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

Liver failure

Liver failure is a clinical condition in which the primary Functions of the liver are impaired or lost. Regardless of the underlying cause, the main manifestations of liver failure are similar because one or more of the liver's core functions are disrupted.

To better understand the Pathogenesis of liver failure, we provide Some data on liver Morphology and function.

The adult human liver weighs about 1.5 kg (2% of body weight). It consists of a large right lobe, a smaller left lobe, and two small lobes — the caudate and quadrate lobes.

Four types of elements are distinguished in the liver: hepatocytes (accounting for more than 60% of the liver's cellular composition), the reticuloendothelial system (up to 20%), Blood and Lymphatic vessels, and Bile ducts (about 20%).

The Main Functions of the liver are performed by hepatocytes, which possess characteristic cellular Organelles visible under Electron Cell/15.html">Microscopy for this purpose (Fig. 25).

A hepatocyte features a vascular pole, where substances are captured from the outside via microvilli and introduced into The Cell (endocytosis), and a biliary pole, where substances are released from the cell via microvilli (exocytosis). The cell membrane is adjacent to the sinusoid over 40–50% of its surface. The cytoplasmic membrane in this region highly actively and selectively transports substances from the blood into the hepatocyte and vice versa. About 30–40% of the cell surface is occupied by the area through which METABOLISM occurs between adjacent hepatocytes. Approximately 10% of the cell surface opens into the bile canaliculi.

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Fig. 25. Electron microscopic Structure of a hepatocyte:

RER — rough (granular) Endoplasmic reticulum;

SER — smooth endoplasmic reticulum

The Cytoplasm contains Mitochondria, the energy "factory" of the cell, where oxidation reactions take place to generate energy from CARBOHYDRATES and Fatty acids.

An important part of the cell is The endoplasmic reticulum (a cytoplasmic network delimiting a cavity of tubules and vesicles). It is connected by pores to the extracellular environment and, at the same time, to the Cell Nucleus. The portion of the reticulum whose walls incorporate Ribosomes is called the granular (rough) endoplasmic reticulum, while the rest is the smooth endoplasmic reticulum. While Proteins are synthesized in the granular endoplasmic reticulum with the help of ribosomes, the smooth endoplasmic reticulum performs detoxification via biotransformation and conjugation of foreign substances (medications, exotoxins) and metabolites (bilirubin, ammonia), thereby converting them from fat-soluble to Water-soluble, as well as synthesizing bile acids. It is also possible that the endoplasmic reticulum is responsible for The transport of various substances into, out of, and within the cell. In doing so, it interacts with the Golgi apparatus, which concentrates and packages the substances being transported. For instance, it forms carbohydrate-Protein Complexes in the form of Glycoproteins and glycosaminoglycans.

Lysosomes are membrane-bound vesicles rich in Hydrolases that break down large molecules of cellular and extracellular origin. Such breakdown occurs with Bacteria that penetrate the hepatocyte. Lysosomes are closely associated with the Golgi complex and participate in bile secretion. Sharp changes in environmental pH and damage to lysosomes can lead to the activation of hydrolases, particularly acid phosphatase, and to cell destruction. The Enzymes enter the vascular bed, where their activity increases sharply.

The cell nucleus contains genetic material in the form of DNA. The Nucleus also contains nucleoli, which harbor RNA that carries information to the cytoplasm, where new substances, such as enzymes, are synthesized in accordance with the received information. The cell nucleus is surrounded by a double membrane. The outer nuclear membrane has numerous pores that ensure the movement of substances between the nucleus and the protoplasm. Each cell is surrounded by a trilaminar cell membrane, the so-called basement membrane, which separates the intracellular environment from the extracellular one.

The anatomical unit of the liver is the hepatic hexagonal lobule (Fig. 26), formed by cords of hepatocytes radially arranged around the central vein (the Origin of the hepatic Veins) and separated by clefts called sinusoids.

Fig. 26. Hepatic lobule

Wedge-shaped periportal spaces (Fig. 27) are located between the hepatic lobules, containing Branches of the portal vein, hepatic artery, Lymphatic vessels, and small bile ducts.

