US3436455A

US3436455A - Respiratory stimulant comprising neon

Info

Publication number: US3436455A
Application number: US263065A
Authority: US
Inventors: Richard A Flinn; Jack A Young
Original assignee: Air Products and Chemicals Inc
Current assignee: Air Products and Chemicals Inc
Priority date: 1963-03-05
Filing date: 1963-03-05
Publication date: 1969-04-01
Anticipated expiration: 1986-04-01

Description

United States Patent 3,436,455 RESPIRATORY STIMULANT COMPRISING NEON Richard A. Flinn, Emmaus, and Jack A. Young, Allentown, Pa., assignors to Air Products and Chemicals Inc., Philadelphia, Pa., a corporation of Delaware No Drawing. Filed Mar. 5, 1963, Ser. No. 263,065 Int. Cl. A6lk 13/00 US. Cl. 424127 4 Claims This invention relates to respiratory gas mixtures and to compositions and methods for using such compositions to achieve advantageous physiological effects. For example, such compositions make it possible to increase the tidal flow of respiratory gas.

The noble gases include helium, neon, argon, krypton, xenon, and radon. Xenon has an anesthetic affect of significant magnitude. Helium is a preferred gas for utilization in respiratory gases at super atmospheric pressures,

as explained in Cooke 1,473,337 and Yant et al. 1,644,-

363. As explained in Cooke vs. United States, 80 United States Patent Quarterly 374, helium can diffuse from the body fluids with greater rapidity than nitrogen, and thus can decrease the tendency toward the development of a dangerous illness sometimes called the bends. The relative diffusion rates of gases are generally proportional to the square roots of their molecular weights, so that helium has a diffusion rate which is somewhat greater than twice that of nitrogen, whereas the predicted diffusion rate of neon, based upon the ratio of square roots, is only about 16% greater than that of nitrogen. Thus, the incremental diffusion advantage for helium was known to be more than six times greater than any incremental diffusion advantage for neon. Accordingly, little interest has been shown in the untested possibility that neon might diffuse from biological fluids more rapidly than nitrogen. Each of the Yant et a1. and Cooke patents clearly indicates that no tests substituting neon for the preferred helium were conducted.

In accordance with the present invention, a respiratory gas composition is characterized by the presence of a significant amount of neon. The respiratory gas mixture must contain at least 2% by volume of neon, but not more than about 80% by volume neon. The respiratory gas mixture must contain a concentration of oxygen suitable for sustaining life under the circumstances employed, which life sustenance is conveniently designated as fulfilling the respiration requirements of lungs, thus embracing animal life having lungs but excluding vegetation, fish, and other life not having lungs supplying oxygen to circulating blood. The respiratory gas composition must contain sufficient oxygen for supplying oxygen to the blood in the lungs or it would not be designated as a respiratory gas. At atmospheric pressure, a respiratory gas generally con tains 99% oxygen, but smaller amounts may suffice at high pressures. The respiratory gas composition may or may not include other respiratory gases such as helium, nitrogen, cyclopropane, tetrafiuorornethane', carbon dioxide, and/or other gases having a desired function in a respiratory gas mixture of controlled composition. The concentration of the total of all other respiratory gases should desirably be not more than nine times the volume of the mixture of oxygen and neon, and is generally less than four times the volume of the mixture of oxygen and neon.

The advantages of neon as a component of a respiratory gas mixture are surprising, and different from what might have been predicted on the basis of the known physiological effect of other gases. Among the useful results obtained by the advantageous respiratory gas compositions of the present invention are the increased minute volume of respiratory gas. Such use of neon increases the gas inhaled and exhaled by the lungs measured by the volume per minute. The use of neon may either increase or decrease the breathing rate. Similarly, the use of neon may either increase or decrease the volume per breath or tidal volume. The neon inhalant compositions achieving some of the most advantageous increases of the minute volume also tend to decrease the breathing rate as compared with the breathing rate employing air as the respiratory gas and to increase the tidal volume. The respiratory gas mixture characterized by a significant concentration of neon and containing an effective amount of oxygen has other advantageous characteristics, but the respiratory stimulant advantage is a convenient attribute for illustrating the superiority of such compositions.

The nature of the present invention is further clarified by a plurality of examples.

Example I Five mongrel dogs were used in a series of five experiments. In preparing each dog for a test, the trachea was exposed and intubated with a cuffed endotracheal tube of maximum cross-sectional diameter. The animal was allowed to breath room air until accustomed to the presence of the endotracheal tube. Tidal and minute volumes were measured with a Wright Respirometer. The animal was connected to a Heidbrink Kinet-o-meter anesthesia machine after three successive and agreeing measurements of tidal volume had been obtained. A semi-closed circuit for carbon dioxide adsorption was used. A sufficient flow of gas was maintained so that the reservoir bag was threequarters full and yet no flow was going through the respirometer except during active inhalations. The pop-off valve was kept open to assure a lack of pressure in the system.

