JPS6155883B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a device for preserving an excised organ, and more particularly, a device for preserving an excised organ that preserves the organ while maintaining its activity by perfusing the excised organ with a liquid containing a bicarbonate-based PH buffer. It is related to. Conventionally, it has been known to preserve removed organs while maintaining their activity by circulating a perfusate, and it is also known to adjust the pH of this perfusate using a bicarbonate-based PH buffer. When a perfusate is perfused into a preserved organ, the pH of this perfusate changes over time,
Eventually, the organ becomes unsuitable for preservation. Therefore, in order to preserve the excised organ while maintaining its activity, it is necessary to monitor the pH of the perfusate and adjust it appropriately to make it suitable for organ preservation. Conventionally, for this purpose, the PH of the perfusate is manually controlled by sampling the perfusate over time and measuring the pH of the perfusate, and increasing or decreasing the amount of carbon dioxide injected according to the measured value, or The method used was to constantly immerse a PH electrode in the perfusate and inject carbon dioxide intermittently to maintain the PH of the perfusate within a set range. However, the former has the disadvantage that the range of PH fluctuation is large and is time-consuming, while the latter requires a PH electrode that is complicated to operate, and has the disadvantage that the PH measurement value often causes errors due to dirt on the electrode. . Therefore, there is a desire for an organ preservation method that eliminates the various drawbacks associated with the above-mentioned conventional techniques and that can easily and reliably control the PH of the perfusate. When preserving the excised organ with a perfusate, using a bicarbonate-based PH buffer in the perfusate will reduce its pH.
It is known that the formula (A) PH=6.1+log[HCO ₃ ^- ]/[CO ₂ ] follows the Henderson-Hatsselbach equation (A). This time, the inventors found that the value of [HCO ₃ ^- ] in formula (A) hardly changes in the perfusate, and therefore the PH of the perfusate is the same as that of [CO ₂ ] in formula (A). We focused on the fact that it is uniquely determined by the CO ₂ gas partial pressure in the perfusate, and after various studies, we found that if we measure the initial stage of perfusion [HCO ₃ ^- ], then the CO 2 gas in the perfusate can be measured. ₂ It was found that the PH of the perfusate could be set to any desired value simply by controlling the gas partial pressure, and for this purpose an oxygenator with a high CO ₂ gas exchange capacity was installed in the perfusate circuit, i.e., this High enough to make the CO ₂ gas partial pressure on the gas side of the oxygenator approximately equal to the CO ₂ gas partial pressure in the perfusate.
By placing an oxygenator with CO ₂ gas exchange ability and adjusting the CO ₂ gas partial pressure on the oxygenator gas side by adjusting the mixture ratio of CO ₂ gas and air, the PH of the perfusate can be easily and reliably adjusted to any desired value. We have discovered that it is highly controllable. Therefore, an object of the present invention is to provide a simple and highly reliable organ preservation device that preserves organs while maintaining organ activity by perfusing extracted organs with a liquid containing a bicarbonate-based PH buffer. It's about doing. According to the present invention, an oxygenator with a high CO ₂ gas exchange capacity is provided in the perfusion circuit of a liquid containing a bicarbonate-based PH buffer, and CO ₂ and air are exchanged on the gas side of this oxygenator. This is achieved by controlling the pH of the liquid in an open loop by adjusting the mixing ratio of the liquid. In addition, the CO ₂ gas exchange capacity of the oxygenator is
The oxygen exchange rate should be 1 cm ³ /S or more per ml/min., and the oxygenator may be of any type (for example, membrane type, coil type, or hollow fiber type) as long as it has this exchange capacity, and its material may also be It can be selected as appropriate. Furthermore, the organ preservation device of the present invention can use any device well known to those skilled in the art, except for providing the oxygenator having the above configuration in the perfusate circuit. Hereinafter, the invention will be further explained by way of example with reference to the accompanying drawings. The organ preservation device according to the invention includes a perfusion fluid reservoir 1
0 and an irrigation pump (e.g. roller pump) 12
, a heat exchanger 14, an oxygenator (for example, a membrane lung) 16, which is a main part of the present invention, an air trap 20 equipped with a filter 18, and an arterial cannula 22.