The rate of hepatic blood flow is 100 ml/min per 100 g, which is 25% of Cardiac Output. The hepatic artery provides 25% of hepatic blood flow and 45–50% of oxygen, while the portal vein provides 75% of blood flow and 50–65% of oxygen, despite the fact that the portal vein has previously delivered some of its oxygen to the digestive Organs and Spleen. The pressure in the hepatic artery equals systemic arterial pressure, while in the portal vein it is 7–10 mmHg. Blood enters the sinusoids from the smallest branches of the v. porta and arterioles of the a. hepatica at a pressure of about 40 mmHg. Pre-sinusoidal (precapillary) sphincters regulate the alternating blood flow from the V. porta and a. hepatica, preventing excessive pressure fluctuations in the sinusoids. Possessing alpha-adrenergic receptors, The system of pre- and post-sinusoidal sphincters participates in the body's compensatory response to a decrease in cardiac output, such as during Shock. Thus, during Hemorrhage, the liver can release up to 500 ml of blood into the Circulatory system. Liver disease reduces sensitivity to catecholamines, thereby disrupting the central Circulation response. Prolonged hemorrhage can lead to necrobiotic changes in hepatocytes. Particularly sensitive to oxygen deprivation are the centers of the lobules, where Cells normally receive worse oxygen supply than at the periphery of the lobule.

Fig. 27. Periportal spaces

Optimal conditions for the exchange of gases, nutrients, and waste products between cells and mixed blood are created within the sinusoids. Sinusoids function similarly to capillaries in other PARTS OF THE body. From them, blood flows into the central veins (see Fig. 26). The sinusoids are lined with a very loose layer of endothelium; through numerous fenestrae (pores) smaller in diameter than formed blood elements, plasma easily passes from the sinusoids into the space between the endothelium and liver cells (Disse space) and bathes the hepatocytes. On the side facing the Disse space, the hepatocyte has numerous very narrow channels that ensure exchange between the cell and the Disse space. When necessary, they can dilate, increasing the intensity of exchange.

Kupffer stellate macrophages are located within the sinusoids, protecting hepatocytes from foreign particles entering the blood by engulfing and digesting blood clotting products, contrast agents, artificial colloids used for volume therapy, etc.

The apposing sides of adjacent hepatocytes form bile canaliculi in the middle, into which bile is secreted (see Fig. 25). Thus, the walls of the bile canaliculi are none other than the walls of the liver cells. They transition into bile ductules, which in turn connect with larger intrahepatic bile ducts. The right and left lobes have main ducts that together form the common duct — ductus hepaticus, which after merging with the ductus cysticus is called the choledochus. It empties into the duodenum at the papilla duodeni.

Carbohydrate Metabolism. Carbohydrates from digested food in the Small Intestine are absorbed mainly as glucose, fructose, and galactose and transported to the liver via portal blood. Galactose, which can be utilized only by the liver, and fructose are converted into glucose. The latter undergoes breakdown (Glycolysis) to generate energy or is polymerized into larger Glycogen molecules and stored in this form within liver cells.

Once the liver's limited capacity as a glycogen "depot" is fully utilized, excess carbohydrates are converted into fat and stored in various parts of the body.

When carbohydrate intake is insufficient, liver glycogen is broken down and released into the bloodstream (Glycogenolysis). If glycogen reserves are depleted, glucose can be synthesized in the liver, notably from lactic acid or Amino acids (Gluconeogenesis).

Protein metabolism. Plasma Proteins (albumin, α- and β-globulins) and blood clotting factors (fibrinogen, factors II, V, VII, IX, X) are synthesized in the smooth endoplasmic reticulum of hepatocytes. The breakdown of amino acids (primarily during protein putrefaction in the gut) produces ammonia. The liver converts this ammonia and carbon dioxide into urea.

Lipid Metabolism. The Liver and small intestine produce about 90% of the body's Cholesterol. In the liver, cholesterol serves as the precursor for the synthesis of bile acids, as well as a structural component for cell membranes and Hormones.

Dietary fatty acids absorbed in the intestine are broken down in the liver and either oxidized for energy or used to synthesize the body's own fatty acids, Steroids, and Phospholipids. The liver is also capable of synthesizing saturated and Unsaturated fatty acids, primarily from carbohydrates, amino acids, and other precursor Organic compounds.

Bile secretion. Hepatic cells secrete bile into the bile canaliculi at a pressure of up to 26 cm $H_2O$. If the pressure in the biliary tract exceeds 35 cm $H_2O$, bile secretion ceases.

