WO2014177143A1 - Infusion solution - Google Patents

Abstract

The invention relates to an infusion solution for use as a plasma expander, said solution containing exclusively 135 to 145 mmol/l of sodium ions and exclusively ≤ 100 mmol/l of chloride ions, the anions needed to compensate for the cation content being supplemented by hydrogen carbonate ions (HCO₃-).

Description

infusion Technical area

The present invention relates to an infusion solution, in particular for use in humans.

State of the art

Almost all commercially available crystalloid solid electrolyte solutions have too high a chloride content of more than 100 mmol / l.

These are v. A. the classical saline solution (NaCl 0.9%) with 154 mmol / l, but also the so-called balanced infusions with organic anions (for example, acetate, maleate, etc.) with an average of 110 mmol / l.

Alone by the induction of hyperchloraemia (plasma chloride value> 100 mmol / l) virtually all commercially available crystalloid infusion solutions have an acidifying effect (pH-lowering, acidotic).

Here, the base excess (BE), which arises at a normal sodium value (140 mmol / l) only by the increase of the chloride, according to the formula of Gilfix as a deviation of the chloride from the standard value 100 mmol / l, d. H. with a hyperchloraemia of 115 mmol / l, the BE, which causes only the chloride

- 15 mmol / l: that's very high.

At a BE of - 15 mmol / l, the activity of the coagulation factors has already fallen by half. There is considerable evidence in the literature that hyperchloremia is an independent risk factor for acute renal failure, impaired bowel blood flow and immune deficiency: all factors that significantly worsen the chances of survival, especially in intensive care patients.

The main causes of hyperchloremia are the exsiccosis (lack of water) and v.a. the supply in the form of infusion solutions (iatrogen).

It can be assumed that the kidney has the plasma pH v.a. controls over the plasma chloride value.

An electrolyte solution is electroneutral, i. it contains as many positive as negative charges. In an infusion solution containing about 135 mmol / l sodium ions and only 110 mmol / l chloride ions, the missing proportion of negative charge (anion gap) must be compensated by other negatively charged particles.

The newer so-called balanced infusion solutions contain, in addition to the chloride, which usually has concentrations of about 110 mmol / l, as further anions, so-called metabolizable organic anions, such as. Acetate, maleate, succinate, etc.

These anions are i.d.R. Intermediates of cell metabolism and can be broken down by the body. These are usually the anions of organic acids (acetate is the anion of acetic acid). For each acid-base pair, a pKa value indicating the acid strength relative to the water may be given.

The lower a pKa value, the stronger the acid in question, i. the more easily the acid transfers a proton to a reactant (in case of doubt always to the water).

However, the low pKa value also indicates that the corresponding corresponding base is very difficult to resorb a proton: in the case of a strong acid (defined as pKa value <4), the acid-base pair is at a physiological pH of 7.4 va in the form of its corresponding base before, or in the form of its anion before.

The presence of an anion requires i.S. Electroneutrality is a positive opposite: in case of doubt, this is a so-called proton (better an oxonium ion: H3O +).

However, the increase in proton (better: oxonium) ion concentrations is nothing other than a decrease in the pH, that is, acidification of the aqueous solution.

That means the presence an anion per se makes a solution more acidic and the presence of a cation makes a solution more alkaline.

The metabolizable anions in question are virtually always the anions of strong acids, i. These particles are always present at physiological pH values with at least one negative charge in the plasma: they make you sour! This circumstance is i.d.R. overlooked in the literature.

What's more, it is said of the so-called balanced solutions that they are degraded to bicarbonate, which should buffer, so the pH should be within the normal range.

This view is not sustainable:

1) The metabolic pathway through which the organic anions are degraded to bicarbonate is undetectable. All the molecules in question are degraded to carbon dioxide and water. The carbon dioxide diffuses from the cells into the blood and is converted in the erythrocytes to bicarbonate (transport form): 30% remain in the red blood cell, 60% are released through an anion exchanger in exchange for a chloride ion in the plasma. The bicarbonate is also an anion! That It also acidifies contrary to the classic textbook opinion: we are talking here of a respiratory acidosis and not of a buffering molecule.

2) Simply the fact that the organic anions are removed from the plasma causes their acidifying effect to disappear.

3) Thus, it is their length of stay in the plasma that determines the duration of their acidifying effect. Because these metabolic intermediates are absorbed very quickly, especially by the liver, their acidifying effect is significantly shorter than that of added chloride, which must first be excreted by the kidney. This leads u.a. In addition, so-called balanced solutions have less acidifying effects than solutions with a high chloride content (NaCl 0.9%, Ringer's solution).

4) However, they still acidify contrary to the prevailing idea! They are neither pH-neutral nor primarily alkalising! This can be easily verified in any major operation that involves administering larger volumes of balanced infusions: the blood gas analyzes show a decrease in pH, which is explained by the increase in chloride and the increase in the (unmeasured) metabolizable anions.

But what still has to be taken into consideration is the fact that albumin, which is not considered in the classical world view, also plays an important role in the acid-base balance.