and an organ preservation chamber 24 for preserving the extracted organ, and are provided with a piping system that forms these as a closed circuit. Furthermore, the oxygenator 16 is equipped with an open loop system for supplying a mixed gas of CO ₂ and air to the oxygenator and an exhaust system (not shown in detail) from the oxygenator, and the supply system is formed by connecting a carbon dioxide gas source 26 and an air pump (for air supply) 28 via gas flowmeters 30 and 32, respectively, and CO ₂ mixed to a desired mixing ratio by the settings of these gas flowmeters 30 and 32. It is equipped with piping that supplies a mixed gas of air and air to the oxygenator. In order to control the temperature of the perfusate, a temperature sensor (not shown) is provided in the organ storage chamber 24, and the cold water from the cold water jacket 34 is transferred to the heat exchanger 14 through the cooling water circulation device 36.
It can be circulated by Furthermore, the perfusion pump 12 is provided with a pump control section 38, while the air trap 20 is provided with a pressure transducer 40 and an amplifier 42, and the temperature, flow rate, etc. of the perfusion fluid are controlled by the cooperation of these detection sections and control sections. You can also input these values to amplifier 4.
It is also possible to display and record the information on the display 44 and the recorder 46 via 2. When operating the organ preservation device of the present invention, a perfusion solution containing a bicarbonate-based PH buffer is added to the reservoir 1.
0 to the oxygenator 16 via the heat exchanger 14 by the perfusion pump 12. In the heat exchanger 14, the irrigation fluid is cooled to a desired temperature by heat exchange with cold water circulated by the cooling water circulation device 36.
A mixed gas of carbon dioxide and air is supplied to the oxygenator 16 to add oxygen to the perfusate and adjust the pH of the perfusate.
The fluid is perfused through the arterial cannula 22 to the excised and preserved organ, and then perfused from the organ to the reservoir 10. The main part of the present invention is to arrange an artificial lung 16 (for example, a membrane lung) in the perfusate circuit configured as described above, which not only performs oxygen addition but also CO ₂
The advantage is that the PH of the perfusate is also adjusted by controlling the gas partial pressure. As mentioned above, when the perfusate contains a bicarbonate-based PH buffer, the PH of the perfusate is calculated by the following formula (A) PH = 6.1 + log [HCO ₃ ^- ] / [CO ₂ ] ... (A ), and the value of [HCO ₃ ^- ] hardly changes during perfusion, so it can be seen that the pH is uniquely determined by the value of [CO ₂ ) in the perfusate. Will. Therefore, if you measure the [HCO ₃ ^- ] value in the perfusate only at the beginning of the perfusion period, then the
It will also be seen that the PH can be determined by controlling only the CO ₂ gas partial pressure. From this point of view, we use an oxygenator with a _high CO ₂ gas exchange ability, such that the partial pressure of CO ₂ gas on the gas supply side of the oxygenator and the partial pressure of CO ₂ gas in the perfusate can be almost equal. The organ preservation device of the present invention is configured to set the PH of the perfusate to a desired value by adjusting the mixing ratio (that is, the partial pressure of CO ₂ gas in the mixed gas). Here, the present invention is theoretically considered as follows. First, the partial pressure of CO ₂ gas in the perfusion fluid (hereinafter expressed as Pco ₂ ) is: (1) The amount of CO ₂ gas exchanged in the oxygenator: V ₁ (2) From the organ storage chamber and reservoir in the perfusion circuit Amount of CO ₂ released into the atmosphere: V ₂ (3) Amount of CO ₂ produced from preserved organs: V ₃ In this case, the perfusate is being circulated so that it reaches equilibrium at a certain value. These relationships can be expressed as follows: V ₁ = k ₁ × S ₁ × (P _G - P _L )/760 × α ... (B) V ₂ = k ₂ × S ₂ × (- P _L )/760×α ...(C) V ₃ = so small that it can be ignored. [In the formula, k ₁ is the CO ₂ exchange coefficient in the oxygenator (cm/
S), k ₂ is the CO ₂ exchange coefficient between the liquid and the atmosphere (approximately 5 ×
10 ^-4 cm/S or less), S ₁ is the membrane area of the oxygenator (cm ² ), S ₂ is the contact area between the perfusate and the atmosphere (the perfusate is usually about 1, and the contact area is about 200 cm ² at maximum). ), P _L is the value when Pco ₂ in the perfusate reaches an equilibrium state.
