Intensive Care of Emergency Conditions - V. M. Zaporozhan 2006

Maintenance of Homeostasis

The constancy of the internal environment, as described by C. Bernard, is "the primary condition for the existence of a living Organism." Cannon proposed designating it with the term "Homeostasis." Over time, this concept in biology and medicine has expanded to various aspects of the functioning of a living organism.

This chapter discusses Water and Electrolyte METABOLISM (WEM), acid-base balance (ABB), and the Blood Coagulation and anticoagulation systems, as the normalization of these Functions is one of the most critical elements of intensive care in critical conditions.

Class="center">Water and Electrolyte Metabolism

In critical conditions, numerous factors can disrupt this aspect of homeostasis, including the pathological process itself, pharmacological therapy, the course of the post-resuscitation period, etc. The task of the intensivist is to prevent WEM disorders or promptly correct any arising imbalances.

Water serves as the medium in which all biochemical processes take place. Electrolytes ensure the constancy of the Osmotic Pressure of Body Fluids; without them, no enzymatic reaction is possible (e.g., The conversion of ATP to ADP and vice versa, enolase activation, Oxidative Phosphorylation in Cell/35.html">Mitochondria, Glycogen formation in the Liver, etc.). Furthermore, electrolytes play a crucial role in regulating ABB and in cellular excitation processes.

Water and electrolyte metabolism constitute a unified, dialectically interconnected, and interdependent process. However, for the sake of convenience, it is acceptable to consider Water Metabolism separately from electrolyte metabolism.

Total body water averages 60% (50% in overweight individuals, 70% in lean individuals). The percentage of body water is higher in children than in adults, and higher in men than in women. Water is in constant motion between body compartments separated by semipermeable membranes: the intracellular compartment (accounting for about 40% of body mass, i.e., 2/3 of total body water) and the extracellular compartment (20% of body mass or 1/3 of total water). The extracellular space, in turn, is subdivided into the intravascular space, which represents Blood Plasma (5% of body mass), and the interstitial space, representing tissue fluid (15% of body mass).

Total body water is completely renewed within 9 days.

Maintenance of water balance is achieved by timely replenishment of losses. In a healthy adult, this occurs automatically in response to physiological signals such as thirst and hunger, through the intake of fluids and food, and via The production of so-called endogenous water generated within the body through metabolism (The oxidation of 100 g of fats yields 107 ml of water, while 100 g of Proteins and CARBOHYDRATES each yield 55 ml of water). Under physiological conditions, the daily water balance is distributed as follows (Table 5):

Table 5 Daily water balance in The Human Body under physiological conditions, ml

However, in severely ill patients, maintaining fluid balance becomes a medical challenge due to the underlying pathological process, mechanical ventilation, tracheostomy, forced restriction of fluid intake, and impaired enteral Nutrition. Therefore, calculating daily water losses is essential. These losses are divided into visible losses, which can be quantified in a hospital Setting, and invisible losses, which under normal conditions can only be estimated approximately through theoretical calculation.

Visible losses are quantified by measuring daily urine output (for which critically ill patients are fitted with a urine collection bag or an indwelling urinary catheter), stool (this route of loss can become primary in diarrhea), vomitus, fluid drainage from gastric tubes and body cavity drains, exudate from extensive Burns, wounds, and desquamated Skin, as well as fluid accumulation in blisters covering large areas of the body, etc. Water loss through sweat can be roughly estimated based on the degree of perspiration: intermittent mild sweating (primarily in the axillary and pubic regions) accounts for about 300 ml of water loss; intermittent moderate sweating (including the HEAD) accounts for 600 ml; intermittent pronounced sweating (over the entire body) accounts for 1000 ml; and continuous sweating ranges from 2 to 15 liters per day.

Under physiological conditions, invisible water losses in an adult via skin perspiration and the Lungs amount to approximately 800 ml per day. For every degree Celsius of Temperature elevation above 37 °C, daily Water Loss via perspiration increases by 200 ml; in the presence of tachypnea, it increases by 500 ml for every 10 breaths above the normal rate of 16 breaths per minute. During prolonged cavity surgeries, fluid loss through evaporation from exposed Body Cavities increases significantly (up to 100 ml/h).

The calculated volume of water is administered to the patient orally or via liquid nutrition, or, when oral intake is restricted or impossible, through parenteral infusion using crystalloid, colloid, and other solutions.

Daily requirements can be calculated based on the patient's age and Anatomical Characteristics. First, one can rely on age and body surface area (Table 6).

Table 6 Water requirements according to age and body surface area (W. Seifart, 1976)

Second, calculations can be based on age and body weight (Table 7).

Table 7 Water requirements according to age and body weight (W. Seifart, 1976)

The Kidneys play a critical role in water metabolism. Water and electrolyte balance is regulated less by The Nervous system and more through humoral pathways: the neurohypophysis via antidiuretic hormone (ADH), and the Adrenal Glands via mineralocorticoids (aldosterone) and glucocorticoids.

Disorders of water metabolism (dyshydria) can manifest in various forms. Among the many existing classifications, the most practical for identifying dyshydria and promptly deciding on the correction of detected water balance disorders is the one that distinguishes between decreases or increases in water content within the extracellular and intracellular compartments (Fig. 13).

By recognizing the clinical signs of each of the 8 types of dyshydria, one can identify The Nature of water balance disorders with a high degree of probability. This approach is particularly valuable because the laboratory capabilities of medical facilities for assessing WEM are typically

Fig. 13. Diagram of water balance disorder forms (J. Hamburger et al., 1965)

are quite limited, and specialized Methods for determining the volumes of body fluid compartments are available only to a few clinical research laboratories.

Extracellular dehydration is the most common type of dyshydria encountered in critical conditions. It can be caused by the loss of salts, primarily sodium and chloride, which leads to the restoration of decreased osmolarity through renal water excretion and its shift into Cells. Another cause is water loss via vomiting, diarrhea, wound exudation in mechanical and thermal injuries, damaged skin surfaces in various dermatological disorders, and through Abdominal cavity drains.

Clinical presentation: dry skin, asthenia, Muscle hypotonia, weak pulse, tachycardia, decreased arterial and central venous pressure, and low Cardiac Output with a tendency toward hypovolemic Shock. Absence of thirst is characteristic due to the fluid shift into the cells. Signs of hemoconcentration include elevated hematocrit, erythrocyte count, Hemoglobin level, and total serum protein.

Treatment: intravenous infusion of hypertonic or isotonic sodium chloride solutions.

Cellular dehydration develops As a result of excessive loss and insufficient intake of water, combined with excessive administration or retention of salts that remain in the extracellular environment. This occurs during fluid restriction without simultaneous parenteral water infusion, fever with profuse sweating during temperature defervescence, renal impairment, antidiuretic hormone deficiency—in other words, situations involving the loss of pure or nearly pure water.

Clinical presentation: dry Tongue and mucous membranes, intense thirst, agitation, delirium, fever, respiratory disorders (dyspnea, Cheyne-Stokes Respiration), and muscle twitching. Plasma sodium levels may be elevated, along with oliguria and hypersthenuria (urine specific gravity of 1.030–1.040).

Treatment: drinking water or intravenous infusion of an isotonic (5%) glucose solution. Administration of saline solutions and blood is contraindicated, except in cases of Hemorrhage.

General dehydration occurs as a result of a negative water balance caused by fluid cessation and excessive fluid loss, provided this situation is accompanied by an adequate concurrent loss of salts. In general, the causes of general dehydration are similar to those of the specific dehydration forms described above.

