Ionic calcium. Which calcium is best absorbed? Indications for a laboratory test

IONIZED CALCIUM, HEART AND HEMODYNAMIC FUNCTIONS

The calcium ion is absolutely necessary for the normal process of myocardial contraction. This was established over 100 years ago by Ringer and thoroughly studied by McLean and Hastings in 1934 when they showed that calcium increased the contractility of the isolated amphibian heart. In the clinic, the use of calcium supplements is widespread: Massachusetts General Hospital uses more than 30,000 doses of calcium, equivalent to one ampoule, annually. Calcium salts have a positive inotropic effect, and also affect the tone of vascular smooth muscle. Due to the fact that the calcium ion is necessary for the contraction of vascular smooth muscles, it is involved in the regulation of blood pressure by acting on peripheral vessels, which determines both beneficial and harmful aspects of the use of calcium. This can be very important if the patient has hyperkalemia and hypercalcemia.
The purpose of this publication is to provide an overview of current views on ionized blood calcium, its measurements and their interpretation, the effect of calcium on the heart and peripheral vessels, as well as the limitations and applications of calcium in therapy. Although calcium channel blockers in this moment are closely studied due to their important pharmacodynamic effects in the treatment of many cardiovascular diseases, this problem is not the subject of this review.

Total calcium concentration and ionized calcium concentration.

Calcium in the blood is a source of extracellular calcium that is able to interact with cells. Calcium in the blood is in several forms: bound (or in a complex) and free (or ionized). This division is of particular physiological interest, since only the ionized form is physiologically active, as first shown by McLean and Hustings in 1934. These authors concluded that ionized calcium is required for the rhythmic mechanical activity of the isolated, perfused frog heart. Four decades later, this was confirmed in an isolated dog heart when it was shown that although the simultaneous infusion of calcium gluconate and sodium citrate increased total serum calcium concentration, the level of ionized calcium and myocardial contractility decreased in parallel.
This work also resulted in the nomogram, which has become a cornerstone in the clinical evaluation of serum ionized calcium concentrations. This nomogram provides ionized calcium concentrations at known total calcium and total protein concentrations, assuming a pH of 7.35 and an albumin/globulin ratio of 1.8. Currently, due to the fact that direct measurement of the concentration of calcium ions is not available everywhere, such or similar nomograms can help assess the concentration of ionized calcium in both therapeutic and surgical patients. This technique is still used to assess calcium homeostasis. However, due to possible deviations in calcium balance, inaccuracies are possible. Measurement of ionized calcium concentrations is essential to understand the hemodynamic effects of hyper- or hypocalcemia.

Clinical determination of ionized calcium in the blood

Plasma ionized calcium can be determined in two ways: indirectly, as a correlation either with total calcium concentration using a nomogram, or with the duration of the ECG P-Q interval, or directly, using a selective electrode system.
Indirect methods give very approximate results, which may or may not correctly reflect the amount of calcium ions in this particular patient. When using nomograms, the correlation between ionized and non-ionized forms of calcium in the body is taken into account. However, in several groups of patients, it has been proven that these indicators can change independently of each other, which determines the difference between the results of calcium calculation by nomograms and the result of its direct measurement. Although for decades the correlation between the duration of the ECG ST segment and the concentration of calcium in the patient's blood has been confirmed in examinations of patients with chronic disorders of calcium metabolism, acute changes in the concentration of calcium in the blood of patients cannot be accurately determined by changes Q-T interval, as proven in the clinic and in the experiment. Only direct measurement of the concentration of calcium ions can provide a picture of the ionic status of the patient, which is very often necessary in the treatment of the patient.