CO ₂ gas partial pressure [mmHg], P _G is Pco ₂ [mmHg] on the gas side of the oxygenator, α is CO ₂ solubility [ml/ml.atom] (at 8℃,
1.18ml/ml.atom). Furthermore, after the Pco ₂ of the perfusate reaches equilibrium, the equation
(D) V ₁ + V ₂ + V ₃ = 0 ... (D) The following relationship holds true, and since V ₃ is small and can be ignored as mentioned above, V ₁ + V ₂ ≒ 0 ... (D') becomes. By substituting the above equations (B) and (C) into V ₁ and V ₂ in the above equation (D'), the following equation (B) is obtained: k ₁ ×S ₁ ×(P _{G −PL} )/ 760×1.18 −5×10 ⁻⁴ ×200× _PL /760×1.18=0 _∴PG / _PL = (10 ^-1 ×k ₁ S ₁ )/k ₁ S ₁ ...(E) Here, P _L (partial pressure of CO ₂ on the oxygenator liquid side) increases as _the oxygen exchange capacity increases.
(partial pressure of _CO2 ), but never exactly the same value. If we assume that P _L becomes equal to P _G and the CO ₂ molar concentration at that time is [CO ₂ ]', then the PH' of the perfusate will be PH' = 6.1 according to the Henderson-Hasselbach equation (A). It is expressed as +log [HCO ₃ ^- ]/[CO ₂ ]' [PH target value when P _G = P _L ]. Furthermore, if the CO ₂ molar concentration when the actual partial pressure of CO ₂ on the oxygenator fluid side is P _L is [CO ₂ ], then the PH of the perfusate at that time is similarly calculated according to the Henderson-Hasselbach equation. It is expressed as PH″=6.1+log [HCO ₃ ⁻ ]/[CO ₂ ]″ [actual PH value of perfusate]. From a physiological perspective, it is desirable that the PH of the perfusate be kept within a small deviation from the target PH value. Therefore, if the deviation between the PH target value and the actual PH value is ε, then |PH″−PH′|=ε PH″ and PH′ are the above Henderson equations, respectively.
Substituting the Hasselbach formula, we obtain the formula log[CO ₂ ]′/[CO ₂ ]″=±ε. Thus, the formula logP _G /P _L =±ε ∴P _G /P _L =10 ^± 〓. If we want to keep the deviation ε within 0.05, that is, to keep the PH error within 0.05, since ε0.05 in the above equation, P _G / _PL 10 ⁰ . ⁰⁵ ∴P _G / _PL 1.1... ...(F). Therefore, from equations (E) and (F), 10 ^-1 +k ₁ S ₁ 1.1×k ₁ S ₁ ∴k ₁ S ₁ 1. Here, k ₁ S ₁ is nothing but the gas exchange capacity of the oxygenator used in the present invention.As can be seen from the above theoretical considerations, the PH of the perfusate
To set the _CO2 of the oxygenator with an accuracy within 0.05
The gas exchange capacity should be 1 cm ³ /S per 100 ml/min of perfusate. As described above, according to the present invention, the PH of the perfusate can be determined by adjusting the mixing ratio of CO 2 and air (i.e., the CO ₂ on the gas side of the oxygenator) without using a complicated PH electrode or measuring the PH over time. This is extremely advantageous in preserving excised organs using perfusate because it can be set to any desired value simply by adjusting the _gas partial pressure). The present invention having the above configuration can be implemented as follows. First, according to the Henderson-Hatsselbach equation, PH=6.1+log[HCO ₃ ^- ]/[CO ₂ ]...(A), and from this equation (A), the equation [CO ₂ ]=[HCO ₃ ^- ] ×10 ^{(6.1 -} PH ⁾ [mol/] ...(A′) is induced. In this formula (A'), [CO ₂ ] is expressed as temperature t