Clinical presentation: less pronounced than in isolated extracellular and cellular dehydration. It manifests as a pale, earthy skin tone, particularly on the face, cyanotic Lips, and sunken eyes. Mental status is usually unimpaired. Moderately expressed symptoms of hypovolemia are observed: a rapid, weak-amplitude pulse, arterial and venous hypotension, and collapse of subcutaneous Veins. Moderate thirst. Dryness of the tongue and mucous membranes is combined with dry skin.

Treatment begins with the administration of an isotonic glucose solution, which, under the Action of Insulin, enters the cells and is metabolized to produce water; the remaining vascular water also enters the cells down the osmotic pressure gradient. Subsequently, to prevent excessive vascular hypotension, normal saline is added to the glucose solution. Hypertonic solutions must never be administered, as this could sharply increase cellular dehydration due to a rise in plasma osmolality.

Extracellular hyperhydration. This develops upon the accumulation of sodium in the extracellular environment due to excessive intravascular administration of hypertonic solutions or its retention within the body. In clinical practice, this is seen with the excessive use of ACTH, corticosteroids, or anabolic Hormones; adrenal hyperfunction (primary aldosteronism with Conn's syndrome or aldosterone-producing tumors with Cushing's syndrome). Extracellular hyperhydration also occurs with elevated venous and hydrostatic pressure in the venous end of the capillary (right-sided Heart Failure or renal failure, liver cirrhosis), hypoproteinemia (Nephrotic Syndrome, protein malnutrition), and increased vascular permeability (acidosis, Hypoxia, intoxication).

Clinical manifestations can occur in two variants. First, with a predominant accumulation of water in the interstitial space, accompanied by "renal-type" edema (in areas with loose Connective Tissue), which is typical of nephrotic syndrome and other hypoproteinemic states. Second, with a predominant accumulation of water in the vascular bed, manifested by an increased circulating blood volume (CBV) and circulatory overload with signs of hemodilution (decreased hematocrit and total blood protein concentration), arterial and venous Hypertension,

right-sided heart failure, and "cardivein-type" edema (in the lower PARTS OF THE body).

Treatment: restriction of salt intake and administration, Diuretics, laxatives, and, in renal failure, hemodialysis in ultrafiltration mode or hemofiltration.

Cellular hyperhydration. This develops when the osmotic pressure within cells exceeds that of the interstitium. Causes include the excessive administration of electrolyte-free solutions (e.g., glucose) and excessive intake of plain water, especially if preceded by diarrhea, vomiting, diuresis stimulation, or salt restriction without water restriction, often against the Background of renal impairment; enhanced Catabolism with hyperproduction of endogenous water (up to 3–5 L instead of the usual 300 mL per day); and increased sodium loss due to adrenal hypofunction or Central Nervous System lesions.

Clinical manifestations are associated with cellular edema, primarily affecting the Brain's Nerve Cells, which are most sensitive to water overload; asthenia, headache, mental disturbances, epileptiform seizures, coma, and vomiting occur, which further exacerbates sodium loss and promotes cellular hyperhydration. There is no thirst, and the tongue and mucous membranes are moist. Body temperature is normal or reduced. Oliguria (due to renal cell edema), azotemia, and papilledema may be observed. Plasma potassium concentration increases due to hypercatabolism.

Treatment: restriction of plain water intake up to a complete prohibition. Administration of hypertonic sodium chloride solutions under blood pressure monitoring (if blood pressure rises, sodium administration is stopped); in case of Protein deficiency, blood protein preparations are used. Accelerated water elimination using diuretics and laxatives. Reduction of catabolic rates through a high-calorie diet with Vitamins, anabolic hormones, and intravenous glucose (up to 200–300 g per day to meet energy needs) as 15–40% solutions with an adequate dose of insulin (1 IU of insulin per 3–4 g of glucose).

General hyperhydration, or so-called true water intoxication. Most commonly a consequence of improper management of patients with renal failure: excessive water intake and administration of isotonic glucose solutions combined with severe salt restriction. It can also develop during enhanced endogenous water production associated with hypercatabolism (purulent-infectious complications).

Clinical presentation is a combination of extracellular and cellular hyperhydration manifestations: alongside neurological symptoms inherent to nerve cell edema, signs of hypervolemia are observed—arterial and venous hypertension, right- and left-sided heart failure, pulmonary edema, and peripheral edema.

Treatment: restricted intake and enhanced elimination of water using diuretics and laxatives. Since hyponatremia in these cases results from hemodilution, the administration of iso- and hypertonic sodium salt solutions to normalize natremia is a major error. In anuric patients unresponsive to diuretics, hemodialysis in ultrafiltration mode and hemofiltration are recommended.

Extracellular dehydration with cellular hyperhydration. This occurs during rapid and intensive salt loss against the background of renal failure, causing water to shift into the cellular environment where the osmotic pressure exceeds the reduced extracellular pressure resulting from salt depletion.

Clinical presentation: signs of hypovolemia (weak pulse, tachycardia, decreased arterial and central venous pressure, low cardiac output with a tendency toward hypovolemic shock) and hemoconcentration are complemented by symptoms of cellular hyperhydration (absence of thirst and aversion to water, anorexia, asthenia, headache, mental disturbances, epileptiform seizures, coma, vomiting).

Treatment: the main objective is the restoration of the normal Electrolyte Composition of the extracellular environment following the same principles used in the management of extracellular dehydration. In cases of anuria, infusion therapy is supplemented by hemodialysis, which achieves the normalization of plasma electrolyte composition much faster and more completely.

Extracellular hyperhydration with cellular dehydration. It occurs due to salt retention in the body and their accumulation in the extracellular environment, where water shifts from cells driven by a higher osmotic pressure gradient.

Clinical presentation: neurological signs of cellular dehydration (intense thirst, agitation, delirium, fever, respiratory disorders, muscle twitching, and dry mucous membranes) paradoxically combine with peripheral edema, particularly in the lower extremities, signs of hypervolemia, and circulatory overload.

Management: extremely cautious intravenous administration of an isotonic glucose solution with insulin, closely monitored by arterial and central venous pressure measurements, alongside lung Auscultation (due to the risk of pulmonary edema!).

Electrolyte Metabolism

Electrolytes are salts, acids, and bases that dissociate into free ions to varying degrees In aqueous solutions.

Ions are electrically charged particles that become freely mobile when an electrolyte dissociates in an aqueous solution. In a direct current field, positively charged particles migrate toward the cathode (cations), while negatively charged particles migrate toward the anode (anions). The most important cations in the body are sodium (Na⁺), potassium (K⁺), calcium (Ca⁺⁺), and magnesium (Mg⁺⁺), whereas the key anions include chloride (Cl^-), bicarbonate (HCO₃^-), phosphates (H₂PO₄^- ; HPO₄^--), sulfate (SO₄^-), proteins, and residues of organic acids such as acetic (acetate), pyruvic (Pyruvate), lactic (lactate), ß-hydroxybutyric (ß-hydroxybutyrate), and acetoacetic (acetoacetate).

Electrolyte quantities can be measured in weight units, which is more convenient when weighing out a specific mass of a substance. However, for Chemical Reactions, it is more practical to use electrochemical units, such as moles or millimoles (mmol).

A millimole is the relative molecular (or atomic) mass expressed in milligrams (mg), meaning:

1 mmol = relative molecular (atomic) mass in mg.