Calcium electrode system

As with other electrolytes frequently tested (sodium, potassium, and hydrogen ions), calcium ion activity in whole blood, plasma, serum, and aqueous solutions can be measured using an electrode system that is highly specific and sensitive to that ion. A detailed description of ion-selective electrodes is beyond the scope of this review, but general issues of electrode design and their function will be discussed here.
The calcium ion-selective electrode system consists of an ion-selective membrane and an external standard electrode, both connected to a high-impedance scaled voltmeter. Since both electrodes are also in contact with a solution containing electrolytes, the system is an electrical circuit.
Any ion-selective membrane generates a membrane potential. The diffusion potential, which is formed by unequal diffusion rates of charged electrolyte particles, was described more than a hundred years ago. The electrochemical properties of membranes were discovered in 1890, using the concept of a semi-permeable membrane, that is, a membrane that is permeable to a certain type of ion and not to any other. The membrane theory of electrochemistry of cells and tissues was developed at the beginning of the century, and it still remains the basis of the concept of bioelectric potentials. Research into compact solid membranes led to the invention of hydrogen ion selective glass and the invention of the hydrogen electrode in the 1920s. At present, the theoretical aspects of the application of this electrode and its practical use well researched and developed. The calcium electrode was invented in 1898, and several other types of electrodes have been developed over the past fifty years. These electrodes are practically not used due to their low selectivity and low stability in protein-containing solutions. The calcium electrode suitable for biomedical research was invented in 1967.
The mechanism of action of the calcium electrode is the same as that of the electrode for measuring pH - it is an ion exchange mechanism, which includes the passage of a free fraction of ions through the membrane into the washing solution.
The calcium selective membrane separates two inorganic solutions containing calcium: one of them, a calcium chloride solution of known and constant composition, is called the internal filling solution, in which a silver-plated silver chloride electrode (internal calibration element) is immersed, and the other solution is a sample, in which it is necessary to measure the activity of a calcium ion in the presence of other ions. The calcium electrode was invented in 1967 and is well suited for the clinical examination of various liquids, that is, the calcium selective membrane is suitable for the examination of viscous organic liquids. Organic liquids containing calcium are dissolved in a special organic solvent. Other organic derivatives of calcium with high molecular weight dissolve in the polyvinyl matrix, which significantly increases the sensitivity of the electrodes. The design of the electrodes has also been improved.
Within each phase, aqueous solution and membranes, there is electrical neutrality, that is, the same number of positively and negatively charged particles. In contrast, in the presence of an organic membrane and an inorganic electrolyte solution, the charge equation shifts, since calcium ions on the membrane and calcium ions in the aqueous phase of the medium can freely exchange, organophilic phosphate ions have an affinity for the membrane, since they are insoluble and immobile in water. The thickness of the membrane is of particular importance, since it is on it that the boundary between the two media will depend, and the transport of calcium ions from the aqueous phase to the membrane, where calcium ions lose their hydrophilic shell and form complexes with organic phosphates. However, the total amount of transported calcium ions depends on the amount even in the most dilute solution. Calcium ions form a complex with organophosphorus compounds of the membrane and form a concentration gradient between external and internal solutions, as a result of which a potential difference is formed on the membrane and an electric current arises. The movement of complexes of calcium ions through the membrane occurs until there is not a single free organophosphorus compound available for calcium ions on the membrane. As a result of this process, irreversible changes occur in the electrode and it must be replaced.
Although it is the calcium-selective membrane in the electrode that determines the potential difference, this potential difference cannot be measured without an external calibration electrode. It is mercury-chloride coated with mercury and placed in a highly concentrated solution of calcium chloride, after which it begins to generate a potential. As a result, it becomes possible to register the potential of the measuring electrode.

Ionic selectivity

Ideally, the calcium electrode should respond only to the activity of calcium ions in the sample, that is, this electrode should be calcium-specific. However, the presence of other cations in the solution limits the sensitivity of the electrode to calcium ions. This problem arises when testing blood, which is a mixed electrolyte solution that also contains proteins and sodium ions, which are about 150 times more active than calcium ions. The selectivity of an electrode is determined by the selectivity constant. When the selectivity of the electrode with respect to other cations is high, then the response of the electrode to these cations is minimal. The main problem in this case is the presence of sodium ions in the analyzed solution.
Hydrogen ions only create problems if the pH of the analyzed solution is less than 5.5 or less than 6.0, however, these pH values ​​are almost never encountered in the analysis of biological substrates in the clinic. However, even when physiological values Its change in pH also causes a change in the concentration of calcium ions, possibly due to the fact that when the pH changes, the affinity of calcium ions to protein structures changes. Therefore, ideally, calcium ion measurements should be made in such a way that carbon dioxide does not escape from the analyzed solution, since this can lead to secondary changes in pH. The influence of changes in the concentration of magnesium ions on the concentration of calcium ions is practically reduced to zero, since the specificity of electrodes today is quite high and the concentration of these ions in the solution is low.

Activity and concentration

Ions in very dilute solutions should be considered as gas molecules, but at higher concentrations this rule is not valid, since inter-ionic electrostatic interactions limit their mobility. Determination of liquid vapor pressure, conductivity and freezing point confirmed the idea that a certain number of free ions (activity) in solutions is less than that determined from theoretical calculations of molar concentration, if we consider the dissociation of salts to be complete. The exact amount of unbound ions is defined as ionic activity, which is related to concentration by the following formula:

where A is the activity, y is the activity coefficient and C is the molar concentration.
Ion-selective electrodes depend more on the activity of the ion than on its concentration. Therefore, certain activity standards must be adopted to calibrate the electrodes. The development of such standards requires knowledge of the activity coefficient of the calcium ion in solution. However, there are two serious problems in this area. First, the activity of a single ion in solution cannot be determined in the absence of the corresponding anion. Calcium ion activity is usually calculated by analyzing a calcium chloride solution. Second, the activity of an ion is largely affected by the ionic strength of the solution. Usually, a sodium chloride solution is added to the calibration solution in order to equalize the ionic strength of the calibration solution with the ionic strength of the blood plasma, but the intrinsic activity of sodium ions and its influence on the ionic composition of the solution cannot be ruled out. Therefore, calibration solutions are prepared from highly purified crystalline calcium chloride in distilled water. The concentration of calcium in these solutions is expressed in millimoles.
In the analytical cycle of the calcium electrode system, the standard solution and the analyzed blood plasma move through the electrode, after which the concentration of calcium ions in these solutions is equalized. Adjusting the ionic strength of the calibration solution to match the ionic strength of the blood plasma using sodium chloride solution results in an additional potential of unknown power and distorts the results of the study. In this regard, calcium cannot be determined in urine using this electrode system.
Changes in the ionic strength of the solution in different plasma samples are practically insignificant, with the exception of the rather rare severe hypernatremia and hyponatremia.

Use of calcium electrodes in the laboratory.

In the clinical laboratory, the electrode is calibrated with different solutions with different calcium ion concentrations. When examining samples, the electrode generates a potential, which is then converted to a result in millimoles using a calibration curve. This method is quite accurate and allows you to determine even the minimum values ​​of the concentration of calcium ions in solution.