Albumin is a polyanion, i. it carries about 12 mmol / l of negative charge (charge, not: particles) via its side chains at normal concentration, that is at least half of the negative charges that make up the bicarbonate, which after the chloride is the highest concentrated anion of the plasma.

A decrease in albumin concentration leads to a loss of negative charge: hypoalbuminemia leads to metabolic alkalosis.

While acidosis is a rarity and clinically meaningless due to hyperalbuminaemia, hypoalbuminaemia is very common, even commonplace. In the case of the large OP with a high supply of balanced infusions, a dilution of the albumin concentration results with a consecutive hypoalbuminemia leading to alkalosis.

This means that in addition to the acidification by the anions, the delivery of a crystalloid infusion solution leads to a decrease in the albumin concentration (alkalization), which at least partially offsets (balances out) the acidification.

In the case of the larger OP, one sees on the following day that the pH shifts back into the more alkaline range, which is attributed to the bicarbonate in the classical sense. In my view, this alkalization is due to the degradation of the metabolizable anions, the renal excretion of the chloride and the still existing alkalizing (dilution) hypoalbuminemia.

A decrease in the albumin concentration may also be due to loss (bleeding, open wounds, burns), consumption (sepsis) or decreased education: it is very common, even common, especially in intensive care units.

Presentation of the invention

Based on this prior art, it is therefore an object of the present invention to provide an infusion solution which avoids the above-mentioned disadvantages of the infusion solutions known in the prior art, in particular does not act or almost non-acidifying. According to the invention, this object is achieved by an infusion solution containing 135 to 145 mmol / l sodium ions containing only 100 mmol / l or less chloride ions, wherein the anions required to balance the cation content are supplemented by hydrogencarbonate ions.

In particular, the infusion solution may contain 95 mmol / L or less, 90 mmol / L or less, or even only 85 mmol / L or less chloride ions.

If necessary, the infusion solution according to the invention may preferably additionally contain up to 4 mmol / l potassium ions and additionally just as much hydrogen carbonate ions. In this way, the natural plasma is reproduced even better.

It is particularly preferred if the infusion solution according to the invention contains 140 mmol / l sodium ions. In this way, exactly the natural plasma is reproduced.

Furthermore, it may be preferred that the infusion solution according to the invention contains up to 45 g / l albumin. 45 g / l albumin corresponds to approximately 12 mmol / l negative charges through the albumin side chains. Accordingly, the proportion of hydrogencarbonate ions is reduced by the amount of albumin ions. In this way, although the albumin content of the natural plasma is advantageously reproduced exactly. As a result, for example, a dilution-hypalbumin anemia can be counteracted. However, this is offset by certain disadvantages in the production effort and in terms of the risk of infection and with regard to possible interactions with drugs.

Best way to carry out the invention

The novelty is the choice of the bicarbonate anion as a so-called "metabolizable" anion, but bicarbonate, in contrast to the previously used ions (for example acetate, maleate) does not have to be metabolized, but is exhaled as carbon dioxide through the lung physiologically.

Due to the very high pKa value of the carbonic acid-bicarbonate acid-base pair, the bicarbonate easily adapts to the concentration changes of the other ions. In this case, from a negatively charged particle bicarbonate (acidifying anion) easily an electrically neutral (and thus pH-neutral) particles, namely the carbonic acid, arise. This is due to the buffering effect of the bicarbonate-carbonic acid pair.

The metabolizable anions used so far have significantly lower pKa values: they do not buffer.

So far, no infusion solutions with bicarbonate as a "metabolizable" anion are produced on the basis of the following prejudices in the prior art:

1) The bicarbonate must be exhaled as carbon dioxide, d. H. It causes respiratory acidosis and increases the patient's work of breathing.

2) The bicarbonate "guest out", i. it does not remain stable in the solution, but escapes as carbon dioxide.

In contrast, according to the invention, the following arguments

1) An adult human produces about 1000 mmol carbon dioxide per hour in its metabolism. That would correspond to approximately 25 liters (!) Of the infusion solution according to the invention in one hour! Such a quantity receives no patient even approximately infused and the usual amounts of the infusion solution according to the invention lead to no appreciable increase in plasma carbon dioxide concentration. In a ventilated patient can be easily exhaled by appropriate Respiratoreinstellung the low carbon dioxide excess.

2) If the bicarbonate is chemically bound in an anion gap, then do not spit it out! A corresponding constellation can be found in the classical buffer solution sodium bicarbonate: it contains 100 ml of sodium ions and 100 mmol of bicarbonate (1 molar solution) in 100 ml. If this 100 mmol bicarbonate were converted into carbon dioxide, that would be equivalent to 100 mmol carbon dioxide - the carbon dioxide production of an adult human in 6 minutes.

But if you vigorously shake this 100 ml sodium bicarbonate bottle and pierce a cannula into the stopper, the hissing will stop: no carbon dioxide escapes because the negatively charged bicarbonate is held in solution by the positively charged sodium ion.

In the infusion solution according to the invention, the bicarbonate is bound in an anion gap: it does not exhale!