When converted to gas partial pressure at °C, the following formula (G) Pco ₂ (t °C) = [CO ₂ ] [mol/l] x 10 ^-3 [/ml] / αt [ml (G) / ml( L). atm] × 22.4 × 10 ³ [ml (G) / mol] × 760 [mmHg / atm] ... (G) [In the formula, ml (L) is the volume of the aqueous solution, ml (G) is the volume of CO ₂ , αt is the solubility of CO ₂ at t°C] is obtained. Furthermore, CO ₂ on the gas side of the oxygenator
Regarding the gas partial pressure (Pco ₂ ) and the flow rates of air and carbon dioxide (Qair, Qco ₂ ), the following relational expressions (H) and (H') hold true. Qair: Qco ₂ = (760−Pco ₂ ): Pco ₂ ……(H) Qco ₂ = Qair × Pco ₂ / (760−Pco ₂ ) ……(H′) Above formulas (A′), (G) and From (H'), the following formula (I) Qco ₂ (t℃) = [HCO ₃ ^- ] x 10 ^{( 6.1-} PH ⁾ x 22.4 x 760/αt/760 - [HCO ₃ ^- ] x 10 ^(
6 . ^1- PH ⁾ ×22.4×760/αt(ml/min.]...(I) is induced. The target PH value is expressed in the above formula (I), [HCO ₃ ^- ]
The following Table 1 was obtained by substituting the values and the solubility α at each temperature.

【table】

[Table] By using this Table 1, the PH of the perfusate can be determined.
It was confirmed that the settings could be set accurately. In addition, in Table 1, the mixing ratio of CO ₂ and air was determined with the target pH of 7.0 to 7.5, the perfusate temperature of 4° to 12°C, and the [HCO ₃ ^- ] concentration of 5 to 25 meq. Create a similar table from the above formulas even outside the range,
It will be appreciated that by mixing air and CO ₂ accordingly, the PH of the perfusate can be set to any desired value. It will also be understood that the perfusate circulation circuit shown in the drawings is in direct contact with the atmosphere in the organ preservation chamber and reservoir that house preserved organs.

[Brief explanation of the drawing]

FIG. 1 is a block diagram of an organ preservation device according to the present invention. 10...Reservoir, 12...Irrigation pump, 14
... Heat exchanger, 16 ... Artificial lung, 18 ... Filter, 20 ... Air trap, 22 ... Arterial cannula, 24 ... Organ storage chamber, 26 ... Carbon dioxide gas source, 28 ... Air pump, 30,32 ... Gas flow meter, 34 ... Cold water jacket, 36 ... Cooling water circulation device, 38 ... Pump control unit, 40 ... Pressure transducer, 42 ... Amplifier, 44 ... Display, 46 ... Recorder .

Claims (1)

[Scope of Claims] 1. A preservation device for an extracted organ that preserves the organ while maintaining the activity of the organ by perfusing the extracted organ with a liquid containing a bicarbonate-based PH buffer, comprising: a perfusion circuit for the liquid; An oxygenator with a high CO ₂ gas exchange capacity is installed inside the oxygenator, and the pH of the liquid is controlled in an open loop by adjusting the mixing ratio of CO ₂ and air on the gas side of the oxygenator. An organ preservation device. 2. The CO ₂ gas exchange capacity of the oxygenator is 100ml/min of perfusate.
2. The organ preservation device according to claim 1, wherein the organ storage capacity is 1 cm ³ /S or more.