Interpretation of the obtained results.

In order to interpret the results, you need to know the average fluctuations in calcium concentration in humans. However, this value is quite variable (the average value, according to various sources, is from 0.96 to 1.27 mmol). Such a wide spread can lead to erroneous interpretation of the results.
Recent studies suggest that more attention should be paid to the details of the calcium measurement process and process standardization.
When assessing calcium concentrations in the blood of patients, some details of the measurement process itself must be borne in mind, since they may slightly change the analytical results. An important factor is the electrode system itself for measuring the calcium concentration. Although the technology for manufacturing electrodes is almost the same everywhere, a significant difference in results was noted when using instruments from two different manufacturers. According to various researchers, there is usually a difference of up to 15% between instruments from different manufacturers.
Another factor that determines the result is pH. Because pH shifts cause changes in protein-containing solutions, it is imperative that calcium analyzes be performed under anaerobic conditions to prevent loss of carbon dioxide and secondary pH changes. Changes can also be caused by competition between calcium ions and hydrogen ions for a place of attachment to blood plasma proteins.
Thirdly, plasma protein concentration is very important, since plasma proteins are the main site of fixation of calcium ions. The difference between the total calcium concentration and the concentration of ionized calcium is primarily due to the association of calcium with proteins. The clinical significance of protein affinity for blood plasma is illustrated by the fact that in recipients who are rapidly injected with albumin solutions, a transient decrease in the level of ionized calcium is observed.
Heparin, which can reduce the calcium concentration either by adding a calcium ion to the heparin molecule or by diluting the sample with a heparin solution, can in principle be ignored if its concentration is below 10 units per milliliter of whole blood. So, the measurement of calcium concentration can be performed in serum, plasma and whole blood. The place of blood sampling (artery or vein) in principle does not matter, since the difference in calcium concentration in different vessels is practically very insignificant in order to pay attention to it in the clinic.

calcium and the heart

Activity of pacemaker cells

All heart cells have a phospholipid membrane that separates the cytoplasm from the intercellular environment. According to modern concepts, the membrane contains specific protein complexes that function as ion-selective channels. Each channel with varying specificity controls the passage of sodium, potassium and calcium ions. Thus, the distribution of ions inside and outside the cell is controlled. This results in a potential difference, which is measured as a membrane potential between the cytoplasm and the extracellular fluid. The cycle of opening and closing of ion-selective channels leads to the movement of ions relative to the cell membrane, which ends with depolarization and electrical activation. The movement of ions into and out of the cell, including the release of sodium from the cell, returns the membrane potential to its original level. The characteristics of the transmembrane ion current are: direction (into or out of the cell) and transported ion (sodium, potassium, calcium, or chloride ions). Electrically dependent changes in transmembrane transport occur during membrane depolarization and repolarization and can be recorded as action potentials of the heart, which differ depending on the region of the heart where the recording was made. Therefore, their shape, amplitude and duration differ in different parts of the heart. For example, in the sinoatrial and atrioventricular regions, the action potential appears as a flat low-amplitude curve with a plateau that is primarily dependent on calcium (slow calcium channels). Thus, the calcium ion is absolutely necessary to maintain the automatism of the heart. In Purkinje fibers and myocardial fibers, the general characteristics of the action potential are as follows: rapid depolarization, which is accompanied by a long plateau. This plateau is the result of a slow back and forth of potassium, which determines the depolarization.
There are two hypotheses explaining the different form of potential in different parts of the heart. The first is the rapid current hypothesis, in which sodium is rapidly expelled from the cell and this causes the appearance of an initial spike in the action potential. The second is the hypothesis of a slow current of ions into the cell, which is fundamentally characterized by a slow current into the cell of calcium during the plateau phase of the action potential. So, the calcium ion is necessary for excitation and contraction of the heart muscle. If the level of extracellular calcium drops to zero, then the phase of slow repolarization will be carried out at the expense of sodium ions. The release of calcium from the cell is accompanied by two fundamental mechanisms: the exchange of calcium for sodium and the operation of the calcium pump. Both mechanisms are energy dependent and require ATP in order to conduct the calcium ion against a 10,000-fold transmembrane gradient.

Conjugation of excitation and contraction

The entry of calcium ions during the plateau phase is a phase moment in the process of conjugation of the processes of excitation and contraction in the cells of the working myocardium. So, the calcium ion is an important link between events such as what happens on the surface of the cell (depolarization) and what happens inside (the work of the contractile apparatus). The conjugation of excitation and contraction in the heart muscle depends on a rapidly replacing pool of intracellular calcium, and therefore the contraction of cardiomyocyte fibers is absolutely dependent on extracellular calcium. This phenomenon was first described by Ringer, who found that the contractions of an isolated frog heart ceased a few minutes after the start of its perfusion with a solution without calcium ions.
Calcium is a universal factor that ensures the process of conjugation of excitation and response to it in various types cells. Thus, calcium is a key factor in the links between membrane depolarization, for example, and the synthesis and excretion of second messengers and cellular hormones and enzymes. The secretion and release of insulin, aldosterone, vasopressin, prostaglandins, renin and neurotransmitters is thus regulated. A decrease in the amount of calcium in the blood, for example, leads to a slowdown in the synthesis of insulin. Calcium also activates enzymes in the blood coagulation cascade, and plays a central role in the mechanism of action of hormones and many drugs.