Bile consists of 80–90% water and is isotonic with plasma, sharing the same pH. It contains bilirubin, bile acids, cholesterol, steroids, phospholipids, mucus, enzymes, hormones, and electrolytes. Approximately 700–1200 mL of bile is produced daily.

Bilirubin, which gives bile its characteristic color, is formed during the breakdown of Hemoglobin and heme-containing enzymes within the reticuloendothelial system, particularly the spleen (about 300 mg daily). This newly formed bilirubin is water-insoluble and must bind to serum albumin for transport. This water-insoluble form is also known as unconjugated or indirect bilirubin.

In the liver, enzymes within the smooth endoplasmic reticulum of hepatocytes attach two molecules of glucuronic acid to bilirubin, rendering it water-soluble, conjugated, and direct. In this form, it loses its potential to cause toxic damage to Brain cells and can be secreted from hepatocytes into the bile canaliculi, and subsequently through the biliary tract into the intestine. Here, it is broken down by intestinal bacteria into stercobilin (100–200 mg daily), which gives feces its color, as well as urobilin and urobilinogen. A smaller fraction of this pigment is reabsorbed and returned to the liver via the portal blood. A small amount of urobilinogen enters the systemic circulation and is excreted by the Kidneys.

Impaired liver excretory function is marked by elevated urobilin levels in the urine. The body contains about 4 g of fatty acids. Due to their strong surfactant properties, they can form structures known as micelles, arranging themselves with their hydrophilic (water-soluble) ends outward and hydrophobic (fat-soluble) ends inward. The fat-soluble substances trapped inside thus become water-soluble, transportable, and capable of being absorbed in the intestine. This mechanism allows the intestinal mucosa to absorb dietary components containing water-insoluble Lipids (dietary fats, cholesterol, Fat-soluble Vitamins, fat-soluble medications, and fat-soluble toxins). Thus, Fatty acids are a crucial prerequisite for the intestinal absorption of fat-soluble substances. A further requirement for this process is the presence of pancrealipase (a fat-splitting enzyme), which is activated by fatty acids.

Up to 99% of the fatty acids entering the intestine via bile are reabsorbed in the small intestine and returned to the liver. Out of this enterohepatic circulation, only about 1% of the daily secreted fatty acids reach the Large Intestine and are eliminated from the body. Consequently, only this small lost fraction of bile acids needs to be replenished daily. The higher the fat content of the diet, the more intensively and rapidly this enterohepatic circulation of fatty acids occurs.

Detoxification. Hepatocytes—specifically their smooth endoplasmic reticulum—contain numerous enzymes that, owing to their broad substrate Specificity, can neutralize A wide variety of foreign substances by converting them into complex, excretable structures. These enzymes can even detoxify compounds they have never previously encountered. Such substances include medications, certain food components, mushroom poisons, and the body's own toxic metabolites at certain concentrations (e.g., ammonia, phenol, indole and its derivatives, hormones, etc.). According to Brodie's hypothesis, these enzymes evolved gradually to convert fat-soluble foreign substances into their opposites, thereby increasing their water solubility and facilitating their elimination via the liver into the bile and via the kidneys into the urine.

Biotransformation in the liver occurs in two phases. The first phase involves preparing foreign substances for the subsequent conjugation process, for example, by introducing necessary molecular fragments into the xenobiotic molecule. This reaction leads to partial inactivation of the initial substance. The second phase completes the conjugation process (e.g., with glucuronic acid), making the metabolite water-soluble so that it can be directly excreted via bile or urine.

The Rate of Enzymatic biotransformation of foreign substances varies individually. The same medications are eliminated rapidly in some patients, while in others they are cleared much more slowly. In humans, many hepatic enzyme systems mature within a period ranging from a few days to a week after birth. This explains the high toxicity of many medications in early life.

The enzymatic activity of mature liver cells is regulated according to physiological demands (enzyme induction, which reflects a well-known adaptive mechanism). Today, more than 200 foreign substances are known to stimulate The production of hepatic enzymes involved in breaking down the respective xenobiotics. Phenobarbital serves as a classic example: administering this drug for several days stimulates the synthesis of a whole range of enzymes involved in its metabolism.

Liver failure is a syndrome resulting from hepatocyte damage that leads to the impairment of all liver functions and, ultimately, to hepatic coma. It is the most striking example of a situation where liver damage requires immediate emergency interventions.

