Use of 1,1,1,2-Tetrafluoroethane for lung function evaluation

The invention relates to the use of 1,1,1,2-tetrafluoroethane for pulmonary function measurement, especially for determining the functional residual capacity (FRC) of lungs during ventilation. The lung function measurement and especially the FRC determination in the ventilation using fluoropropane, namely heptafluoropropane, hexafluoropropane or perfluoropropane as trace / tracer gas goes out <patcit id="pcit0001" dnum="DE10046465B4"><text>DE 100 46 465 B4</text></patcit> and the equivalent <patcit id="pcit0002" dnum="US6544191B2"><text>US 6,544,191 B2</text></patcit> so that for the method of pulmonary function measurement and FRC determination, reference is explicitly made to these prior publications.

In the <patcit id="pcit0003" dnum="US6254546B1"><text>US 6,254,546 B1</text></patcit> describes a method for determining lung properties outside of mechanical ventilation by means of bolus dosing of a mixture of different blood-soluble gases, the measurement being evaluated by means of an optimization algorithm for the expiratory gas concentrations measured after the inhalation.

In addition, various other trace gases have been used for the FRC measurement with additions to the respiratory gas of generally a few vol. %, which greatly reduces the health burden on the ventilated and examined patient and avoids risks. Disadvantages of trace / tracer gases used hitherto are high procurement costs and the generally great technical complexity with which the filling and application of the trace gases used take place, with the result that lung function diagnostics using trace gases has hitherto only established itself in niche markets such as high-performance sports medicine and in particular is not part of the clinical routine of mechanically ventilated intensive care patients. Some trace gases, such as helium, also require a high level of metrological effort due to the mass spectrometric determination to be applied, while others such as sulfur hexafluoride do not have medical approval for medical use in most countries.

Thus, the object of the invention is the selection of a trace gas for use in pulmonary function measurement and especially the FRC determination of the lung of a patient or subject during ventilation, which is easily detectable, physiologically harmless, environmentally sound and cost-effective.

The object is achieved according to claim 1 by the use of the practically world-wide, medically approved, but for the FRC measurement hitherto unused fluorocarbon 1,1,1,2-tetrafluoroethane of the formula F.₃C-CH₂F and corresponding empirical formula C₂H₂F₄, INN designation Norflurane; further designation: "R 134a". Significant advantages of 1,1,1,2-tetrafluoroethane, also in comparison to the also medically approved 1,1,1,2,3,3,3-heptafluoropropane (further designation: "R 227") are:<ul id="ul0001" list-style="dash" compact="compact"><li>An optical absorption line at 10.3 microns, where cross sensitivity to anesthetics and nitrous oxide (N₂O) is largely reduced, as can be seen in the single figure, where in the upper part the absorption spectra of the different known anesthetic gases (enflurane, isoflurane, sevoflurane, desflurane, halothane) and nitrous oxide (N₂O) over the wavelength λ and in the lower part the absorption spectra of the fluorocarbons 1,1,1,2-tetrafluoroethane ("R 134a") and 1,1,1,2,3,3,3-heptafluoropropane ("R 227 "). From the figure it can be seen that when using "R 134a" even in the presence of volatile anesthetics and nitrous oxide (N₂O) Infrared concentration measurements are readily possible due to the characteristic absorption peak at 10.3 microns, while this is not possible for "R 227".</li></ul>

Further advantages include the lower purchase price of "R 134a" compared to "R 227" due to the simpler manufacturing process and the increased penetration as well as the better environmental compatibility with a lower "Global Warming Potential" (GWP) related to CO₂ from 1300 ("R 227": 2900).

The application of the tracer gas can either be done directly from an inhaler in the form of a bolus dosing during ventilation or with the aid of an intermediate dosing device, which is operated continuously or intermittently and optionally mixes the tracer gas with other respiratory gases in the anesthesia or respirator. The inhalant used here is, for example, a drug in whose composition "R 134a" is contained as an additive to a finished inhalation solution or a subset of the composition which also contains "R 134a". The FRC determination with "R 134a" as trace / tracer gas is carried out, as known from the prior art, especially by a combination of volume and concentration measurement with appropriate evaluation, as in <patcit id="pcit0004" dnum="DE10046465B4"><text>DE 100 46 465 B4</text></patcit> and <patcit id="pcit0005" dnum="US6544191B2"><text>US 6,544,191 B2</text></patcit> specified. The FRC determination is performed on mechanically ventilated patients. By measuring further constituents of the inhalation composition, further functional quantities known per se, such as "pulmonary blood flow", can be calculated as an option, and a compartment analysis of the lung known per se can also be carried out as follows:

Applying a tracer gas wash to end-tidal concentrations semilogarithmically above the number of breaths since the start of washout generally results in a multilinear course. Each linear component corresponds to a washout time constant and may be assigned to a lung compartment. Each compartment is characterized by a volume and an effective tidal volume, where the sum of the volumes of all compartments, the FRC, and the sum of the effective tidal volumes of all compartments gives the effective tidal volume of the lung for the washout in question (parallel connection). The calculation of the tidal volumes makes above all under regular spontaneous respiration or Mandatory mechanical ventilation sense, since in these cases the tidal volumes remain almost constant over the washout.