Intracellular interactions of calcium and proteins

There are four main groups of proteins involved in muscle contraction: the contractile proteins actin and myosin and the regulatory proteins troponin and tropomyosin. Troponin consists of three subunits: troponin T, troponin I, and troponin C. According to the model of calcium interaction with the contractile apparatus, calcium attaches to troponin C, which is a receptor protein for calcium on myofibrils, and the point of attachment of myosin to actin opens. Using the energy of ATP hydrolysis, actin leaves the myosin filament and the sarcomere contracts or tightens.
The amount of calcium in the cytoplasm is the main determinant of the adequacy of the delivery of calcium ions to contractile proteins, this factor also determines the rate of tension of muscle fibers. This relationship was also proven for cardiac myofibrils in which the sarcolemma was removed, so that the sarcoplasmic reticulum remained intact and thus exposed to direct action of calcium ions entering from outside. In such a preparation, contraction did not occur, that is, there was no connection between actin and myosin at a calcium ion concentration of 10 to the minus seventh power, and the maximum fiber tension occurred at a calcium ion concentration of 10 to the minus fifth power. However, the concentration of calcium in the blood (and, accordingly, in the interstitial fluid) is approximately 10 to the minus third power. Thus, it was found that the transmembrane gradient of calcium ranges from 100 to 10,000, depending on the stage of electrical activation.
The calcium concentration in the cytosol necessary to stimulate the contractile apparatus and its rise is provided by three main mechanisms: the introduction of calcium ions from extracellular sources during the action potential plateau phase, the release of calcium from intracellular calcium stores, and the exchange of calcium and sodium.
Of all these mechanisms, the release of calcium from intracellular stores is the most important, since the transmembrane current during contraction is too small to provide a full contraction. The transmembrane current is necessary for the constant replenishment of intracellular reserves, which are located mainly in the cisterns of the sarcoplasmic reticulum.

Muscle relaxation.

The attachment of calcium to troponin C is reversible, so muscle relaxation occurs when the troponin-C-calcium complex dissociates. This dissociation occurs when the concentration of calcium in the cell decreases due to external losses and closing of channels in the cisterns. The removal of calcium from its attachment points is an energy-dependent process and requires the presence of ATP. With ATP deficiency, the process of muscle relaxation worsens.

The role of cyclic adenosine monophosphate in conjugation of excitation and contraction processes.

In addition to calcium ions, cyclic nucleotide adenosine 3-5 monophosphate (cAMP) is required to couple the processes of excitation and contraction. It is a secondary messenger in the reduction process. Calcium and cAMP are related to each other. Calcium regulates the rate of cAMP synthesis and decay, while cAMP controls the entry of calcium ions into the cell. cAMP also controls the intracellular processes of calcium binding and release of stored calcium, and thus cAMP is a regulator of the muscle contraction and relaxation cycle.
Current research suggests that the heart muscle contracts and that this contraction requires oxidative phosphorylation to ensure the activation of slow calcium channels and calcium flow. Then, through a phosphorylation process involving several cell organelles, calcium provides the contraction process. These processes are also regulated by substances such as adenylate cyclase, cAMP and protein kinases. Inhibition of the activity of slow calcium channels due to insufficient energy supply may explain why myocardial contractility decreases not only due to ischemia due to blockage of the coronary artery, but also due to a lack of calcium.

Calcium as a mediator of the action of drugs and hormones

The very important role of calcium in ensuring the rhythmic contractile activity of the heart muscle and smooth muscles becomes clear when hypocalcemia decreases the contractility of both the myocardium and peripheral smooth muscles. In contrast, slow calcium channel blockers slow down calcium flow during the plateau phase and thereby reduce the tension and strength of fiber tension, resulting in a decrease in myocardial oxygen demand. For example, nifedipine reduces myocardial and vascular smooth muscle contractility, while a decrease in myocardial contractility is very difficult to maintain with lidoflazin at therapeutic doses.
Other drugs, the action of which depends on the flow of calcium are very diverse: these are cardiac glycosides of the digitalis group, sympathomimetic amines and anesthetics. The modern concept of the mechanism of action of digitalis connects its action either with an enzyme necessary for the operation of the sodium pump, or with a decrease in the release of calcium from the cell as a result of this process, or with a change in sodium-calcium homeostasis in the cell. Both mechanisms lead to an increase in the intracellular calcium pool and an improvement in the interaction of calcium with contractile elements. Beta-agonists increase the number of functioning calcium channels. Alpha - agonists (for example, norepinephrine) cause peripheral vasoconstriction due to the fact that more calcium enters the vascular smooth muscle cells and the mobilization of calcium from the endoplasmic reticulum cisterns also increases. Inhalation anesthetics depress the myocardium. For example, halothane inhibits the pumping function of the left ventricle, therefore, the cardiac index decreases at any end-diastolic pressure. Similar effects have been observed with enflurane, methoxyflurane, and nitrous oxide.
Several hypotheses have been proposed to explain why halothane depresses the myocardium. First, halothane at clinically used concentrations reduces calcium current by inhibiting calcium transport through slow calcium channels. Secondly, halothane can also affect the release of calcium from the cisterns of the cytoplasmic reticulum, its excess can also affect the level of ATP inside the cell. Both of these mechanisms affect the delivery of calcium to the contractile elements. Consistent with the idea that anesthetics interact with calcium delivery to contractile proteins, there is the following observation: bolus administration of calcium, which increases the level of extracellular calcium, removes the inhibitory effects of anesthetics on the contractile apparatus. This has a certain clinical significance, since the use of powerful inhalation anesthetics depresses the myocardium, and therefore it is possible to neutralize or weaken this effect by administering calcium preparations.

