CA1278242C - Aqueous solution for the urodynamic investigation of the urinary bladder - Google Patents

Abstract

ABSTRACT
Aqueous solution for the urodynamic investigation of the urinary bladder to diagnose voiding disturbances, which contains 50 - 70 mmol potassium ions per liter, is adjusted to a pH of 4.7 - 5.2 which is stabilized by addi-tion of buffer, and furthermore contains amounts of elec-trolytes normally found in urine, and of water-soluble, stable, low molecular weight organic substances, such that the solution has an osmolarity of 1,000 to 1,360 mosmol/l solution.

Description

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Aqueous solution for the urodynamic investigation of the urinary bladder The present invention relates to an aqueous solu-tion for the urodynamic investigation of the urinary blad-der, which is used for the diagnosis of bladder voidingdisturbances.
Such voiding disturbances of the urinary bladder may consist either in areflexia, that is to say even when the urinary bladder is full there is no muscular contrac-tion which result in the urge to urinate, or in a hyper-reflexia of the bladder, which is manifested by a very frequent urge to urinate. It llas been proposed, according to Jonas U. and Thuroff J., Urodynamische Untersuchungen, Urologie in Klinik und Praxis (Urodynamic Investigations,-Clinical and Practical Urology) published by G. Thieme,Stuttgart/New York, 1982, page 254, that, for the diag-nosis of such voiding disturbances by use of commercially available cystometers, the urinary bladder be filled with water, isotonic saline solution or C02, and the volume at which the urge to urinate is triggered be determined.
This ty~e of investigation was based on the doctrine that _ the stimulus to void the bladder is initiated exclusively by neural impulses, it being assumed that the urothelium is impermeable and allows no exchange of matter.
However, this test method has not been satisfactory in practice since it was not possible to detect any void-ing disturbance in a number of patients who complained of symptoms but for whom, nevertheless, it frequently emerged subsequently that there was a urinary bladder disorder.
On the other hand, Fellows G.J. and MarshalL D.H.
have already pointed out, in Invest. Urol. 9, 339, 1972, that under certain conditions the urothelium certainly allows exchange of matter with the blood, with emergence not only of water but also of ions being possible, and this exchange of matter increases further in most dis~
orders of the urinary bladder. Moreover, it has already been observed in animal experiments that potassium can ~P
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bring about contractions of the bladder muscle in pigs (V.
Duyl W.A. and Collsaet B.L.R.A., Urology 20, 53, 198Z).
The present invention has the object of providing a test solution for the urodynamic investigation of the urinary bladder, which allows reliable diagnosis of void~
ing disturbances.
This object is achieved according to the present invention on the basis of the surprising finding that the triggering of the urge to urinate is very greatly deter-mined by the composition of the urine, and the potassiumcontent, pH and osmolarity control the urge to urinate, so that when the urine is concentrated, with, for example, a greatly increased potassium content compared with the blood, and has a high osmolarity, the contraction of the muscles of the urinary bladder, which may be designated the process which effects the voiding of the bladder, is initiated when the volume contained in the bladder is considerably lower than is the case with considerably more dilute urine. Another initiating factor proved to be the Z0 H ion which, up to a certain extent, is able to take the place of the K ion inside the cell.
Thus, a high concentration of K ions and H ions and hyperosmolarity may bring about contraction of the muscles underlying the urothelium without there being neural impulses from the CNS.
Building on this finding, it was found, surpris-ingly, that an aqueous solution for urodynamic investiga-tion of the urinary bladder permits reliable diagnoses of voiding disturbances, namely both areflexia and hyper-reflexia, if its potassium content and osmolarity corres-pond to those of a concentrated urine, and its pH is main-tained constant in the range of an acid urine. A solution of this type reliably brings about early initiation of the urge to urinate for the investigated urinary bladder, so that the figures obtained with it are far more appropriate to the local physiological situation of bladder function than was the case with the previous diagnostic me~hod.
This means that areflexia of the bladder is detected only 7~;~4~

