Nitrous Oxide: Yea or Nay

and Richard A. Jaffe2



(1)
David Geffen School of Medicine at UCLA, Los Angeles, California, USA

(2)
Stanford University School of Medicine, Stanford, California, USA

 



Keywords
SolubilityAnalgesiaComplicationsDiffusion hypoxiaENIGMA trials


In 1783 Joseph Priestly published his study of a drug that he had prepared, which he called “Dephlogisticated Nitrous Air”. His younger friend, Humphrey Davy studied the drug, which he called nitrous oxide, in his laboratory for 2 years and published his findings in 1800. Among his many observations he noted that four or five breaths of nitrous oxide temporarily relieved his headache from indigestion and on another occasion pain from his inflamed gum. In both cases the pain returned after a time but was less intense than originally. Davy’s colleagues in chemistry acknowledged his observations but none of them appreciated the fact that it might relieve the pain of surgery. In 1844 a medical student at New York’s College of Physicians and Surgeons, Gardner Quincy Colton found that he could earn money for his medical school expenses by attracting patrons into a rented hall and having them inhale nitrous oxide in conjunction with a lecture on chemistry. Those inhaling the gas erupted into loud laughter, which amused the audience and greatly enlivened his lecture. Horace Wells, a dentist in Hartford, Connecticut attended one of these lectures, and subsequently asked Colton to administer nitrous oxide to him while a colleague extracted his painful tooth. While Colton continued to administer nitrous oxide for years afterward for dental extractions both in the United States and England, the discovery of ether and subsequently chloroform anesthesia occupied the attentions of those involved in advancing surgical anesthesia. In 1868 Dr. E. Andrews, a Professor of Surgery at Chicago Medical School published a paper indicating that a mixture of nitrous oxide 75 % with oxygen 25 % might be useful for surgical anesthesia, and subsequently used it on some of his surgical patients. With improved methods for delivery of a nitrous oxide–oxygen mixture over the next 50 years the drug became increasingly popular as an adjuvant for clinical anesthesia. The term “balanced anesthesia ” came into the anesthesia lexicon to acknowledge the use of nitrous oxide in combination with a sedative-hypnotic (thiopental), an opiate (morphine, meperidine, etc.) and a neuromuscular blocking drug (succinylcholine, d-tubocurarine). It was widely accepted that nitrous oxide was safe for most patients so long as one avoided a hypoxic gas mixture.

In the last 30 years there has been increasing concern that nitrous oxide may not be as safe as originally thought [1]. This is not a new concern. In 1944 Ralph Waters wrote that there was a growing tendency to abandon the use of nitrous oxide because of the technical danger of delivering a hypoxic mixture and the fact that it did not produce any skeletal muscle relaxation [2]. Even in 2015 the question still arises each day in the operating rooms across the United States: Shall we use nitrous oxide on this patient or not…yea or nay? This chapter analyzes the advantages and disadvantages of nitrous oxide so that readers can decide for themselves whether there is still a place for this drug in clinical anesthesia.


Advantages of Nitrous Oxide



Advantages of Nitrous Oxide





  • Moderate analgesia


  • Rapid onset, rapid recovery


  • Circulatory support


  • Inexpensive


  • Safe in patients with known malignant hyperthermia


Analgesia


The most important advantage of nitrous oxide is its ability to produce analgesia in a dose dependent manner, the greater the dose, the greater the analgesic effect. Unfortunately, the upper limit of dosage is 60–70 % concentration to avoid hypoxemia, and at that dose range nitrous oxide does not provide adequate analgesia for surgery. For surgical anesthesia nitrous oxide must be used in combination with other anesthetics such as propofol, opiates (fentanyl, meperidine, dihydromorphone) or inhalation anesthetics (sevoflurane, desflurane or isoflurane). The minimum anesthetic concentration (MAC) for nitrous oxide is 105 %, so at 60 % concentration it decreases the need for other analgesics by about 50 %. However, since the analgesic requirement of patients is so variable, this is only a rough approximation of its analgesic interaction with other drugs.