Calcium ions and heart function.

The use of calcium salts in anesthesiology is quite wide. Here we show statistics from the Massachusetts General Hospital where approximately 7,500 ampoules of calcium (a mixture of calcium chloride and calcium gluconate) were used during surgery in one year, of which approximately 2,500 were prescribed to patients during cardiac surgery (of which approximately 1,200 are performed each year) and 5,000 patients undergoing other surgeries (about 20,000 are performed each year).
Although the general limitations of extrapolating experimental data to humans must be considered, calcium-induced changes in hemodynamics and cardiac activity in dogs are in fairly good agreement with those obtained in humans.
It has long been known that bolus administration of calcium is accompanied by an increase in myocardial contractility. However, the clinical use of this finding is limited for two reasons: firstly, in humans, the contractility of the myocardium cannot be directly assessed by a direct method. In contrast, the pumping function of the heart, that is, the aspect of cardiac activity directly related to cardiac output, and thus perfusion of vital organs, can be assessed in almost all patients using a special balloon catheter placed in the pulmonary artery. In the operating room and intensive care unit, left ventricular pumping function is assessed by determining cardiac output in relation to end-diastolic pressure in the left ventricle. The second derivative of the ventricular wall oscillation values ​​is an indicator of myocardial contractility in terms of the rate of myocardial fiber contraction in the isovolemic phase of systole. Changes in the peak of this value may indicate a change in the pumping function of the heart, especially if it is evaluated together with the ejection fraction. For example, when using inotropic supports (i.e. catecholamines), and when a situation arises when a negative inotropic effect prevails (for example, in myocardial infarction), there is a disproportion between the speed and force of muscle fiber contraction. Such a disproportion can also occur with the introduction of calcium. However, in the clinic, such an increase in the work of the heart in a patient with ischemic disease fraught with a sharp increase in myocardial oxygen demand and decompensation.
It is now clear that both the heart and the smooth muscles of the peripheral vessels respond with changes in hemodynamics to both hypercalcemia and hypocalcemia. In an intact circulatory system, if calcium administration increases cardiac output, then a vascular response to calcium administration may not develop. Conversely, if cardiac output does not change, calcium administration may increase peripheral vascular resistance. This is necessary to know in order to understand the conflicting hemodynamic effects of hypocalcemia and hypercalcemia.

Hypercalcemia

In the operating room, acute hypocalcemia may occur in patients with hyperfunction of the parathyroid glands and with rapid intravenous administration of calcium. It is this form of hypercalcemia that is the subject of further discussion.

Kinetics of calcium ions during bolus administration of solutions of calcium salts.

Clinically used and recommended doses of calcium chloride for bolus injection are expressed in milligrams of calcium salt rather than pure calcium and range from 3 to 15 mg per kg per minute, which is quite a wide range. In adults, intravenous administration of calcium chloride at a dose of 5-7 mg / kg increases the concentration of ionized calcium in the blood by 0.1-0.2 mmol for about 3-15 minutes, followed by a decrease, but not to the initial level. The fact that the concentration of calcium in the blood after intravenous bolus administration increases only for a short time is of great clinical importance, especially with the rapid exchange of calcium on the membrane of the contractile elements of the cell, the reactions of the heart and blood vessels in this case are also of a short-term nature, as shown in the experiment and in the clinic. At a dose of calcium chloride of 15 mg/kg, the peak concentration of calcium in the blood is observed after two minutes, but its concentration in this case will also fall faster.
The rates of increase and decrease in the concentration of calcium ions in plasma are influenced by several factors. Firstly, the level of bioavailability of calcium ions (and hence the ionization of the calcium salt) in the formulation, together with the dose and time over which it was administered, are the most important determinants. Both chloride and calcium gluconate are 10% solutions of the corresponding salts, produced in 10 ml ampoules. However, despite the same concentration of salt solutions and the same volume, there will be more calcium in chloride than in gluconate, since the elemental calcium content in chloride is 27%, and in gluconate - 9%. In addition, calcium chloride in solution is completely ionized. So, the reaction to the introduction of the same amount of such solutions will be different due to the unequal content of calcium in them. With the exception of varying amounts of calcium in these salts and the slightly acidic properties of calcium chloride, no advantage of one salt over another has been recorded. However, accurate comparative information about these two calcium salts has not yet been published.
The second determinant of the increase in the concentration of calcium ions in plasma after intravenous administration of calcium preparations is the rate of its distribution, redistribution and collection from the blood. Although we do not have data on the distribution of calcium in the body after its intravenous administration, we believe that low cardiac output (which leads to a decrease in the distribution rate) in clinical practice should be used low doses of calcium supplements in order to avoid too high a rise in concentration calcium, so as not to disturb the heart rhythm and conduction, especially in the presence of therapeutic doses of digitalis.

Action on the heart.