For example, 1 mmol Na = 23.0 mg, and 1 g Na = 43.5 mmol;

1 mmol K = 39.1 mg, and 1 g K = 25.6 mmol;

1 mmol Ca = 40.0 mg, and 1 g Ca = 25.0 mmol;

1 mmol Mg = 24.4 mg, and 1 g Mg = 41.0 mmol;

1 mmol Cl = 35.5 mg, and 1 g Cl = 28.2 mmol;

1 mmol HCO₃ = 61.0 mg, and 1 g HCO₃ = 16.2 mmol.

Accordingly:

1 g NaCl contains 17.1 mmol Na and 17.1 mmol Cl;

1 g NaHCO₃ contains 11.9 mmol Na and 11.9 mmol HCO₃;

1 g KCl contains 13.4 mmol K and 13.4 mmol Cl;

1 g KH₂PO₄ contains 7.4 mmol K and 7.4 mmol H₂PO₄;

1 g K₂HPO₄ contains 11.5 mmol K and 11.5 mmol HPO₄.

In the SI system, the concentration of electrolytes and ions in biological fluids is conventionally expressed in millimoles per liter (mmol/L).

The distribution of ions between blood plasma and interstitial fluid is nearly identical. Their concentrations in these fluids maintain a Donnan equilibrium, meaning they are adjusted for the varying protein content across these compartments.

Intracellular ion concentrations and profiles differ significantly from those in the extracellular environment. While the latter (Fig. 14, a, b) mainly contains Na⁺, Cl^-, and HCO₃^-, the intracellular space is rich in K⁺, Mg⁺⁺, and PO₄^--, as well as SO₄^-- and proteins (Fig. 14, c).

This gradient is maintained by the active operation of the so-called "sodium-potassium pump" (Na⁺/K⁺-ATPase, which functions utilizing energy and oxygen). Consequently, in cases of energy failure and hypoxia, the physiological ratios of the water-electrolyte composition in the body's biological fluids are disrupted, driving the concentrations of electrolytes toward equalization. This exerts a detrimental effect on cellular viability and, by extension, on the organism as a whole.

Ions perform vital functions, including maintaining the osmolarity of body fluids, generating bioelectric potentials across membranes, catalyzing metabolic processes, determining the acid-base balance of body fluids, stabilizing Bone tissue, serving as an energy reserve, and participating in blood coagulation. At the same time, each individual ion exhibits specific functions.

Fig. 14. Ionogram of blood plasma (a), interstitial fluid (b), and cellular space (c) (after W. Hartig, 1982)

Sodium is primarily responsible for the osmolarity of the extracellular environment, thereby influencing fluid shifts between all fluid compartments and establishing the bioelectric Membrane Potential.

Potassium is involved in carbohydrate utilization and Protein Synthesis (3 mmol of potassium is bound per gram of nitrogen synthesized, and released upon breakdown) and plays a crucial role in neuromuscular excitation.

Several factors significantly affect plasma potassium levels. A drop in pH (acidosis) increases plasma potassium, whereas a rise in pH (alkalosis) decreases it.

Elevated plasma potassium levels are observed in tissue hypoxia (shock), accelerated protein breakdown (catabolism), impaired carbohydrate utilization, and cellular dehydration. Conversely, potassium influx into cells occurs with enhanced glucose utilization driven by insulin, accelerated protein synthesis, and cellular rehydration. An excess of sodium and calcium lowers plasma potassium, while their deficiency raises it. Under conditions of potassium depletion, the kidneys struggle to retain it, meaning losses may exceed intake. Conversely, in the event of an overdose, potassium is relatively easily excreted in the urine. In oliguria and anuria, its plasma concentration rises.

Hypokalemia (K⁺<4.5 mmol/L) may result from reduced intake, increased renal and gastrointestinal losses, redistribution during insulin therapy, or alkalosis.

Clinical presentation: neuromuscular signs (hyporeflexia, muscle weakness, paresis), gastrointestinal symptoms (constipation, paralytic ileus), renal manifestations (isosthenuria, polyuria, polydipsia, Urinary Bladder atonia), and cardiovascular signs (arrhythmia, tachycardia, ventricular flutter, hypersensitivity to Glycosides, ECG changes consisting of T-wave flattening followed by inversion below the isoelectric line, S-T segment depression with the appearance of additional waves and Q-T interval prolongation, and arterial hypotension).

Treatment: oral potassium supplementation (80-150 mmol daily via potassium supplements or food), intravenous potassium administration at a rate not exceeding 20 mmol/h (i.e., 50 mL of 3% KCl) and no more than 100-150 mmol daily (i.e., 240-360 mL of 3% KCl). When renal function is intact, potassium overdose via oral administration is virtually impossible. Intravenous administration, however, carries a constant risk of overdose leading to cardiac rhythm disturbances.

Hyperkalemia (K+>5.5 mmol/L) may occur due to excessive intake, release of intracellular potassium during hemolysis, acidosis (ketoacidosis, lactic acidosis) and other catabolic states, impaired renal excretion in acute and chronic renal failure, adrenal insufficiency, or an Addisonian crisis.

Clinical presentation: general signs (weakness, confusion, nausea), cardiovascular symptoms (bradycardia, arrhythmia, tall and peaked T waves on the ECG, cardiac arrest), and neurological signs (paresthesia, lethargy).

Treatment: stimulation of diuresis, intravenous administration of glucose with insulin, calcium preparations, management of acidosis, and emergency hemodialysis.

Chlorine. The most important extracellular anion, which participates in metabolic processes alongside sodium and potassium ions. Its imbalance occurs concurrently with sodium and potassium imbalances.

Bicarbonate is of major importance in the Regulation of the acid-base balance.

Other ions are of lesser significance in emergency settings.

Modern clinical practice employs various methods to calculate water and electrolyte deficits and determine the quantities required for metabolic correction. One approach for quantitatively assessing extracellular water deficit is to determine the deficit in circulating blood volume (CBV), including calculating the difference between the predicted and actual values for a specific patient while taking hematocrit into account (Table 8).

The volume of fluid required for correction can also be calculated using the following formulas:

The latter formula is valid provided there is no active bleeding.

Table 8 Calculation of circulating blood volume (CBV) based on hematocrit values, mL

Criteria for the adequacy of infusion therapy include ARTERIAL BLOOD PRESSURE, pulse rate, central venous pressure (4-12 cm H₂O), hemoglobin levels (not less than 80 g/L, hematocrit not less than 0.3), and hourly diuresis (not less than 40 mL).

Calculating electrolyte deficits is only possible if the concentrations of constituent ions in at least the blood plasma are determined using flame photometry or ion-selective electrodes. Once the values in millimoles per liter are obtained, the electrolyte deficit and the volume of the solution required for its correction can be calculated using the formula:

where K₁ is the normal ion content in millimoles per liter: for K⁺ it is 5 mmol/L; for Na⁺, 142 mmol/L; for Cl^-, 103 mmol/L; for Ca⁺⁺, 2.5 mmol/L;

K₂ is the plasma ion content prior to correction, mmol/L;

0.2 is the extracellular fluid fraction, of which the blood plasma under study is a part, relative to total body weight;

body weight is the total body mass, kg;

A is a coefficient indicating the volume of a given solution in milliliters that contains 1 mmol of a given ion, which for:

3% KCl solution = 2.4;

7.4% KCl solution = 1.0;

10% NaCl solution = 0.58;

0.9% NaCl solution = 12.3;

10% CaCl₂ solution = 1.11.