where it actually exists and not in cases where the bladder has a very large capacity for water, and likewise hyper-reflexia, for example caused by increased permeability of the urothelium, is not concealed.
Accordingly, the present invention relates to an aqueous solution for the urodynamic investigation of the human urinary bladder, comprising potassium ions in an amount of 50 - 70 mmol/l, electrolytes which occur in huMan urine, and water-soluble organic substances which are stable in aqueous solution, are tolerated by the human urinary blad-der and do not have a strongly acid or alkaline intrinsic pH, and whose molecular weight is in a range which is suf-ficiently low for them to have osmotic activity, which solution has an osmolarity of 1,000 -1~360 mosmol/l, and a pH of 4.7 - 5.2 which is stabilized by addition of buf-fer substances.
The choice of the concentration, according to the invention, of K ions is based on the usual figures for the concentration of K ions in concentrated urine of around 60 mmol/l, so that the figure according to the invention complies with the physiological condition for early ini-tiation of the urge_to urinate. When setting up the pH
of 4.7 - S.Z, preferably of 5.0, it has to be borne in mind that when the urine present is acid the urinary blad-der attempts to increase the pH by water leaving the cir-culating blood through the urothelium, that is to say that the acid pH would not be maintained during the stay of the test solution in the urinary bladder, especially when the urothelium is highly permeable, and the consequence would be faulty diagnoses. For this reason, it is essential that the solution according to the invention contains buffer substances which bring about the stabilization of the pH in the acid range.
It has to be borne in mind in the selection of low molecular weight, and thus osmotically active, substances, which are used in addition ~o electrolytes to see up the osmolarity which is to be chosen according to the 1;~'78~4;~

invention, that these substances do not decompose in the ueakly acid aqueous solution. Urea, which substantially determines the osmolarity of urine, is not suitable for this purpose because of its instability. Furthermore, S all those substances which, because of a strongly acid or alkaline intrinsic pH, would shift the pH of the solution have also to be excluded, and, finally, substances which affect the activity of the bladder, whether they result in manifestations of irritation or inhibit the activity of the bladder, are also unsuitable. The use of water-soluble polyhydroxy compounds has proved to be very appro-pr;ate, and sugar alcohols such as, in particular, sor-bitol, xylitol and mannitol, glucose and fructose, and glycerol, have proved part;cularly useful. The sugar alcohols sorbitol and mannitol, and glycerol, are pre-ferred in this context, sorbitol being particularly pre-ferred. It is frequently appropriate, especialLy in the case where monosaccharides are used as substances for setting up the osmolarity, to add a small amount of dis-infecting agents to the solution, since these sugars rep-resent nutrients for bacteria and thus, in certain cir-cumstances, in cases of bladder infections contribute to a multiplication of the bacteria which have caused them, and thus might result in a deterioration in the condition of the patient. Mention may be made, as examples of dis-infectants which have proved to be very useful, of benz-alkonium chloride or, especially, the esters-of 4-hydroxy-benzoic acid, which can be used alone or in mixture.
Furthermore, the addition of stabilizing additives, such as antioxidants, has proved useful in some cases, especially when reducing sugars are used as low molecular weight organic substances for setting up the osmolarity.
Examples of these which may be mentioned are sulfites or pyrosulfites.
Apart from the polyhydroxy compounds, which can usually be added in relatively large amounts, for example in amounts of about 100 - 170 g/l of solution, it is also possible to rnake use of, in addition, stable substances ~'~7~3~4~

excreted in the urine, such as, for example, creatinine, to set up the osmolarity required according to the inven-tion.
Since the intention is that the constitution of the solution according to the ;nvent;on be as close as possible to the composition of urine, it has proved appro-priate also to make use of, in addition to the prescribed content of K ions and in addition to low molecular weight organic substances, other electrolytes which normally occur in urine to set up the osmolarity. Water-soluble salts of sodium, calcium and magnesium are primarily used for this, preferably in an amount and composition which is typical of urine. This means that relatively large amounts of sodium salts, for example 2 - 4 times the molar 1S amount relative to the content of potassium salts present, can be used, whereas the appropriate molar amounts of Ca and Mg salts should be only a fraction of the molar amounts of alkal; metal salts present. The salts of potassium and sodium are preferably chlorides and sulfates, whereas cal-cium is preferably used as chloride, and magnesium is usedas chloride and as sulfate.
Since phosphates, for example those of sodium or potassium, are primarily advisa_le as buffer substances, ~ it is appropriate also to add complexing substances such as, for example, salts of ethylenediamineteeraacetic acid - - in order to prevent the formation of a precipitate with Ca and/or Mg ions present.
An aqueous solution which contains the following constituents per liter has proved particularly useful according to the invention:
as cations K ion 50 - 70 mmol Na ion 100 - 140 mmol Ca ion 1.5 - 4 mmol 3S Mg ion 5 - 10 mmol as anions:
chloride 120 - 145 mmol sulfate 10 - 20 mmol ~xt7s~4~