The causes of liver failure are highly diverse, which accounts for The complexity of its pathogenesis and Clinical presentation. They can be conventionally divided into those that cause hepatic overload by

bilirubin (blood transfusions, hematomas, hemolysis), those that damage liver cells (Viral Hepatitis, cirrhosis, exacerbations of chronic hepatitis, Hypoxia, shock, drug-induced liver injury, hepatotoxic poisoning), and those that cause intrahepatic cholestasis (infection, drugs) or extrahepatic cholestasis (bile duct lesions, pancreatitis, cholelithiasis).

Based on the clinical course and the time of symptom onset, liver failure is classified into:

1) fulminant hepatic failure, in which the primary symptoms of liver insufficiency develop within less than 4 weeks;

2) acute liver failure, which develops in the course of various diseases over 1 to 6 months;

3) chronic liver failure, which is a consequence of acute and chronic diseases, develops over 6 months or more, and may exhibit a persistent character.

The most unfavorable outcome of liver failure is liver cirrhosis complicated by hepatic coma.

Fulminant hepatic necrosis is caused by a wide spectrum of injurious factors and is fatal in 75–90% of cases. The most frequent causes of fulminant hepatic failure are viral hepatitis, poisoning, and drug overdoses (particularly acetaminophen).

Primary acute liver failure may occur in a previously healthy individual (e.g., As a result of acute viral hepatitis or poisoning), as an acute exacerbation of a chronic liver disease (such as cirrhosis or chronic active hepatitis), or as part of multiple organ dysfunction syndrome in critical conditions of various etiologies.

The risk of developing liver failure due to hepatitis is negligible (less than 1%), yet viral hepatitis is becoming increasingly prevalent. At least 6 Viruses are known to cause severe hepatitis: types A, B, C, the delta agent, Epstein-Barr virus, and cytomegalovirus. Hepatitis B and C account for over 90% of viral hepatitis cases, while hepatitis A accounts for approximately 5%.

Life-threatening hepatic dysfunction is typically observed in debilitated and malnourished patients with limited compensatory reserves. This condition develops as a result of impaired nutrient delivery in congestive Heart Failure, shock, or hepatocellular injury caused by Sepsis.

Acute liver failure is invariably rooted in damage to cellular microstructures—namely, hepatocyte organelles. Consequently, the primary pathogenetic mechanisms driving the diverse clinical manifestations are impaired Protein Synthesis AND a progressive rise in blood levels of uncleared endogenous toxins. For instance, the primary cause of hemorrhagic syndrome is impaired synthesis of clotting factors II, V, VII, and X, which are produced exclusively by liver cells. Under normal hepatic function, the ammonium cation (NH₄⁺) generated during Protein Catabolism is detoxified in the liver by being converted into urea. In acute liver failure, the progressive accumulation of free ammonia in the blood leads to metabolic alkalosis and, consequently, to hypokalemia and hyponatremia. Furthermore, alkalosis significantly facilitates the penetration of ammonia across the blood-brain barrier. As ammonia levels rise in the blood and CEREBROSPINAL FLUID, metabolic processes in brain tissue adapt to minimize the toxic impact of ammonia. The energy level of metabolic processes decreases, oxygen demand drops, and there is an accumulation of incompletely oxidized glycolysis products, alongside increased production of glutamic acid, glutamine, and y-aminobutyric acid. These substances act as Neurotransmitters, mediating synaptic transmission. Therefore, in liver failure, the main mechanisms underlying neuropsychiatric disorders (ranging up to coma) include a pH shift toward alkalosis, electrolyte imbalances, reduced cerebral Energy Metabolism, and elevated production of neuroactive substances.

The prognosis of the disease depends on the extent to which the unaffected parenchyma can maintain the functions of the entire organ.

The clinical picture comprises manifestations of both hepatic and Central Nervous system (CNS) dysfunction. Irritability, confusion, and vomiting serve as early signs of CNS involvement. Characteristic Clinical Features include dyspeptic symptoms, progressive hemorrhagic syndrome (petechiae, epistaxis, gum bleeding), jaundice of the Skin and sclera, decreased tissue turgor, a characteristic hepatic fetor, and frequently Splenomegaly and ascites, which—together with peripheral edema—reflect portal Hypertension and hypoalbuminemia. These signs are not mandatory for confirming the Diagnosis.