Single-stage correction of plasma ionic composition via intravenous administration of the calculated dose results only in a temporary normalization of its plasma levels, since this calculation method leaves the intracellular ion content unknown. Following the administration of the required volume of the solution, re-Determination of the plasma electrolyte profile and additional correction are necessary.

Furthermore, maintaining water-electrolyte balance requires careful accounting of the electrolytes excreted daily via urine, exudate, vomit, etc.

In clinical practice, various pathological conditions frequently present with simultaneous alterations in multiple ions. Correcting these imbalances is significantly more challenging and must follow a fundamental rule: replenishment of the deficient cations and anions should begin with the smallest deficit. Otherwise, correcting the deficit of one ion contained in the solution may lead to an overdose of another.

If laboratory determination of the plasma ionogram is unavailable, data on daily ion requirements can be used to outline an approximate infusion therapy plan for maintaining electrolyte balance (Table 9).

Table 9 Daily electrolyte balance in adults (W. Hartig, 1982)

Osmotic concentration

Osmolarity (osmolality) is the property of solutions to generate a specific osmotic pressure.

Osmosis refers to the unidirectional movement of a solvent (primarily water in biology) through a semipermeable membrane (permeable to the solvent but not to the solute) from a region of lower solute concentration to a region of higher solute concentration.

The driving force of osmosis is the system's tendency toward thermodynamic equilibrium. This manifests as osmotic pressure, which is the hydrostatic pressure that must be applied to a solution to halt osmosis.

The osmotic pressure of a solution depends on the number of osmotically active particles (ions or undissociated molecules) contained in a given volume of solution. The concentration of particles per 1 L of solvent is termed osmolarity, while per 1 kg of solvent it is termed osmolality. Since biological fluids consist of more than 90% water, the difference between these two concepts is negligible and usually ignored; thus, the term osmolarity is commonly used and expressed in mOsm/L, which corresponds to the osmolarity of a solution with a concentration of 1 mmol/L.

Consequently, while the osmolarity of a 1 mmol/L glucose solution (180.2 mg/L) is 1 mOsm/L, the osmolarity of a 1 mmol/L NaCl solution (58.5 mg/L) is 2 mOsm/L. This is because 1 mmol of glucose, which does not dissociate in water, yields half as many particles in solution as 1 mmol of NaCl, each molecule of which dissociates into 2 particles: Na⁺ and Cl^-.

Plasma osmolarity is generated by Na⁺ (140 mOsm), Cl^- (100 mOsm), glucose (5.5 mOsm), urea (17.5 mOsm), and several other particles, totaling 285-310 mOsm/L.

The formula for calculating osmolarity is as follows:

Calculated osmolarity (mOsm/L) = Na (mmol/L) ∙ 1.86 +

+ glucose (mmol/L) + urea (mmol/L) + 5.

It follows that the primary determinant of plasma osmolarity is the concentration of Na⁺.

True osmolarity is determined via osmometry, for instance, by measuring the freezing point of the solution.

The difference between true and calculated osmolarity indicates the presence of unidentified solutes, such as toxins, which is particularly useful when determining indications for extracorporeal blood purification.

The osmolarity of the intracellular and extracellular environments must remain equal, despite differences in their chemical composition.

A decrease in plasma osmolarity may result from hyponatremia. Hyperosmolarity can be observed in hypernatremia, hyperglycemia, uremia, elevated concentrations of other solutes, or a combination of various factors.

The osmotic pressure exerted by substances that cannot permeate the semipermeable membrane is called effective osmotic pressure. For example, it is generated by plasma sodium ions, which are prevented from entering The Cell due to the action of the "sodium pump." Conversely, urea, which permeates the membrane relatively easily, cannot generate effective plasma osmotic pressure at normal concentrations. Protein molecules are larger and barely permeable to the membrane; therefore, despite their low osmolarity (only about 1.6 mOsm/L in plasma, or just 0.55% of total plasma osmolarity), they are capable of exerting significant effective osmotic pressure, known as colloid-osmotic (oncotic) pressure. The major portion of this pressure (85%) is provided by albumin. Its deficiency plays a major role in fluid shifts from the vascular bed, leading to reduced circulating blood volume (CBV) and hypoproteinemic edema. Significant colloid-osmotic pressure is also generated by polyglucukin (1 g of which can retain 14 mL of water within the vascular bed), gelatin preparations (gelatinol, gelofusine), and hydroxyethyl starch solutions (reforman, stabizol).

Acid-Base Balance

Acid-base balance is a striking example of Structure/19.html">The Importance of internal environment constancy. To ensure normal physiological function, fluctuations in this homeostasis component are permitted within very narrow limits. The reaction of body fluids is determined by the concentration of hydrogen ions (H⁺), which, given its extremely low values in biological systems, is conventionally expressed as the negative decimal logarithm of its concentration in millimoles per liter (e.g., if [H⁺] = 10^-7 mmol/L, then pH = -lg 10^-7 = 7.0).

Acids (compounds capable of donating H⁺) and bases (compounds capable of accepting H⁺) are continuously produced within the body. They tend to shift the acid-base balance outside the narrow limits compatible with life (6.8–7.8), and even outside the stricter limits required for normal physiological function (7.35–7.45). These values fluctuate around a pH of 7.4, which is considered neutral in biological systems. Metabolic acids (0.13 mmol/kg of body weight per day of volatile carbonic acid and 3080 mmol/kg of non-volatile acids) must be eliminated from the body by the lungs and kidneys, keeping pH within permissible limits thanks to buffer bases.

The regulatory mechanism governing the pH of biological fluids is complex and largely unknown in many aspects. Its primary, well-established components are buffer systems.

A buffer is a mixture of a weak acid and its salt (which acts as a weak base), capable of neutralizing («buffering») pH changes.

The first line of defense neutralizing acidic and alkaline products in the extracellular environment, particularly in blood plasma, is the bicarbonate system—a mixture of

where B is a monovalent cation (most commonly Na⁺, occasionally K⁺).

The MECHANISM OF ACTION of all four human body buffer systems is clearly illustrated by the bicarbonate system.

When a strong acid ("aggressor") enters the environment, it reacts with the weak base:

HCl + NaHCO₃ = H₂CO₃ + NaCl       (1)

This results in The formation of a new weak acid (which replenishes the buffer system) and a neutral salt, both of which have minimal impact on the pH of the medium.

When a strong base ("aggressor") enters the environment, it reacts with the weak acid:

NaOH + H₂CO₃ = NaHCO₃ + H₂O       (2)

This produces a weak base (a component of the buffer system) and water, both of which have little effect on the pH of the medium.

Through such reactions, the buffer system can restrain changes in pH, provided that the quantity of its components exceeds that of the aggressor. Consequently, a buffer has a quantitative characteristic known as buffer capacity.

The duration of the aggressor's action is also significant. For example, the interaction between the buffer and an acid aggressor yields a weak acid, such as H₂CO₃, the greater part of which breaks down into H₂O and CO₂, while a smaller portion dissociates into H⁺ and HCO₃^-. Under prolonged exposure to the aggressor, H⁺ ions accumulate and, once they exceed permissible levels, trigger a sharp drop in pH.

Other buffers function in a similar manner:

Phosphate buffer which operates in the intracellular environment and in urine buffering;

protein buffers, where proteins, acting as amphoteric substances, can exhibit both acidic and basic properties;

Each of these specified buffers acting at the whole-blood level (1/5 of all body buffer systems) has its own capacity: hemoglobin buffer — 35%, plasma bicarbonate buffer — 35%, erythrocyte bicarbonate buffer — 18%, plasma protein buffer — 7%, organic phosphate buffer — 3%, and inorganic phosphate buffer — 3%.