as buffer substance:
phosphate 40 - 65 mmol as water-soluble organic substance:
creatinine 0 - 2~5 9 and sorbitol, mannitol or glycerol in an amount which, together with the other constituents of the solution, results in an osmolarity thereof of 1,000 - 1,360, preferab!y of 1,000 1,300, mosmol/l.
It is appropriate for a small amount of a complex-ing agent and small amounts of disinfecting additives also to be present.
It is particularly preferred in such solutions that the content of potassium ion is 60 - 70 mmol, and that of sodium ion is 125 - 140 mmol, of calcium ion is 2.5 mmol, and of magnesium ion is 7.5 mmol, and that the water-soluble organic substance which is present is sor-bitol in an amount of 120 - 160 9, in each liter, it also being possible for the solution to contain creatinine in ~0 addition~
The pH of` the solution is preferably set at 5.
~ he present invention also relates to an advanta-geous and safe method for the urodynamic investigatiûn of the human urinary bladder with the aid of a commercially available cystometer, in which the solutiorn described above in accordance with the present invention is intro- --duced into the urinary bladder of the patient, and the introduction is continued until the urge to urinate is initiated, whereupon the volume of the solution present in the urinary bladder is determined.
It is possible, using the solution according to the invention, to obtain by this fully reproducible, uni-form test results, so that it is outstandingly suitable for the diagnosis of disturbances of bladder function.
If the figures for the bladder volumes, at which the urge to urinate is initiated, obtained with the solu-tion according to the invention and using a commercially available cystometer (see, for example, Urodynamische ` ~LX~78~4;~

Untersuchungen, published by G. Thieme 1982, pages 254 et seq.) are compared with those attained on filling the urinary bladder with water, it emerges that the figures obtained with water may be up to 80% larger, and thus S existent hyperreflexias are, in certain circumstances, co~pletely masked. The solution according to the inven-tion brings about significantly higher bladder interior pressure amplitudes and affects the sensitivity or urge in the sense of earlier initiation~
For the preparat;on of the solution according to the invention, the electrolytes and/or low molecular weight substances, with the exception of the buffer, in the amount necessary to attain an osmolarity within the l;mit according to the invention, are completely dissolved in approximately the desired amount of water, which is at a temperature of 40 - 80C, it being necessary to bear in mind in apportioning the amount of potassium salts whether the subsequent addition of buffer contains potassium or not. After the pH has been set up, for wh;ch usually an acid is required, it being appropriate for its anion to correspond to the anions present in the solution, the buffer substance is added and thus the pH is stabilized~
The solution is then, where appropriate~ filtered_sterile, where appropriate adjusted to the desired final volume with water for injections, and is sterilized in a custom-ary manne~r.
- For use, it is particularly appropriate to dis-pense the solution according to the invention into flex-ible bags, for example made of P~C. However, glass ves-sels are, of course, also suitable as containers.
In some cases, especially where a long transportroute or maintenance of a relatively large store is en-visaged, it has proved useful to freeze-dry the finished solution according to the invention and to market the lyophilisate. The latter is dissolved in sterile water on the spot before use.

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Example 1:
897 9 of water for injections at a temperature of 20C are preheated to 60C and, while agitating, 0.37 9 of CaCl2.2 H20~ 0-75 9 of KCl, 1.525 9 of MgCl2.6 H20, 5.5 9 of NaCl, 5.32 9 o~ Na2S04.10 H20, 150 g of sorbito~, 2.2 9 of creatinine, 0.1 9 of ethylenediaminetetraacetic acid disodium salt and, for the purposes of disinfection, 0.15 9 of methyl p-hydroxybenzoate, 0.025 g of ethyl p-hydroxybenzoate and 0.025 9 of propyl p-hydroxybenzoate are added, and mixing is continued until the constituents have completely dissolved. The pH of the solution is then set at S.0 by addition of 0.6 9 of concentrated hydrochlo-ric acid, whereupon 6.8 9 of potassium dihydrogen phosphate are added as buffer substance, and the volume is adjusted to exactly 1 l.
This results in a solution which contains 128 mmol of sod;um ion, 60 mmol of potassium ion, 2.5 mmol of cal-cium ion~ 7.5 mmol of magnesium ion, 132 mmol of chloride ion, 50 mmol of H2P04 ion and 16.5 mmol of sulfate ion, and has an osmolarity of 1,240 mosmol, per liter.
Example 2:
For the preparation of a solution according to _ the invention of approximately the same osmolarity as in Example 1, but not containing creatinine, 0.370 9 of 25 CaCl2.2H20, 0.750 g of KCl, 1.525 9 of MgClz.6H20, 6.250 9 of NaCl, 5.320 9 of Na2S04.10 H20, 150 9 of sorbitol and the complexing agent and the disinfecting additives as in Example 1 are dissolved in preheated water, as described in Example 1, and further processed as in Example 1.
The content of sodium ion in the solution has been increased by this, compared with Example 1, to 140.0 mmol/l, and that of chloride ion to 144.20 mmol/l. The osmolarity of the solution is 1,247 mosmol/l.
Example 3:
The constituents indicated in Example 1, but with the difference that 150 9 of mannitol are used in place of 150 g of sorbitol, are processed to give 1 liter of solution as indicated in Example l. The pH thereof is ~78~

