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General anesthetic drugs (GAD) are essential in medical practice as they make surgical procedures possible in the absence of pain and consciousness. However, there are adverse effects and toxicities involved with inhaled anesthetics including nephrotoxicity, hepatotoxicity, cardiac arrhythmias, neurotoxicity, postoperative nausea and vomiting, respiratory depression and irritation, malignant hyperthermia, and post-anesthesia agitation. Unwanted effects include cardiac depression and reductions of blood pressure. Early work has also identified an interference with mitochondrial respiration. The effects of anesthetic drugs were described in young animals as impaired neurogenesis, neuronal cell death, and long-term cognitive dysfunction.

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An inhalational anesthetic is a chemical compound possessing general anesthetic properties that can be delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vaporizer and an anesthetic delivery system. GADs include volatile anesthetic agents such as isoflurane, sevoflurane and desflurane, as well as certain anesthetic gases such as nitrous oxide and xenon. The full mechanism of action of volatile anesthetic agents is unknown and may vary between agents. Anesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience and has been the subject of intense debate. Generally speaking, the anesthetic potency of a gas is proportional to its lipid solubility (isoflurane is very high), which is also altered by barometric pressure. Thus, diet and membrane fatty acid composition (e.g. PUFA content) may influence anesthetic potency of certain agents.

Anesthetics that are used through inhalation, such as isoflurane can easily cross the blood-brain barrier, and absorbs into and crosses neuronal and mitochondrial membranes to induce general anesthesia. Under isoflurane-evoked anesthesia, the blood glucose level increases, likely through impaired glucose clearance and increased glucose production (gluconeogenesis and glycogenolysis), potentially through altering the neural control of autonomic regulation. The hyperglycemic effect of isoflurane anesthesia may generate a range of acute and potentially persistent side effects.

Acute hyperglycemia in the perioperative period is associated with significantly increased complications. Blood glucose increased during maintenance of anesthesia with isoflurane compared to propofol during the surgery, which has greater implications for those with pre-existing metabolic dysfunction.

Hyperglycemia and insulin resistance (impaired insulin sensitivity) is often associated with immunosuppression, infectious complications, cardiovascular problems, increased risk in neurocognitive dysfunction and ischemic brain damage, and could worsen the prognosis and mortality of the patients undergoing surgical procedures. Insulin resistance and hyperglycemia may result from surgery-evoked stress, while isoflurane anesthesia further exacerbates the surgical stress-provoked hyperglycemic reaction and impairs glucose tolerance.

One of the most important metabolic reactions (occurring on a spectrum) during surgery is resistance to insulin and hyperglycemia. Hyperglycemia in the perioperative period is due to stress hormones such as epinephrine, cortisol, and inflammatory mediators. Even short-term hyperglycemia can lead to immunosuppression and it is associated with significantly increased infectious complications and patient mortality.

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Acute hyperglycemia during surgery can worsen prognosis even in the patients with a normal oral glucose tolerance test (OGTT). Thus, the effect of surgical stress on the blood glucose during the surgery is even more important and potentially deleterious in diabetic patients. These kinds of hyperglycemic reactions to the surgical stress are even more frequent during inhalation anesthesia. Some studies showed impaired glucose tolerance and hyperglycemia even without surgical stress during isoflurane anesthesia.

In a newly published study by a team of Hungarian and American scientists, an exogenous ketone formulation was used before administering anesthesia and the exogenous ketones eliminated the increase in blood glucose level that was caused by isoflurane-anesthesia, while the time required for recovery has changed as well:

The researchers` goal was to find out whether the administration of exogenous ketone supplements would change both the time required for recovery from isoflurane anesthesia and isoflurane-induced increase in blood glucose level.

Exogenous ketone supplements (EKSs), such as ketone salts (KSs) and ketone esters (KEs), as well as their mix with medium chain triglycerides (MCTs; e.g. KEMCT) were previously shown to increase and maintain blood level of ketone bodies (e.g., β-hydroxybutyrate/βHB) and decrease blood glucose level in animal models and in humans.

In this study, laboratory rats were administered either water (control) or KEMCT once per day for 7 days. To generate anesthesia, isoflurane was used one hour after the last (7th) treatment. The isoflurane anesthesia was induced in an airtight anesthesia chamber for 20 min to ensure enough time to both loss of righting reflex and develop significant increase in blood glucose level by isoflurane

In this study the researchers found that isoflurane anesthesia-evoked increase in blood glucose level was eliminated when the exogenous ketone formulation was administered before anesthesia. In addition, the exogenous ketone formulation treatment significantly increased the time required for recovery from isoflurane-induced anesthesia.

The findings of this new study can be considered important as hyperglycemia might also contribute to impaired cognitive function after anesthesia. The impact of general anesthesia on cognitive impairment is controversial and complex. A large body of evidence supports the association between exposure to surgery under general anesthesia and delayed neurocognitive recovery in some patients. Scientists continue to debate the relationship between anesthesia exposure and the development of long-term neurocognitive disorders, or the development of incident dementia in patients that had normal cognitive function before surgery.

What is the significance of the present study?

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It is difficult to determine the concentrations of volatile anesthetics in the brain and on the cellular level because that data does not exist.

Mitochondrial alterations can be expected in the therapeutic range of volatile anesthetics.

Hyperglycemia can contribute to post-surgical cognitive dysfunction that is often observed in elderly patients.

The exact mechanism of how ketones might mitigate metabolic and cognitive impairment is unknown, but there are several possible underlying theories:

• It has been suggested that ketosis may generate an increase in adenosine level and modulation of sleep and sleep-like processes. Previous studies show that adenosine has a role in the isoflurane-generated anesthetic influence.
• Inhibition of mitochondrial respiration/function has long been acknowledged to contributes to the anesthetic action of these compounds. Mitochondria is particularly sensitive to volatile anesthetics and less or not affected by injectable anesthetics. Ketones are known to improve and preserve mitochondrial function under stressors.
• Isoflurane can cause a rapid, four-fold increase of lactate in mouse brain, indicative of mitochondrial impairment. This effect was accompanied by increases of glucose and lactate in blood. Ketones can reduce blood glucose and ketosis decrease plasma lactate concentrations
• Isoflurane strongly inhibits complex I of the mitochondrial electron transport chain and ATP synthesis. Ketones generate more ATP than glucose, and this may be more pronounced under conditions of surgical tissue hypoxia and stress.

This new study shows that ketosis, in this case induced by an exogenous ketone, can change the effects of anesthesia, which can be clinically and surgically relevant.

The change that was observed in the anesthesia recovery time suggests that administration of exogenous ketones may modulate the requirement for isoflurane during surgery. The effect of ketosis on alteration of blood glucose level under isoflurane, and potentially when using other anesthetics, should be considered by anesthesiologists. For example, considerations should be taken when patients may be in self-induced ketosis due to its use as a medical therapy (epilepsy) or as a required fasting prior to anesthesia administration associated with medical procedures. It may be crucial to monitor not only blood ketone body level, but also glucose level pre-, intra-, and postoperatively in humans undergoing isoflurane anesthesia to make sure that the proper blood glucose level is maintained to avoid potential harmful metabolic and cognitive changes.

As our population ages and the prevalence of Alzheimer’s disease and other forms of dementia continues to increase, it would be beneficial to have a better understanding of potential factors that impact cognitive function changes post-surgery. Future research is needed to determine the inhalation anesthesia associated risk factors and determine whether the administration of certain procedures/compounds before anesthetic approaches may lower the potential risk of further metabolic and cognitive disfunctions in the future.

Written by: Dr. Csilla Ari D`Agostino

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