Anesthetic Gases


Article Author:
Derek Clar


Article Editor:
John Richards


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Jeanie Skibiski
Kathrin Allen
Brian Cornelius


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Nazia Sadiq
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Phillip Hynes
Tehmina Warsi


Updated:
4/8/2019 10:34:27 PM

Indications

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.[1] 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.[2] 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.[3]

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.[4] 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[2][3][4]; however, there is a need for further study of these agents in this setting.

FDA-label indications:

  • Preoperative sedation – primary or adjunctive; rapid induction of sedation, providing amnesia and anesthesia during surgical procedures
  • Perioperative sedation maintenance – adjunctive; maintains anesthesia after sedation by IV benzodiazepines or propofol

FDA-off-label indications:

  • ICU sedation – primary or adjunctive; facilitates tolerance of intubation, mechanical ventilation, bedside procedures

Mechanism of Action

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.[5] These agents are sub-classified by both their chemical properties and believed mechanisms of action:

  • Non-volatile gases: nitrous oxide (N2O)
  • Volatile gases: halothane, isoflurane, desflurane, sevoflurane 

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.[6] 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.[5]

Administration

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.[6] 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[7]:

  • Minimum alveolar concentration (MAC): used as a measure of potency, defined as the % gas concentration determined to produce immobility to noxious stimuli in 50% of patients. Essentially, the higher the MAC, the less the potency of the gas for sedative purposes.
  • Alveolar concentration (FA) to inspired concentration (FI): used to determine the speed of induction, works on a 0-1 scale in which the FA/FI will approach 1 as the gas is administered; 1 being equilibrium. The rate at which the above ratio approaches equilibrium represents the speed of induction.
  • Partition Coefficients: used to determine the solubility of the gas in both arterial blood (blood:gas) and perfused tissues (brain:blood). These coefficients represent the amount of gas that can enter the blood and the amount that must be reversed for equilibrium to be achieved, forming an inverse relationship with the speed of induction (FA/FI). The higher the partition coefficient, the higher concentration that can enter the blood or the brain and the more that must flow backward along that gradient to reach equilibrium, which causes a slower rate of induction.         

All agents have individualized aspects concerning administration[7]:

  • N2O: >100% MAC, blood:gas partition coefficient of 0.47, brain:blood partition coefficient of 1.1  
  • halothane: 0.75% MAC, blood:gas partition coefficient of 2.30, brain:blood partition coefficient of 2.9
  • isoflurane: 1.4% MAC, blood:gas partition coefficient of 1.4, brain:blood partition coefficient of 2.6
  • desflurane: 6-7% MAC, blood:gas partition coefficient of 0.42, brain:blood partition coefficient of 1.3
  • sevoflurane: 2.0% MAC, blood:gas partition coefficient of 0.69, brain:blood partition coefficient of 1.7

Adverse Effects

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.[8] 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.[9] Symptoms that manifest of this hypermetabolic process include muscle rigidity, hyperthermia, rapid onset tachycardia, hypercapnia, hyperkalemia, metabolic acidosis.[5] 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.[8]

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.[10] Several studies suggest a correlation between specifically N2O administration and PONV incidence[10][11]; however, others have contradicted these findings.[12] 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.[7]       

Contraindications

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.[7][8] There are contraindications worth mentioning that are more drug specific[5]:

  • N2O—venous or arterial air embolus, pneumothorax, acute intestinal obstruction with bowel distention, pneumocephalus following dural closure, pulmonary air cysts, intraocular air bubbles, tympanic membrane grafting
  • Halothane—unexplained liver dysfunction following previous anesthetic exposure, reduced ejection fraction heart failure, pheochromocytoma  
  • Isoflurane—relative contraindication in patients with severe asthma or active bronchospasm due to the pungency of agent  
  • Desflurane—relative contraindication in patients with severe asthma or active bronchospasm due to the pungency of agent  
  • Sevoflurane—relative contraindication in patients presenting with renal dysfunction undergoing extensive surgical procedures

Monitoring

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.[7] Temperature is critical to monitor to detect early signs of malignant hyperthermia.[8] 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.[13] Other organ systems which require continued monitoring and possible correction are[7]:

  • Cerebral effects: nitrous oxide can increase cerebral blood flow and cause increased intracranial pressure; whereas volatile anesthetics can decrease cerebral metabolic rate, decreasing cerebral blood flow to a point until reaching 1.5 MAC and resulting vasodilation can occur increasing the intracranial pressure. Both situations ameliorate with the use of IV anesthetics and/or hyperventilation which reduce cerebral blood flow and decrease intracranial pressure.
  • Cardiovascular effects: all anesthetic gases have shown a depression of cardiac contractility; halothane reduces arterial pressure, and the other volatile gases decrease vascular resistance due to vasodilatation resulting in preserved cardiac output. These effects can cause sympathetic activation and reflex tachycardia, especially with the use of isoflurane and desflurane which cause less baroreceptor reflex depression than the others. Volatile gases can also sensitize the myocardium to catecholamines which can increase the risk of ventricular dysrhythmias if patients were given sympathomimetic drugs perioperatively. These effects can be balanced with BP (hydralazine, labetalol, verapamil, etc.) and HR control (metoprolol, amiodarone, etc.).
  • Pulmonary effects: besides N2O, all anesthetic gases cause a dose-dependent decrease in tidal volume and an increase in respiratory rate resulting in a shallow breathing pattern. All gases are respiratory depressants as the reduction of ventilatory response to increasing blood CO2 occurs. Mechanical ventilation is required to compensate for this response.

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.[14]

Toxicity

As stated above, these gases are relatively benign for acute adverse reactions.[9] The toxic profiles for these gases fall into acute and chronic toxicities.

For the acute toxicities[15]:

  • Nephrotoxicity – can occur with all volatile gases. Sevoflurane is metabolized by CYP 2E1 at a much faster rate compared to the other volatile gases and produces increased levels of inorganic fluoride (F) which has been shown during in vivo studies of rats to cause renal impairment. Clinically this renal impairment has not been reported; however, the recommendation is still that sevoflurane not be used in patients with preexisting renal dysfunction undergoing extensive procedures.    
  • Hepatotoxicity – uncommon, but has been reported in individuals who have been previously exposed to halothane specifically. Patients would present immediately after a procedure with halothane-induced fulminant hepatic failure.
  • Carbon monoxide (CO) poisoning – is a concern as all inhaled anesthetics can produce CO from interaction with the dry CO2 absorbers used in the perioperative setting. The largest producer of CO in this manner is desflurane. This situation can is avoidable with routinely changing the absorbent before each day of cases.  

For chronic toxicities[15]:

  • Hematotoxicity – chronic exposure to N2O has been shown to decrease the activity of methionine synthase, an important enzyme in the recycling of vitamin B. Prolonged deficiency of vitamin B can result in megaloblastic anemia, and peripheral neuropathies in patients who work in dental practices should prompt clinical suspicion of this etiology.  
  • Teratogenic/reproductive effects – early exposure can cause cognitive impairment later in life, particularly N2O as described above, which can disrupt vitamin B dependent metabolic pathways.
  • Carcinogenic – continued exposure to trace concentrations of anesthetic gases by operating room personnel correlated with increasing rates of cancer diagnosis in these individuals   

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.[7]  

Enhancing Healthcare Team Outcomes

Anesthetic gases are chiefly used by the anesthesiologist, anesthesia nurse and the emergency department physician. Since there is no antidote to an anesthetic gas, the patient must be closely monitored during anesthesia. A dedicated nurse should monitor the vital signs continuously during induction and maintenance to ensure that the patient is not only sedated but has no pain. After completion of the procedure, the patient must be monitored by the recovery room nurses until the patient is fully awake and hemodynamically stable.


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Anesthetic Gases - Questions

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Which of the following chemical properties changes after halogenation of an anesthesia gas?



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A 52-year-old male presents to the pain clinic for a chronic back pain followup appointment. The pain is described as aching, and the patient denies any radiating pain. The patient tells you that he believes his pain is due to poor posturing during his work as a dentist, bending over chairs 8 hours a day for 20 years. He reports he has been on a vegan diet for about a year now. On exam, he appears pale, and his blood pressure is 100/68 mmHg, heart rate 102 beats/min, and respiratory rate 18. A CBC is significant for a hemoglobin of 10.0 grams/dL, hematocrit 36%, and mean corpuscular volume (MCV) 108. Which agent that this patient is regularly exposed to could have influenced these lab findings?



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An 89-year-old female is undergoing a cecopexy to repair a cecal volvulus at a rural hospital. The anesthesiology provider wants to give her general anesthesia, inducing with both IV and inhaled anesthetics. The patient’s surgical history is significant for an appendectomy when she was 12 years old. The hospital pharmacy calls and informs the anesthesiology provider that there is a national shortage of sevoflurane and desflurane. The anesthesiology provider orders halothane to be given because he knows based on the patient’s past surgical history she tolerated halothane induction with no complications. While recovering on the medical-surgical floor, the patient develops jaundice, periodic episodes of blood oozing from her IV site, and later in her hospital course, increasingly severe altered mental status. What could be causing this symptomology?



