum.JPG (79010 bytes)Another EEG index of consciousness is based on the EEG power spectrum, derived by a fast Fourier transform (don't ask) of the raw EEG signal.  To make a long story short, the EEG can be broken up into four basic bands based on frequency.  

 


So far as anesthesia is concerned, anesthesiologists typically administer enough anesthesia to maintain a median EEG frequency of 2-3 Hz or less, with a "spectral edge frequency", at the very high end of the distribution, within or below the range of alpha activity (8-12 Hz). 

Bispectral.JPG (101155 bytes) Another derivative of the raw EEG is provided by bispectral analysis, a proprietary algorithm (meaning that it is a patented trade secret!) which employs a complicated set of transformations to yield a bispectral index (BIS) based on a number of features of the EEG, such as the amount of high-frequency activation (indicating wakefulness) and periods of "flat line" EEG (indicating the lack thereof). 



BIS ranges from close to 100 in subjects who are normally awake, to values well under 60 in patients who are adequately anesthetized, and is clearly correlated with brain-imaging measures of cortical activity.

According to conventional standards:

Although most physiological indices of anesthetic depth have been validated against such criteria as movement in response to painful surgical stimulation, they have also been compared to various aspects of memory performance. In one study, a 0.2% end-tidal concentration (a measure related to MAC) of isoflurane produced a substantial impairment of performance on a continuous recognition test even over retention intervals as short as 8 seconds, while a 0.4% end-tidal concentration reduced recognition after 32 seconds to zero. Another study showed similar effects for low and high doses of propofol. In a study comparing midazolam, isoflurane, alfentanyl, and propofol, a 50% reduction in recall was associated with an average BIS score of 86, while an average BIS of 64 yielded reductions of 95%.

Another proprietary device making use of processed EEG yields "stages" of anesthesia, analogous to sleep stages, ranging from A (fully awake) to F (a absence of brain activity).


McSleepy.JPG (108435
          bytes)In 2008, a group of anesthesia researchers at McGill University introduced McSleepy, an automated system for delivering anesthetics.  Given information about a patient's weight and age, McSleepy calculates the amount of anesthetic to be delivered, and then monitors the patient's level of consciousness.  Depending on measurements of the bispectral index, muscle responsiveness (as an index of muscle relaxation), and heart rate and blood pressure (as proxies for pain), will add or withhold additional anesthetic.   


In 2010, McSleepy hooked up with DaVinci, a surgical robot (where the surgeon operates a set of joysticks, but the actual cutting is done by a machine), to perform the first intercontinental surgery -- a prostatectomy.  The patient was in Italy, but the anesthesia was monitored and delivered by McSleepy, and the surgery itself was done by DaVinci, all controlled from McGill.

  1. Another approach to monitoring anesthesia is suggested by the relies on the PCI index of consciousness discussed in the lectures on Mind and Body.  Recall that Casarotto et al. (2016) performed a "benchmarking" study which established a value of PCI* = .31 for distinguishing between subjects who are conscious and those who are not.  This study included four groups of health subjects who underwent general anesthesia with midazolam, propofol, and xenon.  All three groups had median PCImax scores below the PCI* threshold value of .31.  The subjects who received ketamine anesthesia reported after recovery from anesthesia, that they were aware of events while the anesthesia was in effect: they showed PCImax scores during anesthesia that were above the threshold PCI* value of .31.  No such report were given by any of the subjects in the other three anesthesia groups.  This suggests that PCI scores would be useful in monitoring depth of general anesthesia.  

