general anesthesia

General Anesthesia Before Age 36 Months Does Not Impair IQ

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Healthy children who undergo a single episode of general anesthesia before age 36 months show no statistically significant differences in IQ scores later in childhood compared with their unexposed siblings, a new study suggests.

“There was no significant difference in IQ scores between the children who were exposed to anesthesia and siblings who were not,” lead author Lena S. Sun, MD, said in a Columbia University Center news release. “We also saw no difference in most of the secondary outcomes, although more children in the group exposed to anesthesia exhibited internalizing behavior that required further clinical evaluation. That’s an area that needs to be further explored.”

Dr Sun, from the Morgan Stanley Children’s Hospital–New York Presbyterian, Columbia University Medical Center, New York City, and colleagues present their findings in an article published online June 6 in JAMA.

The study included 105 sibling pairs; one sibling in each pair had undergone a single exposure to general inhaled anesthetic (43 sevoflurane, 5 isoflurane, and 57 both sevoflurane and isoflurane) for inguinal hernia repair before age 36 months. The children underwent assessment at ages 8 to 15 years for the primary analysis of an increased risk for impaired global functioning. Between 97 and 105 sibling pairs also underwent analysis for the secondary outcomes of abnormal domain-specific neurocognitive functions and behavior.

Overall, the mean IQ scores were similar between the exposed cohort (full-scale IQ, 111 [95% confidence interval (CI), 108 – 113]; performance IQ, 108 [95% CI, 105 – 111]; verbal IQ, 111 [95% CI, 108 – 114]) and the unexposed siblings (full-scale IQ, 111 [95% CI, 108 – 113]; performance IQ, 107 [95% CI, 105 – 110]; verbal IQ, 111; 95% CI, 109 – 114]).

In addition, the between-group differences were not statistically significant when the researchers divided the cohort according to age of exposure: 0 to 11 months (full score difference, 1; 95% CI, −4.1 to 6.1), 12 to 23 months (1; 95% CI, −3.4 to 5.4), and at 24 to 36 months (−1; 95% CI, −5.8 to 3.8). Similarly, there was no significant differences seen when the researchers stratified the group based on duration of exposure: 0 to 59 minutes of exposure (full score difference, 2; 95% CI, −4 to 8), 60 to 119 minutes of exposure (0; 95% CI, −3.4 to 3.4), and 120 or more minutes of exposure (−2; (95% CI, −8.2 to 4.2).

A number of children received general anesthesia after 36 months (18 exposed and 23 unexposed siblings); however, subset analyses taking these later exposures into account did not alter the primary finding.

Secondary Outcomes

Statistically significant differences were found between exposed and unexposed siblings in terms of verbal fluency (difference, −1; 95% CI, −1.7 to −0.3); behavior (Child Behavior Checklist; internalizing: difference, 3.2 [95% CI, 1.1 – 5.3]; externalizing: difference, 2.1 [95% CI, 0 – 4.2], and total problems: difference, 2.7 [95% CI, 0.6 – 4.7]); and adaptive behavior (Adaptive Behavior Assessment System, Second Edition; social composite: difference, −3.3; 95% CI, −6.1 to −0.6).
There were no statistically significantly differences between siblings in the remaining secondary outcomes of domain-specific neurocognitive functions of memory, learning, motor or processing speed, visuospatial function, attention, language, executive function, and other areas of adaptive behavior.

“Differences in mean behavior scores between exposed and unexposed siblings became statistically nonsignificant after adjustment for sex. However, even after adjustment for sex, more exposed children had clinically abnormal internalizing behavior scores than unexposed siblings. With the limited number of exposed girls and same-sex female sibling pairs, further analysis to examine the apparent sex exposure interaction in behavior was not possible,” the authors write.

General Anesthesia: 8 Interesting Facts About The Procedure That Puts You To Sleep

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Woman under anesthesia
Learn the surprising facts about the medical mystery of anesthesia, from waking up during surgery to suffering amnesia post-surgery.

If you’ve had surgery, your anesthesiologist has probably told you to count backward from 100 in order to be “put to sleep.” Anesthesia is administered in hospitals, and has been for almost 200 years, to block pain or the memory of pain. But despite its widespread use, doctors still don’t know exactly how it works. While millions of people undergo various surgeries that require pain-numbing medications, there are facts about anesthesia you probably don’t know — but should.

1. Anesthesia causes amnesia.

General anesthesia keeps you relaxed, blocks pain, and may also cause amnesia. A 2012 studypublished in the journal Annals of Neurology found that inhalation anesthetics induced Alzheimer’s-like changes in the brains of adult mice. The drug was toxic to dentate gyru — a type of cell that helps control memory and learning. Although researchers are still unaware of the long-term effects of anesthesia, they do know it takes at least a couple of days before you bounce back from surgery.