Insolubility


The second most important advantage of nitrous oxide is its insolubility. Its blood-gas partition coefficient is 0.47, which means that for every molecule of nitrous oxide in the blood phase there are two molecules in the gas phase. This insolubility and the fact that nitrous oxide is both odorless and tasteless render it an excellent drug for inducing general anesthesia by inhalation. Administering nitrous oxide 6–8 L/min flow with oxygen 3–4 L/min flow will induce a quick loss of awareness and allow for the introduction of sevoflurane in a rapidly increasing concentration with minimal or no recall of the odor of sevoflurane, even though it is a pleasant one. A high total gas flow at the start of an inhalation induction anesthetic is essential to quickly replace the air in the 8–10 L anesthetic circuit and patient functional residual capacity as well as to match the large volume of nitrous oxide uptake in the first 5–10 min. Manually augmenting ventilation during this induction phase will greatly increase the speed of induction, since uptake of insoluble anesthetics is enhanced more by ventilation than by circulation. Inhalation induction with nitrous oxide/sevoflurane is by far the safest type of induction of anesthesia since if any untoward events should occur (hypotension, arrhythmia, etc.), the gases can be quickly replaced with pure oxygen. Since there is very little venous or tissue content of nitrous oxide or sevoflurane during induction, the patient will awaken from anesthesia very quickly. Inhalation inductions with nitrous oxide/sevoflurane will become an increasing part of clinical practice in the future as the ability to easily find intravenous access preoperatively becomes more difficult owing to old age, obesity, chemotherapy, etc. General anesthesia generally makes obtaining peripheral intravenous access easier. The insolubility of nitrous oxide also makes it easier to change anesthetic concentrations quickly when compared to other inhaled anesthetics. If one wishes to increase the anesthetic concentration of nitrous oxide from 50 to 60 % or decrease the concentration from 60 % to zero, it can be done very quickly by either using a high gas flow of nitrous oxide 60 % or a high gas flow of oxygen 100 %, and in both cases also augmenting ventilation.

The combination of high total gas flows and rapid transition from spontaneous to manually controlled ventilation will greatly speed up an inhalation induction with nitrous oxide/sevoflurane.

Once anesthesia is induced and the inspired and expired concentrations of nitrous oxide are in equilibrium, nitrous oxide flow can be decreased to 1 L/min or less with a corresponding oxygen flow of 0.8–1 L/min or less to maintain oxygen saturation at 97 % or greater. Since there is no loss of nitrous oxide to metabolism, and only a very small loss over time via the skin, it is acceptable to use even lower flows of nitrous oxide and oxygen if one wishes.


Circulatory Support


Nitrous oxide is a mild myocardial depressant, but stimulates the sympathetic nervous system with consequent maintenance of both cardiac output and blood pressure. In most circumstances this is an advantage, but it can be a disadvantage if one is trying to decrease mean pressure to decrease blood loss at the surgical site. One of the interesting and totally unstudied side effects of nitrous oxide is that when it is combined with meperidine, a bradycardia ensues, usually with heart rates in the range of 50–60 b/min. This interaction is surprising because meperidine is a derivative of atropine, so one would expect a tachycardia instead of a bradycardia. The only time that bradycardia does not occur is when the patient is hypovolemic or if the depth of anesthesia is inadequate for the surgical stimulus. Nitrous oxide is the only inhaled anesthetic that has been shown not to provide cardioprotection as a result of administering it prior to an episode of ischemia (anesthetic preconditioning).


Cost


No consideration of the value of a drug is complete without analysis of its cost relative to alternative drugs. Most anesthetic drugs are purchased under contract with a vendor, and the exact price will vary depending upon such things as the number and volume of drugs purchased from that vendor, shipping costs, etc. As one benchmark, at one institution the cost of sevoflurane 2 % delivered in a total gas flow of 2 L/min for 1 h is $ 5.14. This is based on a 250 mL bottle price of $ 93.11. The cost for desflurane 6 % delivered at the same flow rate for 1 h is $ 20.47 based on a 240 mL bottle price of $ 142.11. One problem with this comparison is that if an institution does not use much desflurane then the purchase price is higher. The cost of nitrous oxide delivered at a flow rate of 2 L/min for 1 h is $ 0.87. What this illustrates is: (a) the lower the total gas flow rate, the lower the cost of the drug; and (b) nitrous oxide is much less expensive than the commonly used volatile agents. Cost should never be the primary driving force in the selection of anesthetic drugs, but anesthesia providers must be cognizant of the cost savings that can accrue over time by using nitrous oxide in combination with volatile agents rather than using the volatile agents alone.


Disadvantages of Nitrous Oxide


There are several circumstances or transition states where the use of nitrous oxide is inappropriate or highly questionable.

Jul 14, 2017 | Posted by in Uncategorized | Comments Off on Nitrous Oxide: Yea or Nay

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