The second important point in the composition of the infusion solution according to the invention is the level of chloride concentration: it must not be greater than 100 mmol / l, so that no acidification of the patient's plasma by the chloride ion occurs.

There is clear evidence in the literature that too high a plasma chloride concentration has harmful consequences, especially for seriously ill patients.

One of the main reasons for an excessively high concentration of plasma chloride is the supply of commercially available infusion solutions (virtually all solid electrolyte solutions that are on the market).

According to the invention, modified infusion solutions can be designed in which, depending on the starting acid-base status of the patient, the infusions have graded chloride concentrations, with chloride concentrations of 95 mmol / l, 90 mmol / l and 85 mmol / l or less.

The decrease in chloride concentrations in these infusions is offset by a corresponding increase in bicarbonate concentrations.

As the chloride concentration decreases, the pH of the respective infusion becomes more alkaline.

As a result, these hypochloric (alkalizing) solutions according to the invention are suitable for infusing patients who already exhibit a metabolic acidosis or in whom it occurs with a high probability. These include v.a. Bleeding (poly) trauma patients. These cause lactic acidosis due to hypotension, lack of volume and centralization. The negative base excess that these patients show in the shock room upon admission is considered an independent predictor of mortality. To date, adequate control of shock by volume and / or catecholamine therapy is recommended to combat metabolic acidosis in trauma patients. Part of metabolic acidosis, which has not yet been quantified by studies, is certainly due to the hyperchloric infusions (NaCl 0.9%), which are already receiving these patients on a large scale through the emergency response team. The negative effect of metabolic acidosis on blood coagulation, renal function and intestinal perfusion has already been mentioned.

By administering hypochloric solutions already at the accident site, at least the iatrogenic factor of metabolic acidosis can be significantly reduced.

If the bleeding trauma patient in the shock room has a pH of <7.1 (metabolic acidosis), i.d.R. Sodium bicarbonate for buffering (alkalization) administered. As a result, his plasma sodium value is sometimes raised significantly: iatrogenic hypernatremia. The neurological consequences of this acute hypernatremia have not yet been reliably investigated, but probably not insignificant.

The administration of normotonic (sodium 140 mmol / l) and hypochloric (chloride <100 mmol) infusions according to the invention, which contain no acidifying "metabolizable anions" (see point 3), therefore has a positive effect on the (also neurological) outcome of these To expect (trauma) patients.

According to the invention, it is particularly preferred to omit the previous "metabolizable anions" (e.g., acetate). Contrary to the previous opinion, it is easy to show that these negatively charged ions also acidify the plasma as long as they are in the plasma.

The bicarbonate is also an anion, i. acidifies contrary to the classic textbook opinion also, however (pKa value 6.1) significantly less than the other "metabolizable anions" and it can be exhaled via carbon dioxide.

The sodium ion concentration should remain at normal physiological value of 140 mmol / l. In patients with chronic hyponatraemia or hypernatremia (too low or too high plasma sodium concentration), a change in the sodium ion concentration should be slow: this is ensured by the physiological sodium concentration of 140 mmol / l.

The potassium concentration should also have the physiological value of 4 mmol / l.

However, infusions without potassium are also conceivable, e.g. for kidney-deficient patients. If the potassium were omitted, the concentration of bicarbonate would decrease by 4 mmol / l to 40 mmol / l

Compared with the previously used crystalloid infusions, the solution according to the invention is likely to lead much less to disturbances of the electrolyte and the acid-base balance.

It does not lead to potentially harmful hyperchloraemia.

The respiratory acidosis due to the added bicarbonate is negligible.

The physiological sodium ion concentration leads to a gentle normalization of the plasma sodium concentration in the case of previously existing hypo- or hypernatremia.

The infusion solution according to the invention is simple and inexpensive to produce.

However, like any other albumin-free solution, the solution according to the invention can lead to a dose-dependent decrease in the albumin concentration with resulting alkalosis.

The anion gap of the infusion solution can be filled with albumin as a carrier of negative charge, which counteracts the dilution hyp albuminemia. Such infusion is even more physiological than the infusion according to the main claim.

However, the albumin-free infusion solution according to the invention has the following advantages over albumin-containing and should therefore be prepared and used primarily:

- It is easier and cheaper to manufacture

- she has no risk of infection

- there are no interactions with drugs (binding to the albumin molecule)

- The alkalizing effect of hypoalbuminemia is negligible in the clinical routine, or in the case of other existing acidifying disorders (increase in lactate, hypoventilation) even desired

- A severe hypoalbuminemia (for example, in liver disease) can be with

therapy with separate albumin solutions.

Claims (3)

1. Intravenous infusion solution containing only 135 to 145 mmol / l sodium ions, characterized in that it contains only ≤ 100 mmol / l chloride ions, and the anions required to balance the cation content are supplemented by hydrogencarbonate ions (HCO ₃ ^- ) ,
2. Infusion solution according to claim 1, characterized in that it additionally contains up to 4 mmol / l potassium ions and additionally just as much bicarbonate ions (HCO ₃ ^- ).
3. Infusion solution according to claim 1 or 2, characterized in that it contains 140 mmol / l of sodium ions.