A note is in order about the side-effects of general anesthesia.  There is some evidence that general anesthesia can lead to post-operative delirium (POD), including disorientation, hallucinations, and problems with "short-term" memory similar to those seen in the amnesic syndrome.  POD generally dissipates pretty quickly.  More concerning are occurrences of postoperative cognitive dysfunction (POCD), which lasts much longer and includes a wider range of problems in attention, memory, learning, and thinking.  The deeper the anesthesia, as measured by BIS or similar indices, the greater the risk.  Older patients are especially at risk for both POD and POCD.  There is apparently less risk to infants and children, possibly because the immature brain is more plastic than the mature, adult brain.  But the risks at any age have to be balanced against the fact that most modern surgeries wouldn't be possible at all without general anesthesia, and those that would be possible would also be pretty unpleasant (ask any Civil War veteran amputee).  For more details, see "Hidden Dangers of Going Under" by Carina Storrs, Scientific American, 04/2014; and "The Risks of Going Under" by Andrea Anderson, Scientific American Mind, 03-04/2017).


Implicit Memory

While adequate general anesthesia abolishes conscious recollection of surgical events by definition, it is possible that unconscious (or, for that matter, conscious) intraoperative perception may lead to unconscious postoperative memory that influences the patient's subsequent experience, thought, and action outside of phenomenal awareness. 

In fact, clinical lore within anesthesiology includes the "fat lady syndrome", in which an overweight patient's postoperative dislike of her surgeon is traced to unkind remarks he made about her body while she was anesthetized.  Nevertheless, documented cases are hard to find. 

In the late 1950s and early 1960s David Cheek, a Los Angeles physician and hypnotherapist, described a number of patients who, when hypnotized, remembered meaningful sounds that occurred in the operating room -- particularly negative remarks. Cheek claimed to have corroborated these reports, and attributed unexpectedly poor postoperative outcomes to unconscious memories of untoward surgical events. Unfortunately, the interview method he employed, hypnotic "ideomotor signaling", is highly susceptible to experimenter bias, and information that would corroborate such memories is not always available. Accordingly, the possibility cannot be excluded that patients' postoperative "memories", recovered through this technique, are confabulations.

Despite these methodological problems, Cheek's suggestion was subsequently supported by Bernard Levinson, who as an experiment staged a bogus crisis during surgery. After the anesthesia had been established (with ether), the anesthesiologist, following a script, asked the surgeon to stop because the patient's lips were turning blue. After announcing that he was going to give oxygen, and making appropriate sounds around the respirator, he informed the surgeon that he could carry on as before. One month later, Levinson hypnotized each of the patients -- all of whom had been selected for high hypnotizability and ability to experience hypnotic age regression -- and took them back to the time of their operation. Levinson reported that four of the ten patients had verbatim memory for the incident, while another four became agitated and anxious; the remaining two patients seemed reluctant to relive the experience. Levinson's provocative experiment suggested that surgical events could be perceived by at least some anesthetized patients, and preserved in memory -- even if the memories were ordinarily unconscious, and accessible only under hypnosis.

Despite Levinson's report, unconscious perception during general anesthesia remained largely unexplored territory until the matter was revived by Henry Bennett. Inspired by the apparent success of Cheek's "ideomotor signaling" technique for revealing unconscious memories, Bennett gave anesthetized surgical patients a tape-recorded suggestion that, when interviewed postoperatively, they would perform a specific behavioral response, such as lifting their index finger or pulling on their ears. Although no patient reported any conscious recollection of the suggestion, approximately 80% of the patients responded appropriately to the experimenter's cue. Bennett, following Cheek, suggested that unconscious memories were more likely to be revealed with nonverbal than with verbal responses.

038EvansRichardson.jpg
                                        (35743 bytes)At about the same time, Evans and Richardson reported that intraoperative suggestions, delivered during general anesthesia, led to improved patient outcome on a number of variables, including a significantly shorter postoperative hospital stay. Again, the patients had no conscious recollection of receiving these suggestions. Although this study was not concerned with memory per se, the apparent effects of suggestions on post-surgical recovery certainly implied that the suggestions themselves had been processed, if unconsciously, at the time they occurred.


As it happens, subsequent studies have failed to confirm the findings of either Bennett et al. or Evans and Richardson. And more recently, a double-blind study inspired by Levinson's report, in which non-patient volunteers received sub-anesthetic concentrations of either desflurane or propofol, failed to obtain any evidence of memory for a staged crisis. Nevertheless, these pioneering studies, combined with an increasing interest in consciousness and unconscious processing within the wider field of psychology and cognitive science stimulated a revival of interest in questions of awareness, perception, and memory during and after surgical anesthesia, which have been carried out with progressively improved paradigms.