2. Older patients exposed to anesthesia face up to a 35% increased risk of dementia.

Older patients can take up to six months to return to normal after receiving anesthesia during surgery, according to a 2013 study. Specifically, patients are more likely to experience a small change in their mental capacity, possibly facing a higher risk of dementia by 35 percent. Researchers believe this may be because anesthesia causes inflammation of neural tissues that lead to postoperative cognitive dysfunction (POCD) and/or Alzheimer’s disease precursors, such as β-amyloid plaques.

3. Frequent exposure to anesthesia during childhood may lead to neurodevelopmental problems.

Children who are exposed to anesthesia once or multiple times for early-life surgeries may be prone to neurodevelopmental problems. A 2012 study published in the journal Pediatrics found that children who underwent anesthetic surgeries before the age of 3 were twice as likely to develop learning disabilities, including long-term language and reasoning deficits, before the age of 10. However, there were no observed differences when it came to behavior, visual tracking, and attention, or fine and gross motor function. This suggests not all cognitive domains are affected by anesthesia the same way.

4. Anesthesia does not actually ‘put to sleep.’

Anesthesiologists often tell their patients they will be “put to sleep,” but the truth is they’re being put in a reversible coma. Researchers found a fully anesthetized brain is not unlike the deeply unconscious, low-brain activity seen in coma patients compared to a person who’s just asleep, according to a 2010 study published in the New England Journal of Medicine. These states all represent brain regions that have common circuit mechanisms, such as the cortex — located in the outer edge of the brain — and the thalamus — located at the center of the brain. These regions communicate with each other to determine brain activity in patients under anesthesia.

5. You can wake up during surgery.

Patients under anesthesia can wake up during surgery, also known as “anesthesia awareness.” This rare condition occurs when patients are able to recall their surroundings or an event, such as pressure or pain, related to their surgery while under anesthesia, according to the American Association of Nurse Anesthetists. However, surgeons do use brain-monitoring devices to measure their patients’ consciousness as a means to reduce the risk of this happening.

6. Some people have a rare allergic reaction to anesthetic agents.

Patients can have a potentially fatal allergic reaction when inhaling anesthesia, known asmalignant hyperthermia, even if they have no previous history of the reaction. MedlinePlusreported that the disease, which is passed down through families, causes a fast rise in body temperature and severe muscle contractions when the patient inhales. Patients may also experience bleeding, dark brown urine, and muscle ache without an obvious cause, among others.

7. Redheads do not require more anesthesia to get numb.

Redheads were previously thought to require higher doses of anesthesia due to having a specific gene called melanocortin-1 receptor (MC1R). This gene was believed to decrease a patient’s sensitivity to anesthetics, until a 2012 study published in the journal Anaesthesia and Intensive Care proved otherwise. Researchers found there were no differences in anesthetic administration, POCD pain, nausea and vomiting, or the overall quality of recovery in people with red hair and darker hair.

8. Smokers may need higher doses of anesthesia than non-smokers.

Smokers and people exposed to secondhand smoke may require more anesthesia when undergoing operations. A recent study presented at the 2015 European Society of Anesthesiology meeting in Berlin, Germany found that female smokers required 38 percent more anesthesia than non-smokers, and 17 percent more than passive smokers. Cigarette smoke is known to mess up respiratory function while under anesthesia, which interferes with the patient’s tolerance for pain medication.

General Anesthesia: 8 Interesting Facts About The Procedure That Puts You To Sleep

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If you’ve had surgery, your anesthesiologist has probably told you to count backward from 100 in order to be “put to sleep.” Anesthesia is administered in hospitals, and has been for almost 200 years, to block pain or the memory of pain. But despite its widespread use, doctors still don’t know exactly how it works. While millions of people undergo various surgeries that require pain-numbing medications, there are facts about anesthesia you probably don’t know — but should.

 

1. Anesthesia causes amnesia.

General anesthesia keeps you relaxed, blocks pain, and may also cause amnesia. A 2012 studypublished in the journal Annals of Neurology found that inhalation anesthetics induced Alzheimer’s-like changes in the brains of adult mice. The drug was toxic to dentate gyru — a type of cell that helps control memory and learning. Although researchers are still unaware of the long-term effects of anesthesia, they do know it takes at least a couple of days before you bounce back from surgery.

2. Older patients exposed to anesthesia face up to a 35% increased risk of dementia.

Older patients can take up to six months to return to normal after receiving anesthesia during surgery, according to a 2013 study. Specifically, patients are more likely to experience a small change in their mental capacity, possibly facing a higher risk of dementia by 35 percent. Researchers believe this may be because anesthesia causes inflammation of neural tissues that lead to postoperative cognitive dysfunction (POCD) and/or Alzheimer’s disease precursors, such as β-amyloid plaques.