Each dog was kept awake but was kept in a quiet state by controlled supplemental injections of an aqueous solution (also containing 5% glucose) of sodium S-ethyl-S- (l-methylbutyl)-2-thiobarbiturate (Pentothal) using an Abbott microdrip attached to an intravenous needle.

In the various tests, the dogs breathed respiratory gas mixtures having code designations and compositions as follows: (1) 5% neon, 20% oxygen, and nitrogen; and (2) 10% neon, 20% oxygen, and 70% nitrogen. These gases were pre-blended and kept in metal cylinders under pressure. Connection from the cylinders to the gas machines was through a conventional regulator and high pressure hose, and flow was regulated through a nitrous oxide flowmeter. The actual flow rate was of no consequence since the flow was regulated through the requirements of the gas system as stated above.

An outlet was tied into the inhalation side of the circuit and a hose led from the adapter to a Beckman Model D paramagnetic oxygen analyzer. Determination of the oxygen level was semi-continuously (about every minute) and basal oxygen was added as required to maintain the gases at a 20% oxygen concentration. Heart sounds were monitored by a precardial stethoscope.

The data obtained from five experiments are given in Table I. From a review of the percentage changes it is seen that there were definite increases in tidal volume in each test in which a dog breathed a gas containing 540% neon. The increases in volume of gas breathed per minute were generally accompanied by decreases in the number of breaths per minute, or respiration rate. It is apparent that there is some variation in results from animal to animal.

Certain other observations were noted. The animals take the inhalation of neon Without fighting. Salivation is not excessive. There is no apparent pulmonary irritation. The increase in inhalation appears after about two minutes exposure and persists as long as neon is present in the system. Neon exhibits no anesthetic properties whatsoever. Recovery from neon is swift and complete in two to three minutes. Repeated exposure does not result in tolerance. There were no cardiac changes which could be attributed to neon inhalation. Cardiac rate remained relatively constant and no arrhythmia was noted.

Although an attempt was made to keep sedation at a minimum, and although the animals appeared to have a rather constant degree of consciousness, there is a significant possibility that a portion of the varying respiratory response to neon inhalation is attributable to a change in the level of Pentothal sedation. The available evidence required the conclusion that the effect is apparently a unique heterostych of neon. Other members of the noble gas family do not function as respiratory stimulants. No good explanation is apparent for the wide variation in the degree of change when different dogs are tested using the same concentration of neon. It was noted that repeated exposure of the same animal to the same concentration of neon results in similar responses. Thus, the

TABLE I Minute Respiration Tidal Change in Experimen- Neon volume rate avervolume tidal vl tal N 0. average age (numaverage ume (per- (liters) her/min.) (ca/breath) cent) variations in response must be attributed to undefined variations in individual animals. It was also noted that the frequency of the respiratory rate usually decreased when increases in tidal and minute volumes occurred. The nor mal respiratory change with moderate neon concentrations is thus due to marked increases in tidal volume.

A substantial stimulation of respiration does appear to result from the breathing of neon-containing air mixtures. The stimulation results in significantly increased tidal and minute volumes, along with a decrease in respiratory frequency. The magnitude of the effect varies with the concentration of neon in the mixture and also varies from subject to subject. Response to and recovery from the effect are quite rapid, occurring within several minutes.

EXAMPLE 2 Four dogs are anesthetized by injection with sodium 5 ethyl 5 (l methylbutyl) 2 thiobarbiturate (Pentothal) to achieve a steady state of breathing under the control conditions. Instruments are provided to measure: the volume of respiratory gas inhaled and exhaled per minute; the breathing rate; the volume of gas inhaled per breath, conveniently designated as tidal flow or tidal volume; and the rate of oxygen replacement necessary for maintaining the oxygen concentration substantially steady at about 20%. When the respiratory gas contains 1% neon, the increase in the volume of gas inhaled and exhaled per minute is small enough that the stimulant effect is not clearly established. By increasing the neon concentration to about 2.0% by volume, the tidal fiow is measurably increased within ten minutes. When the dogs breathe a mixture of 5% neon, 20% oxygen, and 75% nitrogen, the tidal flow increase is measurable after about one minute. Mixtures providing about 39% neon,