Of particular importance to this revival was the articulation, in the 1980s, of the distinction between two different expressions of episodic memory -- explicit and implicit. To review:
From the 1960s through the 1980s, a growing body of evidence indicated that explicit and implicit memory were dissociable. For example, amnesic patients show priming effects even though they cannot remember the priming events themselves; and they can learn new cognitive and motor skills, even though they do not remember the learning experience. Similarly, normal subjects show savings in relearning material that they can neither recall nor recognize as having been learned before. And, again in normals, priming is relatively unaffected by many experimental manipulations that have profound effects on recall and recognition. In a very real sense, then, implicit memory is unconscious memory, occurring in the absence of, or at least independent of, the individual's conscious recollection of the past. Accordingly, the experimental paradigms developed for studying implicit memory in amnesic patients and normal subjects were soon adapted to the question of unconscious processing of intraoperative events in anesthesia.

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                                            (56643 bytes)In one of the first controlled studies of implicit memory following surgical anesthesia, Kihlstrom et al. worked with patients receiving isoflurane anesthesia for elective surgery.  Through earphones, these patients were played an auditory list of 15 paired associates consisting of a familiar word as the cue and its closest semantic associate as the target -- e.g, ocean-water. The stimulus tape was presented continuously from the first incision to the last stitch, for an average of 67 repetitions over an average of 50 minutes. In the recovery room, the patients were read the cue terms from the stimulus list, as well as a closely matched set of cues from a control list of paired associates, and asked to recall the word with which each cue had been paired on the list read during surgery: this constituted the test of explicit memory. For the test of implicit memory, they were read the same cues again, and asked simply to respond with the first word that came to mind. The subjects recalled no more target words from the presented list than from a control list, thus showing that they had very poor explicit memory for the experience. On the free-association test, however, they were more likely to produce the targeted response from the presented list, compared to control targets, thus displaying a priming effect. Compared to explicit memory, which was grossly impaired (as would be expected with adequate anesthesia), implicit memory was relatively spared.

Despite this early success, subsequent studies employing similar paradigms produced a mix of positive and negative results. 

032Sufentanyl.jpg
                                            (55162 bytes) For example, Cork et al. precisely replicated the procedure employed by Kihlstrom et al. with another group of patients receiving sufentanyl, and found that explicit and implicit memory were equally impaired. Although the two studies, taken together, suggested the interesting hypothesis that different anesthetic agents might have different effects on implicit memory, a more parsimonious conclusion might have been that the isoflurane effects were spurious. 


 

 In a debate at the Second International Symposium on Memory and Awareness in Anesthesia, held in 1992, experimental psychologists and anesthesiologists agreed  that memory for events during anesthesia had not yet been convincingly demonstrated by an overwhelming body of research.  

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                                            (51184 bytes) Over the next few years, however, the literature began to settle, so that in 1996 a comprehensive quantitative review by Merikle and Daneman of 44 published studies concluded that adequately anesthetized patients can, indeed, show postoperative memory for unconsciously processed intraoperative events.

 

 

034BoxScore.jpg (62420 bytes)Although the more recent literature continues to contain a mix of positive and negative results, there are simply too many positive findings, from too many different implicit memory paradigms, to be ignored. At the same time, the literature contains enough negative studies, and other anomalous results, to warrant further investigation. 

 

 

For example, in their 1996 review Merikle and Daneman concluded that the evidence for unconscious processing during general anesthesia was not limited to "indirect" measures of implicit memory, and extended to "direct" measures of explicit memory as well. This is a surprising statement, given that adequately anesthetized patients lack conscious recollection by definition. However, these authors included in their survey only the few tests of explicit memory that encouraged guessing, and excluded the many studies that discouraged guessing. While guessing yields a more exhaustive measure of conscious recollection, it is also true that guessing can be biased, unconsciously, by priming itself. Therefore, it is likely that some of the "explicit" memory identified by Merikle and Daneman is, in fact, contaminated by implicit memory. In support of this idea, a study employing the "process dissociation" procedure confirmed that postoperative memory was confined to automatic priming effects, and not conscious recollection.