The physiological systems involved in The regulation of acid-base balance (ABB) include the lungs, kidneys, liver, and gastrointestinal tract.

The lungs rapidly and efficiently regulate pH by eliminating volatile CO₂ through changes in ventilation patterns. CO₂ is eliminated not only in a plasma-dissolved state due to the p_CO2 gradient, but also bound to hemoglobin (20%) via the action of erythrocyte Carbonic anhydrase:

70% of CO₂ is transported by the blood as NaHCO₃:

10% of CO₂ is transported in a free state.

In the kidneys, the phosphate buffer is the primary buffer system. Under The Influence of intrinsic carbonic anhydrase, the following reaction occurs within the tubular epithelium:

When the phosphate buffer capacity is depleted, H⁺ excretion and HCO₃^- reabsorption occur through ammoniagenesis. In tubular cells, NH₃ production begins via the deamination of Certain Amino Acids, notably glutamic acid. Easily diffusing from the cells into the urine, ammonia combines with H⁺ to form ammonium ions (NH₄⁺), which then associate with NaCl and are excreted in the urine as NH₄Cl. Na⁺ ions are dissociated from Cl^-, enter the cell, and form NaHCO₃, which is returned to the bloodstream.

When There is a deficiency of CO₂ in the blood and a decrease in p_CO2, the CO₂ + H₂O reaction in renal tubular cells is inhibited, bicarbonate reabsorption decreases, and it is excreted in the urine. This lowers the plasma NaHCO₃ concentration, compensating for the alkaline shift in pH.

The liver utilizes several mechanisms to regulate ABB. An excess of acidic metabolites (such as lactic and pyruvic acids) in the blood passing through the liver undergoes oxidation to end products H₂O and CO₂, preventing an acidic shift in pH. Excess nitrogenous wastes (ammonia, ammonium chloride, uric acid) are converted in the liver into neutral urea, which also prevents pH shifts. A portion of excessive acidic or alkaline metabolic products is eliminated by the liver into the intestines via Bile.

The gastrointestinal tract also participates in ABB regulation by excreting acid or alkaline radicals, as well as through its role in water and electrolyte homeostasis, with which ABB is closely interconnected—although this indirect action is considerably slower than rapid-acting buffer systems.

To evaluate ABB, measuring pH alone is clearly insufficient, as it is merely the tip of the iceberg, the underwater portion of which consists of the physicochemical and physiological systems regulating hydrogen ion concentration constancy. Primary attention is given to the Blood Buffer Systems—bicarbonate and hemoglobin—because their capacity accounts for about 70% of the total blood buffering system, and also because blood is the most accessible medium for study.

The quantitative assessment of buffer systems is based on the Henderson-Hasselbalch equation, which expresses the dependence of pH on the ratio between buffer system components and, for the bicarbonate buffer, has the following form:

where K is the dissociation constant of carbonic acid in water. It follows that an increase in carbonic acid concentration or a decrease in blood bicarbonate concentration will decrease the ratio and, conversely, a decrease in carbonic acid concentration or an increase in blood bicarbonate concentration will increase the ratio , leading to an elevated pH.

In practice, ABB is determined using Astrup's method (measuring blood pH before and after equilibration with an O₂ and CO₂ gas mixture), Severinghaus's method (direct determination of blood CO₂ using a specialized electrode), or a method based on the simultaneous use of specialized electrodes to determine p_O2 and p_CO2. Regardless of the method, all analyses are calculated using the Siggaard-Andersen nomogram; however, in modern blood gas analyzers, manual calculation using nomograms has been replaced by computerized Processing with digital readouts. Furthermore, modern laboratory equipment often

supplements ABB indicators with data on the concentrations of the most crucial ions, hemoglobin, and its fractions (oxyhemoglobin, carboxyhemoglobin, methemoglobin). For example, the ABL System 620 provides 13 measured parameters and 39 derived parameters. Such parameters offer a comprehensive view of the state not only of ABB but also of other homeostatic elements. In this process, up to 39 blood samples can be analyzed per hour, taking only a few tens of seconds per measurement.

To assess ABB, it is necessary to have at least three indicators: pH (normal range 7.4 with an acceptable variation of 7.35–7.45), p_CO2 (partial pressure of carbon dioxide in the blood; normal range is 40 mmHg with a variation of 35–45 mmHg, which indicates the presence and severity of respiratory ABB disorders), and BE (base excess — the shift in buffer bases; ideally 0, indicating no shifts, but more frequently expressed as a positive or negative value denoting an excess or deficit of buffer bases, respectively; it indicates the millimoles of base that must be added or removed per liter of blood to restore a normal pH at p_CO2 = 40 mmHg; normal range is (0±2.5) mmol/L, reflecting the presence and severity of metabolic ABB disorders).

Forms of ABB shifts in their "pure" form and possible combinations are presented below.

Metabolic acidosis — BE < - 2.5 mmol/L.

This is the most frequently encountered form. It essentially involves the accumulation of under-oxidized non-volatile metabolic products in the body. Potential causes of its development include:

— severe Circulatory Disorders (blood loss, shock, cardiovascular failure, terminal states, regional tissue ischemia) accompanied by the accumulation of Anaerobic Metabolism products (lactic, pyruvic, and other organic acids via anaerobic Glycolysis);

— severe Diabetes Mellitus with accelerated production and accumulation of ketoacids;

— acute poisonings with barbiturates, salicylates, Ethylene glycol, ethyl and methyl alcohols, acetic acid, etc.;

— intestinal and biliary fistulas accompanied by the loss of alkaline digestive juices;

— Kidney damage complicated by acute and chronic renal failure.

Metabolic acidosis can be compensated for by compensatory hyperventilation (enhanced elimination of CO₂). This maintains a normal pH level while reducing p_CO2 below normal values. Such an acid-base balance shift can be defined as primary compensated metabolic acidosis with compensatory respiratory alkalosis. The kidneys (unless they are the underlying cause of the metabolic acidosis) participate in compensation by excreting increased amounts of non-volatile acids and retaining bicarbonates.

Compensated metabolic acidosis may be asymptomatic. Uncompensated acidosis, indicated by a laboratory pH value below 7.35, is accompanied by hyperventilation (e.g., Kussmaul breathing in uremia) with respiratory depression proportional to the worsening of the patient's condition, progressive circulatory failure, and impaired consciousness ranging to coma. This acid-base disorder is combined with water-electrolyte balance disturbances. Metabolic acidosis is characterized by a decrease in plasma HCO₃^- levels, alongside an increase in Cl^- and K⁺, which shift from the cells into the plasma in exchange for entering H⁺ and Na⁺ ions (at a ratio of 3 K⁺ = 1 H⁺ and 2 Na⁺). Intact kidneys actively excrete K⁺, potentially leading to total-body potassium depletion.

Correction largely depends on the underlying causes of metabolic acidosis. Once normal Circulation is restored, hypovolemia, anemia, and protein deficits are corrected, tissue perfusion is re-established, and all forms of hypoxia are resolved, the conditions driving the accumulation of under-oxidized metabolic products disappear, and metabolic acidosis resolves spontaneously without additional interventions. Only in cases of advanced, severe decompensation—such as clinical resuscitation states—is circulatory restoration supplemented by additional measures, namely the administration of alkalinizing solutions (sodium bicarbonate, trisamin) in corrective dosages. Dosages are calculated using the following formulas:

Volume (mL) of 4% Na₂HCO₃ solution = BE ∙ body weight (kg) ∙ 0.3 ∙ 2.7;

Volume (mL) of 3.66% trisamin solution = BE ∙ body weight (kg).