S.0, and the osmolarity is 1,Z40 mosmol/l.
Example 4:
The constituents indicated in Example 1, but with the difference that 76.0 9 of glycerol are used as water-S soluble organic substance in place of sorbitol and crea-tinine, are processed to give 1 liter of solution as in Example 1. The pH of the solution is S.0, and the osmo-larity is 1,Z24 mosmol/l.
Example S:
The constituents mentioned in Example 1, but with the difference that the amount of NaCl used is 5.080 9 and the amount of buffer substance used to increase the buffer capacity is 8.165 9, are processed as described in Example 1 to give l liter of a solution which has the same pH as the solution according to Example 1 and has an osmo-larity of 1,Z27 mosmol/l. Thus, compared with Example 1, tne content of sodium ion was decreased to 1Z0.0 mmol/l, and that of chloride to 124.20 mmol/l, and the phosphate content was increased to 60 mmol/l, and hence the content of potassium ion was increased to 70 mmol/l.
For use, these solutions are filtered sterile, dispensed in 4,500 ml portions into polyvinyl chloride bags and sterili~ed at 115C for S0 minutes. They are completely stable on storage below 20C and can be used as test solution in every commercially available cysto-meter.

Claims (6)

1. Aqueous solution for the urodynamic investigation of the human urinary bladder, comprising potassium ions in an amount of 50 - 70 mmol/l, electrolytes which occur in human urine, and water-soluble organic substances which are stable in aqueous solution, are tolerated by the human urinary blad-der and do not have a strongly acid or alkaline intrinsic pH, and whose molecular weight is in a range which is suf-ficiently low for them to have osmotic activity, which solution has an osmolarity of 1,000 -1,360 mosmol/l, and a pH of 4.7 - 5.2 which is stabilized by addition of buffer substances.

2. Solution as claimed in claim 1, in which the elec-trolytes are salts of Na, Ca and Mg, which are present in a composition and in an amount which are typical of urine.

3. Solution as claimed in claim 1, in which the water-soluble organic substances are one or more compounds selec-ted from the group consisting of sugar alcohols, glucose, fructose, glycerol and creatinine.

4. Solution as claimed in claim 1, containing per Liter 50 - 70 mmol of potassium ion as the electrolytes 100 - 140 mmol of sodium ion 1.5 - 4 mmol of calcium ion

5 - 10 mmol of magnesium ion as cations and 120 - 145 mmol of chloride ion 10 - 20 mmol of sulfate ion as anions, 40 - 60 mmol of phosphate ion as the buffer, as the water-soluble organic substances creatinine in an amount of 0 - 2.5 g, and sorbitol, mannitol or glycerol in an amount which, together with the other constituents of the solution, results in an osmolarity thereof of 1,000 - 1,300 mosmol/l, a complexing agent in an amount which is sufficient to prevent precipitation of Ca and Mg phosphate, and disin-fecting additives.

5. Solution as claimed in claim 4, containing 60 -70 mmol of Potassium ion, as the cations 125 - 140 mmol of sodium ion, 2.5 mmol of calcium ion and 7.5 mmol of magnesium ion, and as the water-soluble organic substances in addition to the 0 - 2.5 g of creatinine 120 - 160 g of sorbitol per liter.

6. Process for the preparation of the solution as claimed in claim 1 , which comprises the electro-lytes, the low molecular weight organic substances which are used to set up the osmolarity, and, where appropriate, complexing agents, stabilizers and disinfecting additives being dissolved in approximately the desired amount of water which has been preheated to 40 - 80°C, the pH of the resulting solution being set at a figure of 4.7 - 5.2 by addition of acid, and being stabilized by addition of a buffer substance, the amount of potassium salts to be dissolved in water being apportioned so that, together with K ion which is, where appropriate, contained in the buffer substance, the resulting content of potassium ion is 50 - 70 mmol per liter of solution, whereupon the solu-tion is made up to the desired volume, where appropriate, by addition of water for injections, and is sterilized in the customary manner.