For example, for a lung with two compartments, the following time course of the end-expiratory concentrations is obtained, where the running index i denotes the number of breaths since the beginning of the wash-out, c (0) is the known initial concentration in the lung and λ₁ and λ₂ are the decay rates of the two compartments to be determined: <maths id="math0001" num=""><math display="block"><mi>c</mi><mfenced><mi>i</mi></mfenced><mo>=</mo><mi>c</mi><mfenced><mn>0</mn></mfenced><mo>⋅</mo><msup><mi>e</mi><mrow><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>1</mn></msub><mo>⋅</mo><mi>i</mi></mrow></msup><mo>+</mo><mi>c</mi><mfenced><mn>0</mn></mfenced><mo>⋅</mo><msup><mi>e</mi><mrow><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>2</mn></msub><mo>⋅</mo><mi>i</mi></mrow></msup></math><img file="EP1759634A2_D0001.tif" /></maths>

Decadic logarithm of concentration and normalization to the initial concentration gives: <maths id="math0002" num=""><math display="block"><msub><mi>log</mi><mn>10</mn></msub><mfenced separators=""><mi>c</mi><mfenced><mi>i</mi></mfenced><mo>/</mo><mi>c</mi><mfenced><mn>0</mn></mfenced></mfenced><mo>=</mo><mo>(</mo><msub><mi>log</mi><mn>10</mn></msub><mo>⁢</mo><mfenced separators=""><msup><mi>e</mi><mrow><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>1</mn></msub><mo>⋅</mo><mi>i</mi></mrow></msup><mo>+</mo><msup><mi>e</mi><mrow><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>2</mn></msub><mo>⋅</mo><mi>i</mi></mrow></msup></mfenced><mo>=</mo><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>1</mn></msub><mo>⋅</mo><mi>i</mi><mo>⋅</mo><mfenced separators=""><msub><mi>log</mi><mn>10</mn></msub><mo>⁢</mo><mi>e</mi></mfenced><mo>+</mo><msub><mi>log</mi><mn>10</mn></msub><mo>⁢</mo><mfenced separators=""><mn>1</mn><mo>+</mo><msup><mi>e</mi><mrow><mo>(</mo><msub><mi mathvariant="italic">λ</mi><mn>1</mn></msub><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>2</mn></msub><mo>)</mo><mo>⋅</mo><mi>i</mi></mrow></msup></mfenced></math><img file="EP1759634A2_D0002.tif" /></maths>

Assuming, without restriction of generality, that λ₁ &gt; λ₂, so that λ₁ representing the dominant decay rate (fastest decay), one can extract the first linear component (first summand on the right side in the above equation). Since the term in the exponent of the second summand is positive and grows with increasing i, one can neglect the logarithm for large i (towards the end of the washout). For large i, approximately:<maths id="math0003" num=""><math display="block"><msub><mi>log</mi><mn>10</mn></msub><mfenced separators=""><mi>c</mi><mfenced><mi>i</mi></mfenced><mo>/</mo><mi>c</mi><mfenced><mn>0</mn></mfenced></mfenced><mo>≈</mo><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>1</mn></msub><mo>⋅</mo><mi>i</mi><mo>⋅</mo><mfenced separators=""><msub><mi>log</mi><mn>10</mn></msub><mo>⁢</mo><mi>e</mi></mfenced><mo>+</mo><mfenced separators=""><msub><mi mathvariant="italic">λ</mi><mn mathvariant="normal">1</mn></msub><mo mathvariant="italic">-</mo><msub><mi mathvariant="italic">λ</mi><mn>2</mn></msub></mfenced><mo>⋅</mo><mi>i</mi><mo>⋅</mo><mfenced separators=""><msub><mi>log</mi><mn>10</mn></msub><mo>⁢</mo><mi>e</mi></mfenced><mo>=</mo><mo>-</mo><msub><mi mathvariant="italic">λ</mi><mn>2</mn></msub><mo>⋅</mo><mi>i</mi><mfenced separators=""><msub><mi>log</mi><mn>10</mn></msub><mo>⁢</mo><mi>e</mi></mfenced></math><img file="EP1759634A2_D0003.tif" /></maths>

For the two-compartment model, the unknowns are determined. In the case of more than two compartments you have to λ₂ by the sum of all decay rates except λ₁ replace. The analysis then gives the smallest decay rate for large i (end of washout), which can be eliminated by subtraction in the output equation. Subsequently, the second smallest decay rate is determined in the semilogarithmic representation, and so on. The larger the quotient from the greatest to the lowest decay rate, the greater the inhomogeneity of the lung.