% oxygen, and 41% nitrogen are effective in increasing the tidal flow to approximately more than observed when using air as the respiratory gas. Mixtures containing about 80% neon are less reliable by reason of the more extreme differences among different dogs when using such excessive neon concentrations but the respiratory stimulant effect is advantageous even at this expensively high concentration. The mixtures containing 80% neon and 20% oxygen produce results which accentuate the differences in the response of individual dogs to neon inhalation. Mixtures consisting of 35% neon and oxygen increase both the tidal flow and the volume per minute, this mixture appearing to have potential usefulness wherever stimulating respiratory gases are employed. By a series of tests, it is established that the volume concentration of neon in the respiratory gas should e within the range from 2% to about The oxygen concentration of the neon inhalant should be within the range suitable, under the circumstances, for maintenance of life of species in which blood circulates for gas exchange in lungs, which concentration is conveniently designated as meeting the respiration requirements of lungs. The oxygen concentration at at mospheric pressure is generally within the range from 21% to 98% by volume, but at superatmospheric pressure, smaller concentrations of oxygen are sufficient to meet the respiration requirements of the lungs. The mixture of neon and oxygen must constitute at least 10% by volume of the inhalant composition. Other respiratory gases such as nitrogen, helium, cyclopropane, tetrafluoromethane, and/or other gases employed as anesthetics, as inert diluents, and/or as medicants having a controlled physiological action must be not more than nine times the volume of the neon-oxygen mixture, that is, the concentration of such other respiratory gases, if present, must be not more than or if expressed by two limits, within the range from 0 to 90%.

Example 3 Control measurements establish for each of eight dogs breathing air the volume per minute, the volume per breath (i.e. tidal volume) and the breaths per minute (i.e. breathing rate). Each dog is tested using an inhalant composition consisting of 20% oxygen, 40% helium, and 40% neon. Notwithstanding differences in the magnitude of the response, the volume breathed per minute increased significantly for each dog.

When a respiratory stimulant is helpful, the principal goal is the result of larger minute volume, so that the blood may be exchanged with a larger volume of gas per minute. Such increase is desirably accompanied by deeper breathing (increased volume per breath or larger tidal volume) inasmuch as rapid shallow breathing (even when achieving increased minute volume) stimulates excitement and other disadvantageous characteristics. In the usual situation, the increased tidal volume is so related to the increased minute volume that the number of breaths per minute is decreased. Thus, the desired effect is increased, deeper, slower breathing, but the increased breathing may involve either faster or slower rates and either deeper or shallower breathing depending on the overall effect on volume per minute.

Various modifications of the invention are possible without departing from the scope of the invention as set forth in the appended claims.

What is claimed is:

1. The method of stimulating mammals having lungs to inhale respiratory gas at a rate expressed in volumes per minute which is greater than normal, which method is characterized by providing to the lungs a respiratory gas mixture consisting essentially of: from 2 to about 80% neon; from 21 to 98% oxygen; an inert respiratory gas an anesthetic respiratory gas, and a medicant respiratory gas, the total concentration of. inert, anesthetic, and medicant respiratory gases being less than nine times the volume concentration of the sum of the volume concentration of the mixture of neon and oxygen.

2. The method of claim 1 in which the mammals are dogs.

3. A respiratory gas composition consisting essentially of: from 2 to about 80% neon; from 21 to 98% oxygen, said neon acting to stimulate the lungs of mammals having lungs to inhale respiratory gas at a rate expressed in volumes per minute which is greater than the rate at which air is normally inhaled.

4. The method of stimulating lungs in mammals to inhale an increased volume of respiratory gas which con sists of providing the lungs of said mammals a respira- References Cited UNITED STATES PATENTS 1,473,337 11/1923 Cooke 167-526 10 FRANK CACCIAPAGLIA, JR., Primary Examiner.

J. D. GOLDBERG, Assistant Examiner.

Claims

1. THE METHOD OF STIMULATING MAMMALS HAVING LUNGS TO INHALE RESPIRATORY GAS AT A RATE EXPRESSED IN VOLUMES PER MINUTE WHICH IS GREATER THAN NORMAL, WHICH METHOD IS CHARACTERIZED BY PROVIDING TO THE LUNGS A RESPIRATORY GAS MIXTURE CONSISTING ESSENTIALLY OF: FROM 2 TO ABOUT 80% NEON; FROM 21 TO 98% OXYGEN; AN INERT RESPIRATORY GAS AN ANESTHETIC RESPIRATORY GAS, AND A MEDICANT RESPIRATORY GAS, THE TOTAL CONCENTRATION OF INERT, ANESTHETIC, AND MEDICANT RESPIRATORY GASES BEING LESS THAN NINE TIMES THE VOLUME CONCENTRATION OF THE SUM OF THE VOLUME CONCENTRATION OF THE MIXTURE OF NEON AND OXYGEN.