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A 45-year-old female who is obese is about to undergo a laparoscopic cholecystectomy to treat cholecystitis. During the preoperative interview, the patient states she does not know if anyone in her family has had complications with general anesthesia. After inducing and intubating the patient, the anesthesia provider notices that the patient is showing signs of hypertonicity and has a blood pressure of 132/90 mmHg, heart rate 114 beats/min, temperature 103.7F, and increasing end-tidal carbon dioxide. The anesthesia provider quickly administers an antidote and stops the surgery from progressing. What is the mechanism of action of the antidote given?



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When discussing anesthetic gas administration, what is the relationship between a gas's speed of induction (FA/FI) and blood solubility (blood/gas partition coefficient)?



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What protein product and gene are most commonly altered in those that are susceptible to volatile anesthetic-induced malignant hyperthermia?



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Anesthetic Gases - References

References

Scheiermann P,Herzog F,Siebenhofer A,Strametz R,Weberschock T, Intravenous versus inhalational anesthesia for pediatric inpatient surgery - A systematic review and meta-analysis. Journal of clinical anesthesia. 2018 Sep     [PubMed]
Jerath A,Parotto M,Wasowicz M,Ferguson ND, Volatile Anesthetics. Is a New Player Emerging in Critical Care Sedation? American journal of respiratory and critical care medicine. 2016 Jun 1     [PubMed]
Spence J,Belley-Côté E,Ma HK,Donald S,Centofanti J,Hussain S,Gupta S,Devereaux PJ,Whitlock R, Efficacy and safety of inhaled anaesthetic for postoperative sedation during mechanical ventilation in adult cardiac surgery patients: a systematic review and meta-analysis. British journal of anaesthesia. 2017 May 1     [PubMed]
Jerath A,Panckhurst J,Parotto M,Lightfoot N,Wasowicz M,Ferguson ND,Steel A,Beattie WS, Safety and Efficacy of Volatile Anesthetic Agents Compared With Standard Intravenous Midazolam/Propofol Sedation in Ventilated Critical Care Patients: A Meta-analysis and Systematic Review of Prospective Trials. Anesthesia and analgesia. 2017 Apr     [PubMed]
Deng J,Lei C,Chen Y,Fang Z,Yang Q,Zhang H,Cai M,Shi L,Dong H,Xiong L, Neuroprotective gases--fantasy or reality for clinical use? Progress in neurobiology. 2014 Apr     [PubMed]
Covarrubias M,Barber AF,Carnevale V,Treptow W,Eckenhoff RG, Mechanistic Insights into the Modulation of Voltage-Gated Ion Channels by Inhalational Anesthetics. Biophysical journal. 2015 Nov 17     [PubMed]
Brown EN,Pavone KJ,Naranjo M, Multimodal General Anesthesia: Theory and Practice. Anesthesia and analgesia. 2018 Nov     [PubMed]
Hopkins PM,Gupta PK,Bilmen JG, Malignant hyperthermia. Handbook of clinical neurology. 2018     [PubMed]
Mullins MF, Malignant Hyperthermia: A Review. Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses. 2018 Oct     [PubMed]
Sert H,Muslu B,Gozdemir M,Kurtaran H,Usta B,Kınacı S,Demircioglu Rİ, Evaluation of recovery and anesthetic gas consumption using remifentanil combined with low-flow sevoflurane anesthesia in tympanoplasty. ORL; journal for oto-rhino-laryngology and its related specialties. 2011     [PubMed]
Fernández-Guisasola J,Gómez-Arnau JI,Cabrera Y,del Valle SG, Association between nitrous oxide and the incidence of postoperative nausea and vomiting in adults: a systematic review and meta-analysis. Anaesthesia. 2010 Apr     [PubMed]
Joshi GP,Pennant JH,Kehlet H, Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia (ENIGMA) Studies: The Tale of Two Large Pragmatic Randomized Controlled Trials. Anesthesia and analgesia. 2017 Jun     [PubMed]
Lee JM, The importance of monitoring volatile anesthetic concentration. Journal of clinical anesthesia. 2018 Nov     [PubMed]
Finger RG,Mallmann C,Nedel WL, BIS monitoring in sedated, mechanically ventilated patients: right tool in the wrong patients? A meta-analysis. Intensive care medicine. 2016 Jun     [PubMed]
Deile M,Damm M,Heller AR, [Inhaled anesthetics]. Der Anaesthesist. 2013 Jun     [PubMed]

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