A persisting issue is whether postoperative implicit memory might be an artifact of fluctuations in anesthetic depth which occur naturally during surgery.  To some extent, this question was addressed in a new review of the literature, by Deeprose and Andrade (2006), which included 24 studies that employed formal (rather than clinical) assessments of anesthetic depth by means of the isolated forearm technique, auditory evoked potentials, or processed EEG (such as the Bispectral Index, spectral edge frequency, or Narcotrend).  This review yielded mixed evidence generally favoring the hypothesis that perceptual priming was often spared during anesthesia.  But no evidence that semantic priming was also preserved.  There was more repetition priming observed in studies that employed a relatively light plane of anesthesia, compared to studies that employed deeper planes, but in all cases the anesthesia was clinically adequate, so there is no question that the preserved priming occurred only in patients who were in some sense "awake" during presentation.

In what is perhaps the best of these studies, Iselin-Chaves and her colleagues (2005, 2006).  Instead of adopting the usual format of a comparison of explicit and implicit memory (e.g., comparing stem-cued recall with stem-completion), these investigators opted to use only a stem-completion test.  However, they employed Jacob's Method of Opposition and Process-Dissociation Procedure to separate out the automatic (unconscious) and controlled (conscious) contributions to task-performance.  In their experiment, 48 patients anesthetized with isoflurane or propofol (but without sedative premedication) were presented with a list of 40 words, each word repeated 40 consecutive times.  There was also an unanesthetized control group.

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                                            (52837 bytes)Then, within 36 hours of surgery, each patient performed a stem-completion test under Inclusion and Exclusion instructions.  The patients produced 17% of targets under both conditions.  That is, they produced the same number of targets when they were instructed to exclude any they consciously remembered, as they did when there were instructed to include those that they consciously remembered.  By contrast, the controls produced 49% of the targets under the Inclusion instructions, and only 15% of the targets under the exclusion instructions.  Obviously, most of the patients' stem-completion performance was mediated by automatic priming, while most of the controls' performance was mediated by conscious recollection.

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                                            (66085 bytes)During surgery, depth of anesthesia was monitored by the bispectral index, and individual test items were classified according to the average BIS score obtained during their presentation.  For the patients, conscious recollection did not vary with BIS score -- after all, even "light" anesthesia is enough to impair explicit memory.  But the automatic component, representing unconscious priming, was much larger than the controlled component, representing conscious recollection.

 

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                                            (60969 bytes)This study has been criticized for its reliance on average BIS scores, which leave open the possibility that the spared priming reflected conscious processing occurring during natural fluctuations of anesthetic depth.  In response, Iselin-Chaves and her colleagues (2006) re-analyzed their data, classifying each target in terms of the maximum BIS score obtained during its presentation.  The results were very much the same, except -- not surprisingly -- less priming was observed for items presented under the vary deepest levels of anesthesia.  Still, it has to be pointed out that considerable priming occurred for items presented during "adequate" anesthesia, and that "adequate" anesthesia was sufficient to take the conscious, controlled component of task-performance almost to zero.  There was priming for items presented during anesthesia, and this priming was spared even when explicit memory was grossly impaired.

 