In the absence of ischemia, left ventricular function curves recorded at different levels hypercalcemia, practically do not differ from normal. Even if the concentration of calcium ions is 1.7 mmol / l, which is the upper limit of the calcium concentration measured in the clinic, there are no significant changes in the pumping function of the heart. Thus, at doses of calcium commonly used in the clinic, there are no significant changes in the pumping function of the left ventricle.
In the presence of myocardial ischemia, an increase in the concentration of calcium ions in the blood to 1.7 mmol improves the function of the heart as a whole, as indicated by a 20% increase in shock work at a given end-diastolic pressure. Although the calcium-induced improvement in ischemic heart function is associated not only with an increase in the level of calcium itself, but also with interactions between different parts of the heart (that is, with changes in the geometry of the left ventricle), regional mechanical function improves precisely due to hypercalcemia as in normal, and in ischemic areas. When the stroke volume, heart rate and mean arterial pressure remain constant, hypercalcemia will be combined with a decrease in the end-diastolic and end-systolic length of the muscle fiber both in the control and in the ischemic zone and systolic dissociation, which characterizes segmental myocardial dysfunction much less expressed with hypercalcemia than with normocalcemia. Regional systolic shortening increases, and therefore the work of the heart increases.
The disadvantage of calcium infusion is an increase in myocardial oxygen demand without an increase in coronary blood flow, despite an increase in contractility. Despite this, the improvement in left ventricular function with the introduction of calcium allows the use of calcium preparations in patients with coronary heart disease, although it is necessary to take into account the impossibility of direct extrapolation of experimental data to the clinic, especially when the circulatory system is intact and the response of blood pressure and heart to intravenous administration of calcium preparations are very diverse. It must be remembered that the administration of calcium preparations has its drawbacks, but in principle, the same problems are inevitable when using other inotropic supports. In deciding whether or not to use calcium to stimulate the heart, consideration must be given to the rate and nature of the development of its effect on the heart (especially pronounced when the initial level of calcium is low, as discussed below), extracardiac effects and the disadvantages of calcium administration mentioned above. Thus, it is necessary to evaluate what outweighs: benefit or harm, as well as evaluate the prospect of using other inotropic supports. For example, comparative data (calcium chloride and catecholamines) obtained in an experiment on dogs under controlled hemodynamic conditions showed that with the same increase in the pumping function of the left ventricle, the increase in myocardial oxygen demand due to the use of isoproterenol exceeds that with the use of calcium by about three times.

hypocalcemia

Although the term "hypocalcemia" is generally defined as a total decrease in the total concentration of calcium in the blood, severe disturbances in ionized calcium homeostasis can occur in the absence of serious changes in the total concentration of calcium. This proves the need for direct measurement of the concentration of calcium ions in plasma in the clinical setting, when hypocalcemia is expected and the need for replacement therapy. In the operating room, hypocalcemia may occur after transfusion of freshly citrated blood, or from transfusion of factory-made albumin solutions after completion of cardiopulmonary bypass. In the intensive care unit, hypocalcemia can be observed in patients with pancreatitis, sepsis, during conditions accompanied by prolonged low cardiac output, after x-ray studies using intravenous contrast agents, and in those patients who require hemodialysis.

Kinetics of calcium ions during citrate infusions.

When a patient is transfused with blood stabilized with sodium citrate, changes in the concentration of calcium ions in the blood and hemodynamics are minimal. However, rapid transfusions at a rate of 1.5 ml/kg/min can cause already recorded, but transient degrees of hypocalcemia and hemodynamic disturbances.

Action on the heart.

With a decrease in the concentration of calcium ions in the serum to 50% of the original, the shock work of the heart deteriorates sharply at any final diastolic pressure, with a final diastolic pressure in the left ventricle of 10 mm Hg. Art. this reduction is about 55%.
In regional ischemia, hypocalcemia-induced inhibition seems to be more easily induced than in non-ischemic myocardium, while in non-ischemic myocardium, compensation is maintained until the concentration of calcium ions in the blood drops to 50% of the initial level, and in the presence of regional ischemia, compensation persists only with a decrease in the concentration of calcium ions in the blood to 70% of the original. The curves of the work of the left ventricle are shifted to the left, which is characterized by the level of oppression of its work. With hypocalcemia, both in normal and ischemic myocardium, all functions are sharply inhibited: both the end-systolic and end-diastolic length of myocardial fibers increase, systolic dissociation is observed in the left ventricle, systolic shortening decreases, and the curves of regional functions mix to the right and down. Hypocalcemia is also accompanied by dilatation of the coronary arteries.
Changes in cardiac function caused by severe hypocalcemia (decrease in calcium levels by 30-50% from baseline), as shown in the experiment, confirm the need for the use of calcium supplements for the treatment of patients with myocardial ischemia and moderate or severe hypocalcemia. This situation may occur immediately after the end of cardiopulmonary bypass and the use of calcium under these conditions is discussed below, but this tactic is not used in all hospitals.
It should also be taken into account that the repeated use of calcium develops resistance, these observations were made for the first time 50 years ago. However, the true mechanism of this phenomenon has not yet been elucidated.

Controversial aspects of the reaction of the heart to hypocalcemia and hypercalcemia.

