Anesthetic gases (nitrous oxide, halothane, isoflurane, desflurane, sevoflurane), also known as inhaled anesthetics, are administered as primary therapy for preoperative sedation and adjunctive anesthesia maintenance to intravenous (IV) anesthetic agents (i.e., midazolam, propofol) in the perioperative setting. Inhaled anesthetics enjoy regular use in the clinical setting due to chemical properties that allow rapid introduction of an agent into arterial blood via the pulmonary circulation as compared to the more circuitous route of venous circulation. The significance of rapid therapeutic effects allows for efficient induction and discontinuation of sedation induced by these agents; providing proper amnesia, anesthesia, and a faster recovery period in postoperative care as compared to IV agents.
Though indicated solely for the perioperative setting, these agents also have a significant off-label use within critical care to facilitate patient tolerance of endotracheal intubation, mechanical ventilation, and bedside procedures. Generally, for these cases, the recommended use of IV benzodiazepines (midazolam, lorazepam, diazepam) or propofol induces this level of sedation. However, more recent studies have explored the regular use of inhaled anesthetics, specifically the volatile anesthetics (halothane, isoflurane, desflurane, sevoflurane), as first-line agents for critical care sedation. Preliminary findings show shorter times to extubation and shorter lengths of stay in the ICU; however, there is a need for further study of these agents in this setting.
Inhaled anesthetics work to depress neurotransmission of excitatory paths involving acetylcholine (muscarinic and nicotinic receptors), glutamate (NMDA receptors), and serotonin (5-HT receptors) within the central nervous system (CNS) and augment inhibitory signals including chloride channels (GABA receptors) and potassium channels to provide an adequate level of sedation. These agents are sub-classified by both their chemical properties and believed mechanisms of action:
The main distinction between the non-volatile and volatile gases originally stemmed from their specific chemical properties. Non-volatile anesthetics have high vapor pressures and low boiling points meaning they are in gas form at room temperature, whereas volatile anesthetics have low vapor pressures and high boiling points meaning they are liquids at room temperature and so require vaporizers during administration. Since these agents work on a myriad of receptors as described above, physiologically distinguishing these subclasses has proven more arduous. Current thought suggests non-volatile agents primarily inhibit NMDA receptors and glutamate signaling, whereas volatile agents augment GABA signaling.
Administration of all anesthetic gases is via inhalation. As described above, N2O being the only non-volatile gas clinically administered at room temperature in its gaseous state; whereas the volatile gases of halothane, isoflurane, desflurane, and sevoflurane are liquids at room temperature requiring a vaporizer for administration. Compared to other agents in pharmacology, where the basis of the therapeutic index is the bioavailability of the agent within serum determined via route of administration (IV, PO, IM, SC), inhaled anesthetics are unique in that they have one route of administration and multiple factors, listed below, that determine therapeutic index:
All agents have individualized aspects concerning administration:
Anesthetic gases, though relatively benign for immediate adverse reactions, have been observed in specific individuals to cause malignant hyperthermia. Classically, halothane was the most common agent causing this reaction; however, all volatile gases (halothane, isoflurane, desflurane, sevoflurane), and depolarizing neuromuscular blockers (succinylcholine) have induced this reaction. Patients susceptible to this reaction possess heritable alterations within various proteins involved in the modulation of muscular cytosolic concentrations of Ca2+. The most common alterations found include the ryanodine receptor/channel encoded by gene RYR1 and dihydropyridine receptor (DPHR) encoded by gene CACNA1S. Both sarcoplasmic proteins are involved with Ca2+ transport, so in the event of their alteration and subsequently exposed to the volatile gases or succinylcholine, excessive release of Ca2+ in skeletal muscle results. Symptoms that manifest of this hypermetabolic process include muscle rigidity, hyperthermia, rapid onset tachycardia, hypercapnia, hyperkalemia, metabolic acidosis. To quickly reverse this process, administration of dantrolene is a must; the mechanism of action is the reduction of Ca2+ release from the sarcoplasmic reticulum. Besides administering dantrolene, appropriate measures to reduce body temperature and restore electrolyte and acid-base imbalances are recommended.
There has been a suggestion that these agents are involved with postoperative nausea and vomiting (PONV). There is only a confirmed correlation between the administration of general anesthesia, both IV and inhalation agents, and PONV incidence. Several studies suggest a correlation between specifically N2O administration and PONV incidence; however, others have contradicted these findings. Independent of the cause, to correct this reaction usually anti-emetic agents (ondansetron, metoclopramide, dexamethasone, etc.) are administered prophylactically and can be administered postoperatively as “rescue” agents.
Anesthetic gases, specifically volatile gases, have the generalized contraindications in known susceptibility to malignant hyperthermia as described above, and use in patients with severe hypovolemia and intracranial hypertension due to the negative inotropic effects and effect of increasing cerebral blood flow that the gases can cause. There are contraindications worth mentioning that are more drug specific:
During the perioperative period when using anesthetic gases to induce and maintain general anesthesia, several key details are monitored. First: the patient’s vital signs due to the suppressive effects on the CNS and sympathetic nervous system that these agents exhibit. Heart rate (HR) and blood pressure (BP) specifically are monitored by the minute to detect tachyarrhythmias or sudden hypertension/hypotension. Temperature is critical to monitor to detect early signs of malignant hyperthermia. Third, one must ensure and monitor a secure airway for continued delivery and manipulation of anesthetic gases throughout the procedure. Ventilation can be important in the delivery of these gases and the reversal of their effects. Achieving these goals involves monitoring and manipulating the end-tidal CO2, tidal volume, and respiratory rate via mechanical ventilation. Other organ systems which require continued monitoring and possible correction are:
Bispectral index (BIS) is applied commonly with the use of anesthetic gases for general anesthesia to determine the level of sedation achieved. This monitoring technique detects brain activity, similarly to EEG monitoring, and gives an average value on a numerical scale (0-100) with values below 60 determined as the level of minimal sedation and below 40 as the level of deep sedation. Though still used commonly in clinical practice, future use of BIS for this type of monitoring is in question because of the lack of studies and no proven gold standard for comparison.
As stated above, these gases are relatively benign for acute adverse reactions. The toxic profiles for these gases fall into acute and chronic toxicities.
For the acute toxicities:
For chronic toxicities:
In the event of overdose or postoperative reversal:
There is no pharmacological reversal of anesthetic gases in use for postoperative recovery or in the event of an overdose. The primary method of reversal is to remove the patient from continued exposure of gas and to hyperventilate to decrease the concentration of gas in the patient’s alveoli.