In diabetes mellitus and intestinal or biliary fistulas, the infusion of alkalinizing solutions is a key component of management. In renal failure, along with these conservative measures, metabolic acidosis and the accompanying hyperkalemia serve as direct indications for emergency hemodialysis.

Respiratory acidosis — p_CO2 > 45 mmHg.

Respiratory acidosis is considered synonymous with hypoventilation, as its primary cause is alveolar hypoventilation resulting from various pathologies causing respiratory failure, as well as inappropriate ventilator settings during mechanical ventilation. Additionally, it may be triggered by pulmonary arteriovenous shunting in shock, acute respiratory distress syndrome, widespread Atelectasis, and Pneumonia.

The Clinical presentation of respiratory acidosis is characterized by signs of hypercapnia (anxiety, elevated blood pressure, followed later by arterial hypotension, progressive tachycardia, and arrhythmias), with or without accompanying hypoxia if mechanical ventilation with a high oxygen fraction is used. In later stages, a compensatory increase in BE is observed, reflecting renal conservation and accumulation of bicarbonate. This mechanism may not always sustain a stable pH, and its decline leads to decompensated acidosis.

The cornerstone of treating respiratory acidosis is the improvement of pulmonary ventilation.

Metabolic alkalosis — BE > +2.5 mmol/L.

Potential causes include excessive loss or inadequate intake amidst baseline potassium and chloride depletion, excessive administration of alkaline solutions during mistimed correction of acidosis, massive transfusion of sodium citrate-containing banked blood, primary or secondary aldosteronism, or aggressive diuretic therapy.

The Pathophysiology of metabolic alkalosis in critically ill patients can be highly complex. Specifically, in hypokalemia, the complexity arises because the increase in extracellular alkalinity is restricted to the extracellular fluid, whereas the intracellular compartment—where H⁺ ions shift in place of K⁺—becomes acidic.

The body's compensatory capacity for metabolic alkalosis is quite limited. Reduced ventilation with CO₂ retention contributes little to normalizing metabolic shifts, and enhanced renal bicarbonate excretion has a minimal effect on the intracellular environment. Metabolic alkalosis is much easier to prevent than to correct.

Prevention involves the administration of adequate amounts of K⁺ and Cl^- alongside mechanisms that promote cellular K⁺ uptake (hypertonic glucose solutions with insulin, sodium hydroxybutyrate), as well as careful calculation of alkalinizing agent dosages when correcting metabolic acidosis. Management of metabolic alkalosis primarily relies on correcting water-electrolyte imbalances (hypokalemia, hypochloremia, hypocalcemia, and dehydration, and less frequently, hyponatremia).

Respiratory alkalosis — P_CO2 < 35 mmHg.

Respiratory alkalosis is synonymous with hyperventilation. Its main cause is excessive CO₂ elimination driven by hyperventilation. To compensate, bicarbonate concentration decreases, as indicated by a negative shift in BE. While pH may remain normal, decompensation shifts it toward a compensatory metabolic acidosis.

The causes of hyperventilation are diverse: agitation, fever, central nervous system disorders, conditions associated with hemodynamic instability, tissue hypoxia, the onset of metabolic acidosis, or inappropriate mechanical ventilation settings.

Moderate respiratory alkalosis is asymptomatic. Severe forms lead to vasoconstriction, particularly in cerebral vessels. Tissue hypoxia ensues, lactate production increases, and hypocalcemia develops, accompanied by tetany and seizures, alongside hypokalemia and Cardiac Arrhythmias.

The management of respiratory alkalosis essentially focuses on optimizing pulmonary ventilation.

Hemostasis

Hemostasis is a vital manifestation of homeostasis, essential for normal physiological function and adaptive bodily responses. It is maintained through the close interaction of the coagulation, anticoagulant, fibrinolytic, and kinin systems.

The hemostatic system not only maintains blood fluidity within vessels and halts bleeding upon injury, but also influences blood rheology, microcirculation, vascular permeability, wound healing processes, and immunological reactions. This multicomponent system comprises the blood, vascular walls, and Organs involved in the Synthesis and degradation of clotting factors (Fig. 15).

The cessation of bleeding from a damaged vessel is viewed as a protective response of the organism.

Under normal conditions, the inner lining of Blood Vessels and the formed elements of blood carry a negative charge. Consequently, erythrocytes, leukocytes, and platelets repel one another and the vascular walls, preventing adhesion. Thus, intravascular thrombosis is prevented by the so-called Z-potential located on the inner lining of blood vessels.

Fig. 15. Diagram of hemostasis

If the integrity of the inner lining is compromised, a positive charge develops at the site of injury. Formed elements are thereby attracted to the affected area, forming a hemostatic plug while restoring the negative charge and the integrity of the vessel wall.

Platelets are the first to arrive at the site of the "defect." Along with the plasma Components of the hemostatic system, they maintain vascular wall resistance by depositing platelets, their fragments, and fibrin at sites of endothelial damage. Daily, about 15% of circulating platelets are consumed in angiotrophic function. They link the platelet-vascular and coagulation mechanisms of hemostasis, serving as the core for thrombus formation.

Within 1–3 seconds of vascular injury, platelets adhere to damaged endothelial cells, Collagen, and the basement membrane. As millions of platelets aggregate, they disintegrate and release ADP, serotonin, adrenaline, prostaglandin metabolites (thromboxane A₂), and their own clotting factors, which render the aggregation irreversible.

Simultaneously, the vascular component of hemostasis is activated. This component depends on the state of the Cytology/cytology/32.html">Smooth Muscle tissue and connective tissue apparatus of the arteriolar and venular walls, as well as on capillary permeability. Upon disruption of the vascular wall integrity, the affected vessel reflexively constricts, reducing blood inflow and capillary permeability.

Thus, the platelet-vascular phase of hemostasis is maintained by physiological (platelets, regulation of vascular tone and permeability) and biophysical (Z-potential) mechanisms.

At this point, the second phase of hemostasis begins—blood coagulation and the formation of a plasma clot—which lasts 1–2 milliseconds. Over this brief span, three sequential processes occur: the generation of thromboplastin, Thrombin, and fibrin.

All substances that participate in this process or create the conditions for its realization are termed blood clotting factors. They are divided into two main groups: plasma and platelet factors.

Clot formation can proceed via closely linked extrinsic and intrinsic coagulation systems.

Upon tissue injury, crushed cells release large amounts of tissue thromboplastin, which facilitates the "repair" of damaged cells and membranes. Owren termed this the extrinsic system, whereas plasma clotting initiated by the formation of plasma thromboplastin was designated the intrinsic coagulation system. Active thromboplastin is the product of both coagulation systems.

Initially, factor XII (Hageman factor or contact factor) is activated and interacts with factor XI (plasma thromboplastin antecedent), which subsequently recruits factors IX (Christmas factor or antihemophilic globulin B) and III (retractozyme, which draws wound edges together) of the intrinsic coagulation system.

The extrinsic system provides factor VII (proconvertin or stable factor), which generates tissue thromboplastin.

Factors X (Stuart factor) and V (proaccelerin or labile factor, A_c-globulin) are present in both blood plasma and Tissues.

In addition to these factors, cephalin and platelet Phospholipids participate in thromboplastin formation, while Ca⁺⁺ acts as a catalyst for most of the reactions.