If one has subtracted the dead volume before, one obtains the following relationships for the decay rates and the volumes of the compartments: <maths id="math0004" num=""><math display="block"><msub><mi mathvariant="italic">λ</mi><mi mathvariant="italic">j</mi></msub><mo mathvariant="italic">=</mo><msub><mi mathvariant="italic">V</mi><mi mathvariant="italic">tj</mi></msub><mo mathvariant="italic">/</mo><msub><mi mathvariant="italic">V</mi><mi mathvariant="italic">j</mi></msub></math><img file="EP1759634A2_D0004.tif" /></maths><maths id="math0005" num=""><math display="block"><mi mathvariant="italic">FRC</mi><mo>=</mo><mstyle displaystyle="false"><mstyle displaystyle="true"><munder><mo>Σ</mo><mi>j</mi></munder></mstyle><msub><mi>V</mi><mi mathvariant="italic">j</mi></msub></mstyle></math><img file="EP1759634A2_D0005.tif" /></maths><maths id="math0006" num=""><math display="block"><msub><mi>V</mi><mi>T</mi></msub><mo>=</mo><mstyle displaystyle="true"><munder><mo>Σ</mo><mi>j</mi></munder></mstyle><msub><mi>V</mi><mi mathvariant="italic">tj</mi></msub></math><img file="EP1759634A2_D0006.tif" /></maths>

Where VT denotes_j the effective tidal volume for the jth compartment, Vj the volume of the jth compartment. For the two-compartment model this results in the following simple relationships:<maths id="math0007" num=""><math display="block"><msub><mi mathvariant="italic">T</mi><mrow><mi mathvariant="italic">T</mi><mo>⁢</mo><mn mathvariant="italic">1</mn></mrow></msub><mo mathvariant="italic">=</mo><mfrac><mrow><msub><mi mathvariant="italic">V</mi><mi mathvariant="italic">T</mi></msub><mo mathvariant="italic">-</mo><msub><mi mathvariant="italic">λ</mi><mn mathvariant="normal">2</mn></msub><mo mathvariant="italic">⋅</mo><mi mathvariant="italic">FRC</mi></mrow><mrow><mn mathvariant="normal">1</mn><mo mathvariant="italic">-</mo><msub><mi mathvariant="italic">λ</mi><mn mathvariant="normal">2</mn></msub><mo mathvariant="italic">/</mo><msub><mi mathvariant="italic">λ</mi><mn mathvariant="normal">1</mn></msub></mrow></mfrac><mspace width="2em" /><msub><mi mathvariant="italic">V</mi><mn mathvariant="italic">1</mn></msub><mo mathvariant="italic">=</mo><msub><mi mathvariant="italic">V</mi><mrow><mi mathvariant="italic">T</mi><mo>⁢</mo><mn mathvariant="italic">1</mn></mrow></msub><mo mathvariant="italic">/</mo><msub><mi mathvariant="italic">λ</mi><mn mathvariant="normal">1</mn></msub></math><img file="EP1759634A2_D0007.tif" /></maths><maths id="math0008" num=""><math display="block"><msub><mi mathvariant="italic">T</mi><mrow><mi mathvariant="italic">T</mi><mo>⁢</mo><mn mathvariant="italic">2</mn></mrow></msub><mo mathvariant="italic">=</mo><mfrac><mrow><msub><mi mathvariant="italic">λ</mi><mn mathvariant="italic">1</mn></msub><mo mathvariant="italic">⋅</mo><mi mathvariant="italic">FRC</mi><mo>-</mo><msub><mi mathvariant="italic">V</mi><mi mathvariant="italic">T</mi></msub></mrow><mrow><msub><mi mathvariant="italic">λ</mi><mn mathvariant="italic">1</mn></msub><mo mathvariant="italic">/</mo><msub><mi mathvariant="italic">λ</mi><mn mathvariant="italic">2</mn></msub><mo>-</mo><mn>1</mn></mrow></mfrac><mspace width="3em" /><msub><mi mathvariant="italic">V</mi><mn>2</mn></msub><mo mathvariant="italic">=</mo><msub><mi mathvariant="italic">V</mi><mrow><mi mathvariant="italic">T</mi><mo>⁢</mo><mn>2</mn></mrow></msub><mo mathvariant="italic">/</mo><msub><mi mathvariant="italic">λ</mi><mn mathvariant="italic">2</mn></msub></math><img file="EP1759634A2_D0008.tif" /></maths>

In addition, determination of the amount of washed-out tracer gas via the known inhalation composition provides a means for calculating the amount of medically effective ingredients that has entered the lungs, thereby allowing a more accurate dosage of inhalant medicaments than previously possible. Another use is for alternating or simultaneous inhalation of "R 134a" or "R 227" to use the different blood solubility of both fluorocarbons for pulmonary function diagnostics.