3. Frequent exposure to anesthesia during childhood may lead to neurodevelopmental problems.

Children who are exposed to anesthesia once or multiple times for early-life surgeries may be prone to neurodevelopmental problems. A 2012 study published in the journal Pediatrics found that children who underwent anesthetic surgeries before the age of 3 were twice as likely to develop learning disabilities, including long-term language and reasoning deficits, before the age of 10. However, there were no observed differences when it came to behavior, visual tracking, and attention, or fine and gross motor function. This suggests not all cognitive domains are affected by anesthesia the same way.

4. Anesthesia does not actually ‘put to sleep.’

Anesthesiologists often tell their patients they will be “put to sleep,” but the truth is they’re being put in a reversible coma. Researchers found a fully anesthetized brain is not unlike the deeply unconscious, low-brain activity seen in coma patients compared to a person who’s just asleep, according to a 2010 study published in the New England Journal of Medicine. These states all represent brain regions that have common circuit mechanisms, such as the cortex — located in the outer edge of the brain — and the thalamus — located at the center of the brain. These regions communicate with each other to determine brain activity in patients under anesthesia.

5. You can wake up during surgery.

Patients under anesthesia can wake up during surgery, also known as “anesthesia awareness.” This rare condition occurs when patients are able to recall their surroundings or an event, such as pressure or pain, related to their surgery while under anesthesia, according to the American Association of Nurse Anesthetists. However, surgeons do use brain-monitoring devices to measure their patients’ consciousness as a means to reduce the risk of this happening.

6. Some people have a rare allergic reaction to anesthetic agents.

Patients can have a potentially fatal allergic reaction when inhaling anesthesia, known asmalignant hyperthermia, even if they have no previous history of the reaction. MedlinePlusreported that the disease, which is passed down through families, causes a fast rise in body temperature and severe muscle contractions when the patient inhales. Patients may also experience bleeding, dark brown urine, and muscle ache without an obvious cause, among others.

7. Redheads do not require more anesthesia to get numb.

Redheads were previously thought to require higher doses of anesthesia due to having a specific gene called melanocortin-1 receptor (MC1R). This gene was believed to decrease a patient’s sensitivity to anesthetics, until a 2012 study published in the journal Anaesthesia and Intensive Care proved otherwise. Researchers found there were no differences in anesthetic administration, POCD pain, nausea and vomiting, or the overall quality of recovery in people with red hair and darker hair.

8. Smokers may need higher doses of anesthesia than non-smokers.

Smokers and people exposed to secondhand smoke may require more anesthesia when undergoing operations. A recent study presented at the 2015 European Society of Anesthesiology meeting in Berlin, Germany found that female smokers required 38 percent more anesthesia than non-smokers, and 17 percent more than passive smokers. Cigarette smoke is known to mess up respiratory function while under anesthesia, which interferes with the patient’s tolerance for pain medication.

Electron spin changes during general anesthesia in Drosophila

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Significance

One hundred sixty years after its discovery, the molecular mechanism of general anesthesia remains a notable mystery. A very wide range of agents ranging from the element xenon to steroids can act as general anesthetics on all animals from protozoa to man, suggesting that a basic cellular mechanism is involved. In this paper, we show that volatile general anesthetics cause large changes in electron spin in Drosophila fruit flies and that the spin responses are different in anesthesia-resistant mutants. We propose that anesthetics perturb electron currents in cells and describe electronic structure calculations on anesthetic–protein interactions that are consistent with this mechanism and account for hitherto unexplained features of general anesthetic pharmacology.

Abstract

We show that the general anesthetics xenon, sulfur hexafluoride, nitrous oxide, and chloroform cause rapid increases of different magnitude and time course in the electron spin content of Drosophila. With the exception of CHCl3, these changes are reversible. Anesthetic-resistant mutant strains of Drosophila exhibit a different pattern of spin responses to anesthetic. In two such mutants, the spin response to CHCl3 is absent. We propose that these spin changes are caused by perturbation of the electronic structure of proteins by general anesthetics. Using density functional theory, we show that general anesthetics perturb and extend the highest occupied molecular orbital of a nine-residue α-helix. The calculated perturbations are qualitatively in accord with the Meyer–Overton relationship and some of its exceptions. We conclude that there may be a connection between spin, electron currents in cells, and the functioning of the nervous system.