In the next stage, prothrombin (factor II) is formed from thromboplastin and is converted into thrombin under the influence of prothrombinase.

Fibrin formation occurs in three stages. First, under the action of thrombin, fibrinogen A yields fibrin monomers (liquid fibrin, fibrinogen B). Next, these monomers polymerize into soluble fibrin (fibrin S). Under the influence of factor XIII (fibrinase or fibrin-stabilizing factor), this fibrin becomes insoluble (fibrin I).

The process of clot Organization does not end here. The action of platelet factors leads to clot retraction (compaction and contraction) followed by its lysis.

Simultaneously with the activation of factor XII, The system of natural coagulation inhibitors is engaged. They neutralize the action of thrombin and other coagulation factors. The anticoagulant system consists of five factors—antithrombins—that block thrombin activity.

The most potent antithrombin is fibrinogen, which adsorbs thrombin and prevents the spread of thrombosis. Heparin and its cofactor are equally active antithrombins; they inhibit thromboplastin formation and the conversion of fibrinogen to fibrin by destroying factor X, while also indirectly activating Fibrinolysis. The third antithrombin destroys plasma thrombin, and the fourth accelerates the action of the third. Additionally, a group of inhibitors exists that degrades factors V, VII, IX, and XIII.

Besides antithrombins, the physiological anticoagulant system includes tissue and plasma antithromboplastins and antifibrinogens, whose mechanisms and sites of action remain insufficiently studied.

The anticoagulant system is activated when an excessive amount of thrombin appears in the blood. In response, mast cells release heparin into the bloodstream, which forms complexes with fibrinogen and other Plasma Proteins. These complexes exhibit anticoagulant and fibrinolytic properties. However, this system alone is sometimes insufficient to lyse the formed clot, at which point an additional protective system—the fibrinolytic system—is engaged.

Its main active agent is plasmin. In the blood, it exists as an inactive precursor, plasminogen. The conversion of plasminogen to plasmin is driven by activators of tissue and plasma origin (produced by the intestines, the adventitial layer of Arteries and veins, and the vascular wall, respectively), urokinase synthesized by kidney tissue, Trypsin, factor VII, streptokinase, and certain pharmacological agents.

In addition to plasminogen activators, its inhibitors have also been identified to date: rapid-acting macroglobulins and alpha-1 antitrypsin, which reacts with plasmin slowly and irreversibly (it also inhibits trypsin, thrombin, and urokinase).

Fibrinolysis is the process of fibrin degradation into peptones, which are excreted in the urine. It promotes free and unobstructed blood flow, maintains normal blood viscosity, and restores patency in thrombosed vessels.

Products of Fibrinogen and fibrin degradation (FDP)—X, A, B, C, I, D, and E—play a significant role in the course of fibrinolysis. They inhibit thrombin activity and disrupt fibrin formation. The entire fibrinolysis process is activated by blood coagulation factor XII. It is factor XII that activates plasminogen, converting it into plasmin. Furthermore, factor XII serves as the link connecting all these systems with the kallikrein-kinin system.

The latter represents a group of Enzymes resembling the BLOOD COAGULATION SYSTEM. The total number of its constituent factors is unknown. These substances are synthesized in the blood or tissues from inactive precursors under the influence of specific enzymes and act similarly to local or tissue hormones.

Activation of blood coagulation leads to an increased concentration of kinins. Both systems are involved in the Pathogenesis of aseptic and allergic inflammatory responses in the body.

In addition to kinins associated with the blood coagulation and fibrinolytic systems, Prostaglandins take part in vascular reactions during thrombosis. Prostaglandin E₁ (prostacyclin), which inhibits platelet aggregation, has a direct effect on thrombosis.

Consequently, the close interconnection among all these systems in clinical practice significantly complicates the Diagnosis of bleeding disorders. The objectives of clinical research are to identify the causes of bleeding; diagnose thrombosis or a pre-thrombotic state; monitor anti- or procoagulant therapy; and determine the functional state of the body.

Bleeding may occur as a result of a deficiency in any factor of the blood coagulation system. Hemorrhagic tendencies also arise with the appearance of abnormal clotting factors in the blood, such as prothrombin "Barcelona" or fibrinogen "Baltimore", "St. Louis", etc.

Hemorrhagic diathesis caused by abnormal factors XII and XIII has been described.

To diagnose hemostatic disorders, a combination of in vitro blood test methods and thrombelastography is proposed.

To clarify the causes of bleeding, it is sufficient to determine: the total blood clotting time; recalcification time; prothrombin; prothrombin time; plasma heparin tolerance; free heparin; fibrinogen; fibrinase; and fibrinolysis time.

The laboratory profile of the vascular and platelet phases of primary hemostasis can be obtained by determining the blood clotting time, platelet count, and thrombelastogram.

The first phase of blood coagulation is characterized by:

— recalcification time;

— plasma heparin tolerance;

— thrombelastogram parameters.

The second phase of blood coagulation is characterized by:

— prothrombin index;

— levels of proaccelerin (factor V), proconvertin (factor VII), and factor X.

The third phase of blood coagulation is characterized by:

— thrombin time;

— levels of free heparin and fibrinogen.

Fibrinolysis is characterized by:

— spontaneous fibrinolysis time;

— euglobulin lysis time;

— level of fibrinogen degradation products.

Identifying thrombosis and pre-thrombosis presents the greatest challenge.

The state of the blood coagulation system is closely linked to emergency care for hemorrhage and thrombosis, which is based on the following intensive care principles:

— restoration of circulating blood volume (CBV);

— prevention or treatment of coagulopathy;

— metabolic correction;

— prevention or treatment of organ dysfunction;

— prevention or treatment of septic complications.

Most of these measures are addressed in chapters covering shock and related conditions. In this chapter, it is appropriate to examine in greater detail The problem of coagulopathies, which frequently accompany critical conditions or may occasionally trigger them. Among coagulopathies, thrombohemorrhagic syndrome (THS) is the most common—a distinct syndrome combining such opposing phenomena as thrombosis and hemorrhagic diathesis.

There are three stages of THS:

Stage I — hypercoagulation. Most authors equate it with disseminated intravascular coagulation (DIC) resulting from the increased consumption of platelets and clotting factors. It varies in duration and is characterized by progressive blood hypercoagulation combined with stasis resulting from the release of thromboplastin into the vascular bed, activation of contact factors, acidosis, and other factors. Stasis may result from heart failure, hypovolemia, neurogenic vasoplegia, or a mechanical obstruction (thrombus, vessel compression).

Stage II — hypocoagulation or consumption coagulopathy. It develops as a result of the depletion of platelets and clotting factors during Phase I and manifests as a hemorrhagic syndrome. Bleeding is exacerbated by the split products of fibrinogen, fibrin, and other plasma proteins generated during blood coagulation, which possess anticoagulant properties and are capable of damaging the vascular wall and microcirculatory system.

Typically, hemorrhages occur in the skin, Muscles, mucous membranes, Internal Organs, and cavities. Bleeding intensity increases rapidly even when CBV deficits are corrected with plasma substitute solutions (due to the dilution-induced decrease in clotting factor concentrations). Bleeding is further aggravated by concurrent hypoxia and intoxication, which disrupt vascular membranes, parietal hemostasis, and coagulation.

Stage III — activation of fibrinolysis coupled with coagulopathy. This intensifies bleeding to a catastrophic degree. In effect, it represents a total failure of the blood coagulation system.