The blood solubility of gases can be described by the blood gas partition coefficient L, which describes the ratio of the volume fractions between gas dissolved in blood and in the gas phase. The prerequisite for this is the presence of an equilibrium with identical partial pressures of the gas in the dissolved in the blood and in the gas phase. For pulmonary function diagnostics, and in particular the determination of the FRC, the lowest possible blood solubility of the tracer gases is desired since it is ultimately desired to determine the lung volume and not the amount of blood in the body. By using at least two gases with different blood solubilities, the FRC measurement can be corrected for blood solubility. In the following denote the indices 1 and 2, the two gases, eg can stand for R 134a and R 227.

Assuming that for the FRC measurement not only the concentration in the lung is in equilibrium, but also that the blood concentration has reached its equilibrium value, an FRC determination depending on the blood solubility results in different values: <maths id="math0009" num=""><math display="block"><msub><mi>FRC</mi><mi mathvariant="normal">j</mi></msub><mo>=</mo><mi>FRC</mi><mo>+</mo><msub><mi mathvariant="normal">V</mi><mi>blood</mi></msub><mo>⋅</mo><mi>Lj</mi></math><img file="EP1759634A2_D0009.tif" /></maths>

The FRC measured with gas j_j is overestimated by the product of blood volume in the body and blood gas partition coefficient L compared to the true value (here called FRC). With knowledge of the blood volume, a correction of the FRC determination can already be carried out with a gas of known solubility. With the help of a second gas one gets by without a knowledge of the blood volume:

It can be assumed below without loss of generality that L₁ &gt; L₂such that the FRC measured with gas 1 (for example R 134a) is greater than that determined with gas 2 (for example R 227). From the difference of the FRC values, the blood volume can be determined:<maths id="math0010" num=""><math display="block"><msub><mi mathvariant="normal">V</mi><mi>blood</mi></msub><mo>=</mo><mfrac><mrow><msub><mi mathvariant="italic">FRC</mi><mn>1</mn></msub><mo>-</mo><msub><mi mathvariant="italic">FRC</mi><mn>2</mn></msub></mrow><mrow><msub><mi>L</mi><mn>1</mn></msub><mo>-</mo><msub><mi>L</mi><mn>2</mn></msub></mrow></mfrac></math><img file="EP1759634A2_D0010.tif" /></maths>

This makes it possible to correct the FRC measurement closer to the true value with the gas 2: <maths id="math0011" num=""><math display="block"><mi>FRC</mi><mo>=</mo><msub><mi>FRC</mi><mn>2</mn></msub><mo>-</mo><mfrac><mrow><msub><mi mathvariant="italic">FRC</mi><mn>1</mn></msub><mo>-</mo><msub><mi mathvariant="italic">FRC</mi><mn>2</mn></msub></mrow><mrow><msub><mi>L</mi><mn>1</mn></msub><mo>/</mo><msub><mi>L</mi><mn>2</mn></msub><mo>-</mo><mn>1</mn></mrow></mfrac></math><img file="EP1759634A2_D0011.tif" /></maths>

In the case of R 134a and R 227, the coefficient L is₁/ L₂ at 4, so that the measured FRC difference is divided by 3.

In particular, in addition to the FRC determination, an estimation of the "Pulmonary Blood Flow" can be performed or the FRC determination can be corrected with regard to the amount of tracer gas dissolved in the blood.

The dependent claims indicate preferred uses of the 1,1,1,2-tetrafluoroethane, said inhalation composition being in particular a pressurized liquid composition having a medicament dissolved therein for asthma therapy or for the treatment of other pulmonary diseases and dosage by means of a spray doser , MDI (= Medical Dose Inhaler) takes place during ventilation. Specifically, the application is such that, assuming an amount of about 10 to 30% of the total amount of gas dosed per dose, the concentration of 1,1,1,2-tetrafluoroethane alone or in combination with 1,1,1,2 , 3,3,3, - heptafluoropropane a maximum of about 1 to 5 vol. %, especially 0.1 to 1 vol. % of the gas mixture in the lungs after inhalation.