Hypercalcemia

There have been several reports of calcium infusions at clinically used doses discussing the need to use calcium supplements when cardiac output cannot be measured. We will try to explain the reason for their appearance. One study did not provide comparative statistics of left ventricular function in hypocalcemia (i.e., before calcium supplementation) and after calcium infusion. In another study, cardiac output and blood pressure increased within one minute of calcium infusion, consistent with the transient effects of a bolus calcium infusion. If the concentration of calcium ions before the infusion of the calcium preparation was normal, then changes in cardiac output are less pronounced than with an initially low calcium concentration. Many studies incorrectly assessed the concentration of calcium ions in the blood plasma, or an incomplete assessment of the hemodynamic profile. The effect of calcium in the presence of powerful inhalational anesthetics is strikingly different from the results that have been obtained in patients with neuroleptoanalgesia. Finally, clinical data suggest that the presence of prior cardiac depression due to coronary artery pathology with calcium administration results in an increase in cardiac output, while in patients without cardiac pathology, calcium infusion is associated with an increase in peripheral systemic vascular resistance.

hypocalcemia

Approximately thirty years ago, the development of methods for measuring cardiac output during citrate infusion began and the term "citrate intoxication" was coined. Numerous experimental and clinical studies have been conducted that support the idea that citrate administration causes hypocalcemia and depression. of cardio-vascular system. Although the intensity of citrate intoxication has been discussed, the occurrence of severe, albeit transient, hypocalcemia with rapid infusion of freshly citrated blood has not been discussed anywhere.
Some investigators suggest that changes in blood pressure and heart function due to citrated blood infusion are minimal and not clinically important. To explain this point of view, the determining factor in this problem should be considered not the total amount of blood transfused, but the rate of infusion. Also, hypocalcemia inhibits cardiac function, and this occurs much faster in the presence of other inhibitory factors, for example, when taking beta-blockers, myocardial ischemia, cardiac denervation, or in the presence of hypovolemia before citrate administration. Nothing is known about inhalation anesthetics in this regard.
Although citrate-induced hypocalcemia was at one time prevented by infusion of dextrose acid phosphate-stabilized blood, its hemodynamic effects were negative and more severe than sodium citrate-stabilized blood.

Calcium and smooth muscles of peripheral vessels.

Although the role of calcium in the regulation of peripheral vascular smooth muscle function has been studied decades ago, it has not been discussed in reports on the hemodynamic effects of calcium. The calcium ion is necessary for the process of conjugation of excitation and contraction in the smooth muscles of the peripheral vessels, and therefore the peripheral blood vessels respond to changes in the concentration of calcium ions in the blood.

Peripheral vascular response to acute hypo- and hypercalcemia.

Since an increase in the concentration of calcium ions in the blood is associated with an increase in smooth muscle contractility, hypercalcemia leads to an increase in resistance to blood flow in peripheral arteries, renal, coronary and cerebral vessels. Such a reaction was not recorded in the vessels of the small circle. Hypocalcemia is associated with a decrease in peripheral vascular resistance, which is an important pathogenetic factor in the development of hypotension in hypocalcemia.
Two major mechanisms are involved in creating a vascular response to calcium administration. First: this is the direct effect of calcium preparations on vascular smooth muscles and their tone. This is supported by the observation that peripheral vascular tone decreases with calcium channel blockers.
Secondly, there is an effect produced through the sympathetic nervous system, through the release of catecholamines or stimulation of adrenergic receptors. The release of catecholamines in connection with the introduction of calcium occurs because the calcium ion is associated with the conjugation of the processes of excitation and secretion. Hypercalcemia acts as a stimulus for the release of catecholamines from both the adrenal medulla and peripheral autonomic nerve endings. Recent experiments in dogs, for example, have shown that the calcium-induced increase in peripheral vascular resistance decreases dramatically after adrenalectomy. Experimental data suggest that hypercalcemia may also stimulate alpha and beta adrenoreceptors. After the use of beta-blockers, the increase in OPSS is more pronounced than under normal conditions. When alpha- and beta-blockers are used simultaneously, changes in peripheral vascular resistance during hypercalcemia vary. These findings may explain the differential response of the cardiovascular system to hypercalcemia under different circumstances.

Controversial aspects of peripheral vascular smooth muscle response to hyper- and hypocalcemia.

Hypercalcemia

Since hypercalcemia may increase the contractility of the heart and smooth muscles of peripheral vessels, an increase in blood pressure is most often observed after the administration of calcium supplements. However, there is mention in the text of an unpublished observation of a reduction in blood pressure with calcium supplementation. While some experimental and clinical data have shown that TPVR increases with calcium infusion, others have shown that it, on the contrary, decreases. It is clear that calcium can cause changes in both the heart and blood vessels. What happens when calcium is administered depends on the initial concentration of calcium ions in the blood, myocardial contractility and the initial activity of the sympathetic nervous system. Moreover, paying attention to the detail - the recording of different hemodynamic parameters in different studies, it becomes clear why such mixed results are obtained. Finally, the state of the adrenergic system affects the hemodynamic response to calcium, as discussed above.

hypocalcemia

A decrease in blood pressure has been reported during hypocalcemia in patients over twenty years ago. However, the important role of the great vessels in the development of hypocalcemic hypotension has been documented but not recognized. These researchers recorded a sharp decrease in cardiac output and work of the heart, as well as a decrease in blood pressure, but they did not indicate that the decrease in systemic arterial pressure could be associated with a decrease in the tone of the great vessels. Since blood pressure is included as one of the variables in the equation for calculating the work of the heart, the work of the heart decreased. Thus, it is impossible to consider the work of the heart in conditions of hypotension as an accurate indicator of cardiac output, moreover, the interpretation of the role of the function of the heart and the function of peripheral vessels during hypocalcemic hypotension is impossible if the pumping function of the left ventricle and its most important determinants are not measured, or if the patient also has hypovolemia (the main indication for blood transfusion) and hypocalcemia combined.