Repetition vs. Semantic Priming

Most work on implicit memory employs tests of repetition priming, such as stem- or fragment-completion, in which the target item recapitulates, in whole or in part, the prime itself -- for example, when the word ashtray primes completion of the stem ash-. Repetition priming can be mediated by a perception-based representation of the prime, which holds information about the physical properties of the item, but not about its meaning. But there are other forms of priming, such as semantic priming, where the relationship between prime and target is based on "deeper" processing of the prime -- for example, when the prime cigarette primes completion of the stem ash- with -tray as opposed to -can. Semantic priming requires more than physical similarity between prime and target, and must be mediated by a meaning-based representation of the prime. The distinction between repetition and semantic priming is sometimes subtle. For example, in the isoflurane study described earlier, the paired associates presented as primes were linked by meaning, but because both elements of the pair were presented at the time of study, the priming effect observed could have been mediated by a perception-based representation, rather than a meaning-based one. The point is that implicit memory following surgical anesthesia is fairly well established when it comes to repetition priming, but conclusions about semantic priming are much less secure. Fewer studies have employed semantic priming paradigms, and relatively few of these studies have yielded unambiguously positive results. If semantic priming occurs at all following general anesthesia, it is most likely to occur for items presented at relatively light levels of anesthesia, as indicated by indices such as BIS. At deeper planes of anesthesia, implicit memory -- if it occurs at all -- is likely to be limited to repetition priming.

 

Implicit Memory or Implicit Perception?

Priming effects are evidence of implicit memory, but they can also serve as evidence of implicit perception -- a term coined to refer to the effect of an event on experience, thought, and action, that is attributable to a stimulus event, in the absence of (or independent of) conscious perception of that event. Implicit perception is exemplified by "subliminal" perception of degraded stimuli, as well as neurological syndromes such as "blindsight" and neglect. In general anesthesia, the patients are presumably unaware of the priming events at the time they occurred. For that reason, evidence of implicit memory following general anesthesia is also evidence of implicit perception.

Link to the website for the 8th symposium on Memory and Awareness in Anesthesia, to be held in 2011 at the Medical College of Wisconsin, Milwaukee.  Link to a brief history of this symposium (several of the symposium proceedings have been published). 


The Efficacy of Therapeutic Suggestions

The distinction between perception-based and meaning-based priming may have implications for the use of intraoperative suggestions to improve post-surgical outcome. As noted earlier, a positive report by Evans and Richardson helped stimulate this line of research to begin with.  If subjects unconsciously retain information about surgical events, it might indeed be possible for them to benefit from therapeutic suggestions offered to them while they were anesthetized.  On the other hand, if implicit memory following anesthesia is limited to repetition priming, implying that the anesthetized patient's state of consciousness does not permit semantic analysis of the intraoperative message, it is hard to see how such suggestions could have any effects at all. 

In  fact, as noted earlier, attempts to replicate the Evans and Richardson study have been largely unsuccessful, and the Evans and Richardson study itself has been criticized on a number of grounds:

Perhaps the best study to date yielded clearly negative results (van Leeuwen et al., 1996).  In this study, patients undergoing partial or total hysterectomy received nonspecific suggestions for improved recovery. 

The suggestions were evaluated double-blind.  As an additional feature, all patients received patient-controlled postoperative analgesia.  This provided an objective measure of the amount of pain they experienced: if the therapeutic suggestions worked, patients who received them would be expected to request less medication than those who did not.

As it happened, there were no significant differences between the three groups of patients in terms of either post-operative pain reports, requests for morphine, or nausea.  In other words, intraoperative therapeutic suggestions had no more effect on postoperative outcome than did pre-operative suggestions of the same sort -- or, for that matter, the pre- and intraoperative reading of short stories.



Intraoperative suggestions will do no harm, and patients may derive some "placebo" benefit from the simple knowledge that they are receiving them during surgery. To the extent that intra-operative suggestions do some good, the limitations on information processing during anesthesia may mean that any positive effects are more likely to be mediated by their prosody, and other physical features, than by their meaning: a soothing voice may be more important that what the voice says. If anesthesiologists want patients to respond to the specific semantic content of therapeutic messages, such messages are probably better delivered while patients are awake, during the pre-operative visit that is already established as the standard of care.

 

General Anesthesia as "Controlled Coma"

General anesthesia is sometimes referred to as a controlled coma, and indeed anesthetized patients superficially resemble comatose patients:


Like coma, general anesthesia underscores two basic dimensions of consciousness -- wakefulness and awareness.  Like comatose patients, adequately anesthetized surgical patients seem to lack both these qualities.



This page last revised 10/30/2017.