General anesthesia (GA) is both indispensable and fascinating. Millions of surgical procedures are performed each year, most of which would be unthinkable if GAs did not exist. However, although the first clinical anesthesia with diethyl ether was reported over 160 y ago (1), the mechanism by which the same GAs act on animals as far apart in evolution as paramecia and man (2)—and even plants (3⇓–5)—is still unclear. In 2005, GA was included in a Science list of major unsolved problems in the august company of cancer, quantum gravity, and high-temperature superconductivity (6). Today, GA remains an intellectual challenge and arguably, one of the few experimental inroads to consciousness (7⇓–9).

The mystery of GA resides in a uniquely baffling structure–activity relationship: the range of compounds capable of acting as GAs makes no pharmacological sense. Adrien Albert (10) called it “biological activity unrelated to structure” (10). In number of atoms, the simplest of the GAs is xenon (11, 12), a monoatomic noble gas, and the most complex is alfaxalone (3-hydroxypregnane-11,20-dione), a 56-atom steroid (13), spanning a 35-fold range in molecular volume. In between is a host of molecules of widely different structures: nitrous oxide, halogenated compounds [sulfur hexafluoride (SF6), chloroform, halothane, etc.], strained alkanes (cyclopropane), phenols (propofol) (14), ethers (diethyl ether and sevoflurane), amides (urethane), sulfones (tetronal), pyrimidines (barbiturates), etc. If one adds gases, like dioxygen and nitrogen, that cause narcosis under pressure and volatile solvents used as inhalational recreational drugs, the list is longer still. What property can all these molecules possibly have in common that causes GA?

A partial answer has been known for nearly a century. GAs are lipid-soluble, and their potency, regardless of structure, is approximately proportional to lipid solubility [with some exceptions (15)], a relationship known as the Meyer–Overton rule (16, 17) that is reviewed in ref. 1. This relationship implies, surprisingly in light of their diverse structures, that, after they have arrived at their destination, all GAs are equally effective. Accordingly, because GAs dissolve in the oily core of the lipid bilayer, they were long thought to perturb the featureless dielectric in which ion channels, receptors, and pumps are embedded (18⇓⇓⇓⇓⇓–24), although an action on proteins could never be ruled out (25, 26). Other theories were also proposed, involving the formation of gas hydrates (27), proton leaks (28), hydrogen bonds (29, 30), and membrane dipoles (31). In the 1980s, however, after the discovery of an effect of anesthetics on firefly luciferase (32), Franks and Lieb (33) first showed enzyme inhibition by GAs (34) and then differences in potency between GAs enantiomers (35, 36). This finding pointed to a protein site of action, likely a weakly chiral hydrophobic pocket (37⇓–39). Indeed, GAs are now believed to act on proteins (40⇓–42) and have now been seen in just such sites in protein structures, where they exert small but definite effects on protein (43) and ion channel (44) conformation. The Meyer–Overton rule then becomes all the more surprising, because protein binding sites are usually highly selective for ligand shape and size.

However, if, indeed, both the Meyer–Overton rule and the Franks–Lieb protein hypothesis are taken to be correct, a single mechanism should be shared by all GAs at the protein binding site(s). Then, the small GAs, especially xenon, drastically constrain the range of possibility. Xenon is uniquely slippery and falls outside the normal confines of molecular recognition. It has no shape, because it is a perfect sphere of electron density. It has no chemistry either at any rate under conditions found in the brain. However, and this is the hitherto overlooked starting point of the ideas developed in this paper, xenon has physics: like many other elements and molecules, it is capable of facilitating electron transfer between conductors: recall the iconic photograph of the IBM logo written in Xe atoms in a scanning tunneling microscope (STM) (45). Each Xe atom is a bump, because it facilitates tunneling from substrate to tip, and the tip must rise above it to keep the current constant (46). Indeed, among the many molecules that have been imaged in the STM are several GAs or close congeners other than xenon: nitrous oxide (47), phenols (48), ethers (49), benzene (50), amides (51), and pyrimidines (52).

Suppose then that there exists, in one or more proteins essential to CNS function, a hydrophobic site lined with an electron donor on one side and an acceptor on the other side. When GAs enter the site, they could connect donor to acceptor by creating a pathway for electron transfer where there was no pathway. Indeed, our calculations show that, for example, xenon can extend the highest occupied molecular orbital (HOMO) of an α-helix in such a way as to bridge the gap to another helix (see Fig. 10). This spread, in proteins as well as the STM, is expected to be such a general property of molecules that if a connection were found between it and anesthesia, the Meyer–Overton rule would follow naturally. How would one detect these electron currents in a whole organism? If the electrons were unpaired, ESR would provide a specific, although not particularly sensitive, detection method, the only one presently applicable to whole animals. It, therefore, seemed interesting to ask whether one could detect changes in electron spin during anesthesia