Therapeutic use of calcium.

In the operating room and intensive care unit, hemodynamic support is carried out with the help of catecholamines and calcium salts. Sympathomimetic amines with a very short lifetime are administered by long-term infusions, that is, the rate of their administration can be selected for each individual patient individually to maintain stable hemodynamics. In contrast, calcium salts are commonly used as bolus injections. They are not administered by continuous infusions, as this would require a system to determine the concentration of calcium ions in the blood right at the patient's bed - so often this would have to be done, because if the rate of calcium infusion is constant and cardiac output for some reason does not respond to the introduction of calcium, dangerously high concentrations of calcium ions in the blood can occur, which will lead to serious heart rhythm disturbances.

Indications and doses

adults

Since hypocalcemia during infusion of citrate blood in different patients varies, usually small and quickly disappears, there is no need for calcium administration with conventional blood transfusion. However, when transfusion is rapid over a long period of time (i.e. 1.5 ml/kg/min over 5 minutes or more), intravenous calcium should be given. The inhibition of myocardial contractility in the combination of hypocalcemia and the use of beta-blockers is stronger than in the presence of only hypocalcemia, therefore, the use of calcium is also justified in blood transfusions at a moderate pace in patients taking beta-blockers. The dose of calcium depends on the degree of hypocalcemia, usually the initial dose is 5-7 mg / kg of calcium chloride, which is repeated after a few minutes, if necessary, confirmed by measuring the concentration of calcium ion in the blood.
If citrated blood is used to fill the AIK oxygenator, then calcium chloride (at a dose of approximately 500 mg/l) can be added to the solution in order to reduce hemodynamic disturbances due to hypocalcemia at the beginning of cardiopulmonary bypass. In this case, heparin is also required.
In some medical centers calcium chloride is used in patients with cardiac surgery after the end of cardiopulmonary bypass. The approximate dose in this case varies from 7 to 15 mg / kg for 30-60 seconds, and then it is repeated if necessary. We believe that in this case it is necessary to monitor the concentration of calcium ions in the blood in order to organize a rational therapeutic use of calcium. Calcium chloride is also commonly used in patients with asystole or cardiac arrest at a dose of 5 to 12 mg/kg. Although we do not have comparative data, the dose of calcium gluconate should be 2.5-3 times the dose of calcium chloride in order to increase the concentration of calcium ions in the blood equally.

Newborns and children.

According to international agreement, only calcium gluconate is used in pediatric practice, since it is safer than calcium chloride in terms of provoking cardiac arrhythmias. However, the safety of administering a calcium preparation depends on its amount and rate of administration, on the bioavailability of the calcium ion in this preparation and on the volume of its initial distribution. The second reason for the use of calcium gluconate alone in pediatric practice is that there is less acid-base disturbance with its administration than with the administration of calcium chloride, but this is not a problem with short-term use of calcium preparations.
The use of calcium preparations is indicated for extensive surgical interventions in children with large blood loss when blood loss and replacement volume are estimated as an approximate BCC in this child. The dose of calcium gluconate is approximately 100 mg for every 100 ml of infused blood, however, frequent determinations of the concentration of calcium ions in the blood are necessary, since hypocalcemia is possible at this rate of calcium administration. So, the dose and preferred time of administration of the calcium preparation need to be strictly determined.
Calcium is also used in exchange transfusions in newborns. Although the recommended dose is 100 mg of calcium gluconate per 100-150 ml of infused blood, it may not be sufficient to prevent hypocalcemia. Therefore, again, careful monitoring of the concentration of calcium ions in the blood of the newborn is necessary. In hypocalcemia in a newborn, calcium gluconate at a dose of 200 mg / kg is recommended only when tetany or convulsions occur due to a sharp decrease in the level of calcium in the blood. In cardiac arrest in a child, calcium gluconate is used at a dose of 10 mg / kg.

Complications of calcium use

The most dramatic description of the complications of calcium infusion was published 60 years ago. The author of this report was given a bolus dose of calcium chloride and experienced nausea, discomfort, convulsions, syncope, and respiratory failure. There are no exact details in the report, but the ECG shows sinoatrial blockade and marked bradycardia. Massage of the heart through the abdominal wall was effective (the experiment was carried out on a volunteer).
Even if hypocalcemia is fixed, the administration of calcium in therapeutic doses can lead to serious disorders: sinus arrhythmia, bradycardia, A-B dissociation and the appearance of ectopic foci. The potential risk of calcium bolus administration is also present in patients treated with digitalis, as discussed above.
A complication of calcium administration, which is not life-threatening, but unpleasant for the patient, is irritation of the vessel wall and necrosis of the subcutaneous tissue in case of accidental administration of calcium chloride or calcium gluconate past the vein. Therefore, calcium preparations are injected into veins of the largest possible diameter, carefully fixing the needle. Is it safe to inject calcium into the aorta in newborns? This issue needs further discussion.

Anesthesia and analgesia
1985,64, 432-51
Lambertus J. Drop, MD, PhD