In some cases, the primary cause of DIC is a disruption of central and peripheral hemodynamics (shock). The triggering mechanism is slowed blood flow or stasis in the microcirculation. Fibrin deposited in the microvasculature activates the fibrinolytic system. Plasminogen is transformed into plasmin, which then lyses fibrin, recanalizing the capillaries. However, against the background of a general deficiency of clotting factors, this leads to increased bleeding, the intensity of which depends on the degree of fibrinolytic activity.

Clinical practice encounters Two Types of THS:

— anticipated (caused by prior pathology—coagulopathy resulting from congenital or acquired deficiencies of various clotting factors);

— unanticipated (resulting from liver, kidney, pancreatic, or skin diseases, as well as drug-induced coagulopathies).

Clinical manifestations of THS:

— symptoms of cerebrovascular disorders;

— cardiovascular failure;

— pulmonary edema, symptoms of pneumonia, and pulmonary microthromboembolism.

— gastrointestinal bleeding;

— pancreatitis:

— hepatitis (bilirubinemia);

— renal cortical necrosis;

— myositis;

— bleeding from skin ulcers and erosions;

— decreased tissue perfusion (elevated lactatemia).

Laboratory signs of THS:

— prolonged bleeding time;

— decreased platelet count;

— reduced fibrin content;

— decreased prothrombin index and prolonged prothrombin time;

— elevated levels of fibrin degradation products.

Intensive care for THS involves eliminating underlying causes (treating pain, hypoxia, and acidosis) and applying specific measures tailored to the particular stage of THS. These measures vary widely and depend on the intensity of intravascular coagulation activation, the degree of microcirculatory impairment, the severity of organ damage, and functional failure of the brain, lungs, liver, and kidneys. In stage II, intensive care is determined by the volume and rate of blood loss and hemorrhages into vital organs.

To correctly assess clinical symptoms and select appropriate treatment methods, it is essential to remember that intravascular blood coagulation and intravascular thrombosis are not synonymous. They reflect different states of the blood within the vascular bed. Even massive intravascular coagulation does not always lead to thrombosis. Intravascular coagulation is reversible, and its timely recognition can prevent thrombus formation in vessels and subsequent parenchymal damage in the perfused organ. Observations have shown that intravascular clots lyse spontaneously in most cases.

The diagnostic complexity of THS is largely due to the high Variability in the duration of its stages. For instance, the duration of stage I in various patients is inversely proportional to the degree of activation of the coagulation system and the intensity of the intravascular coagulation process. The main Clinical symptoms of stage I THS are ischemic lesions of vital organs: thrombosis and thromboembolism of the Arterial System of the brain, lungs, heart, kidneys, Spleen, and adrenal glands, as well as Thrombosis of the VEINS OF THE lower extremities, pelvis, INFERIOR VENA CAVA, and portal vein.

Clear neurological symptoms allow for a correct diagnosis in almost 100% of cases involving impaired renal blood flow. At the same time, thromboembolism in other vascular beds is clinically diagnosed in only 30% of patients (Pulmonary Embolism), and deep vein thrombosis of the lower extremities in 50%.

Massive pulmonary embolism clinically manifests as acute Cor Pulmonale and shock. In subacute and chronic courses affecting smaller Branches of the pulmonary artery, the most consistent symptoms are paroxysmal dyspnea, tachycardia, cyanosis during attacks, and arterial hypotension. When embolism is accompanied by pulmonary infarction, chest pain and hemoptysis join the aforementioned signs.

Instrumental methods are of great diagnostic help: ECG, chest radiography, radionuclide lung scanning, pulmonary artery catheterization, and selective angiography.

Clinical symptoms of acute portal vein thrombosis are obscured due to low Specificity (severe widespread abdominal pain, frequent gastrointestinal bleeding, shock). The chronic form is characterized by ascites, Splenomegaly, dilated collateral anastomoses, and Liver failure.

Thrombosis of the inferior vena cava often presents with abdominal and lumbar pain, acute hepatosplenomegaly, ascites, jaundice, and liver failure.

In stages II and III of THS, both thrombosis and various hemorrhages (gastric, intestinal, nasal, renal, pulmonary) can be observed, along with bleeding across all areas of affected skin and injection sites. Typically, bleeding that initially starts in one specific area becomes generalized, and the blood either fails to clot completely for many hours or forms inadequate clots. This period is characterized by the presence of "shock lung" (high shunt fraction, interstitial edema, impaired gas diffusion across the alveolar-capillary membrane) and "Shock Kidney".

A diagnosis of THS is reliably established if hemorrhagic manifestations are accompanied by a drop in platelet count to 90 ∙ 10⁹/L, fibrinogen to 1 g/L or less, and a prothrombin index below 45%. Simultaneously, levels of factors V, VIII, IX, and XIII decrease. Determining antithrombin III levels is of great diagnostic importance in THS, as it accounts for about 10% of the total anticoagulant potential of blood plasma. Furthermore, the serum of such patients shows elevated levels of fibrin degradation products with secondary enhancement of fibrinolysis, which further exacerbates fibrinogenolysis and the depletion of other clotting factors.

The diverse clinical manifestations of THS and the challenges in determining its stages completely rule out a one-size-fits-all treatment approach. Heparinization remains the traditional method for halting intravascular coagulation to this day. Anticoagulant therapy for THS is recommended to begin with the intradermal administration of small doses of heparin (2500–5000 IU) under the control of fibrinogen and its degradation products, antithrombin III levels, and other laboratory components of the blood coagulation system.

With a properly adjusted dose, hemorrhagic manifestations should disappear or significantly decrease. If no response is observed within the first 2-3 hours after administration, the patient should be switched to moderate doses (5000–10,000 IU). Thus, an individual effective dose must be selected for each patient. Heparin is neutralized using protamine.

Recently, for the prevention of THS development when its threat arises, it has been recommended to use low-molecular-weight heparin fractions (such as fraxiparine, clexane, etc.), which have significant advantages over unfractionated heparin. The low-molecular-weight heparin fraction prevents thrombus formation without impairing blood clotting; therefore, it does not require monitoring of coagulation parameters to avoid the onset or worsening of bleeding.

To improve microcirculation and reduce intravascular fibrin deposition, intravenous administration of rheopolyglucin or rheomacrodex is advisable.

The positive effect of heparin at any stage of THS may be diminished by concomitant acidosis and a decrease in plasma antithrombin III levels. Therefore, it is necessary to rigorously correct metabolic acidosis and combine heparin therapy with 1-2 doses of fresh frozen plasma containing 200-250% of the average normal antithrombin III level. Fresh native plasma transfusion is also an option.

The Introduction of natural fibrinolysis activators—streptokinase, streptodecase, urokinase, and alteplase—into clinical practice has expanded The Scope of thrombolytic therapy in stage I THS.

The Use of aminocaproic acid in the first two stages of THS can lead to a catastrophic increase in intravascular thrombus formation. Such therapy is acceptable only in cases of pronounced fibrinolysis. Aminocaproic acid is administered intravenously and slowly at a dose of 5 g, followed by 2 g every 1-2 hours throughout the day until bleeding stops. Rapid administration may cause hypotension, diffuse intravascular thrombosis, hypokalemia, and severe cardiac arrhythmias. Therefore, it is preferable to use broad-spectrum antiproteases (Trasylol, Contrical at 80,000–100,000 IU intravenously several times a day). The advantage of antiproteases over aminocaproic acid is that they inhibit not only fibrinolysis but also blood coagulation.

In cases of profuse fibrinolytic bleeding, replacement transfusions of fresh heparinized donor blood and platelet concentrate infusions are recommended.

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