Fever is frequently observed at the onset of the disease, followed later by hypothermia. Muscle tremor and hyperventilation are typical manifestations of acute liver failure (ALF), and muscle clonus is frequently observed. In severe cases, the majority of patients develop hypoxemia, and one-third develop acute respiratory distress syndrome (ARDS).

Liver failure is characterized by several complications that can be classified as distinct manifestations of hepatic dysfunction: hepatic encephalopathy, spontaneous bacterial Peritonitis, renal failure, respiratory failure, ascites, cerebral edema, coagulopathy, gastrointestinal bleeding, infection, and hepatic coma.

The most frequent complication of ALF is hepatic encephalopathy, also known as portosystemic encephalopathy. It develops when portal vein blood containing toxins bypasses the liver and enters the systemic circulation directly. Factors contributing to its development include ammonia, fatty acids, mercaptans, and other false neurotransmitters. Encephalopathy can induce central neurological disorders, as well as alterations in consciousness, intellectual performance, and personality. The prognosis is more favorable if consciousness disturbances respond to Treatment within a few days.

Regardless of the specific biochemical cause, A number of factors exacerbate liver failure-induced encephalopathy. Gastrointestinal bleeding increases the protein load on the gut and enhances Ammonia Production. A reduction in intravascular volume resulting from hemorrhage or diuretic administration impairs consciousness, diminishes Blood supply to the liver and kidneys, and promotes alkalosis which, combined with hypokalemia, increases ammonia production and hinders its elimination, further impairing brain function. Excessive removal of ascitic fluid during paracentesis can facilitate fluid shift from the intravascular space into the peritoneal cavity, thereby further markedly reducing hepatic perfusion. Renal insufficiency contributes to the accumulation of ammonia and Other toxins (urea, creatine, creatinine, indole, skatole, middle-molecule toxins, etc.), which additionally suppress the CNS.

The diagnosis of hepatic encephalopathy is supported by elevated blood ammonia levels, specific EEG abnormalities, or an increased glutamine content in the cerebrospinal fluid. Tachypnea and hyperventilation are frequently noted. Brain computed tomography in encephalopathy only reveals nonspecific cerebral edema (V. I. Cherniy, 1999), but the EEG sometimes demonstrates characteristic changes (high-amplitude 5- and 3-phase waves).

Therapy is primarily focused on eliminating the underlying causes of the condition (hemorrhage, medications, infection, alkalosis, hypovolemia). However, once hepatic encephalopathy is diagnosed, the substrate that undergoes biochemical conversion into cerebral toxins is reduced—specifically, Dietary Protein Intake is restricted, and gastrointestinal bleeding and blood breakdown in the gut are prevented. Aromatic amino acids (phenylalanine, Tyrosine) contribute to the progression of liver failure; therefore, it is advisable to use branched-chain amino acids (e.g., valine, leucine, isoleucine).

Mild laxatives and enemas reduce the production of fecal nitrogenous toxins, though severe diarrhea capable of causing excessive water loss and electrolyte disturbances must be avoided. To reduce intestinal toxin production, lactulose is commonly used—a synthetic non-absorbable and poorly digestible oligosaccharide. Lactulose is broken down by bacteria in the colon into lactic and acetic acids, substances that improve bowel motility. Lactulose is initially administered hourly until a laxative effect is achieved, after which the dose is adjusted to maintain two soft bowel movements per day. Excessive diarrhea caused by lactulose, as well as other laxatives, can significantly reduce circulating blood volume and thereby exacerbate hepatic encephalopathy and occasionally accelerate the onset of hepatorenal syndrome. As an alternative, neomycin is administered (orally at 100-150 mg/kg or via enema 1-2 times daily); it is poorly absorbed in the gut and reduces the population of toxin-producing intestinal bacteria. Because up to 5% of orally administered neomycin—which is nephrotoxic—can still be absorbed into the bloodstream, higher doses of this antibiotic in patients with pre-existing Renal Dysfunction may precipitate renal failure. Neomycin also exhibits ototoxicity; we observed The Development of complete deafness induced by neomycin in a female patient with ACUTE RENAL FAILURE. Occasionally, neomycin causes reversible diarrhea. Some patients respond to neomycin but not to lactulose, and vice versa.

A frequent complication of acute liver failure is spontaneous bacterial peritonitis (SBP), in which bacteria seed the peritoneal cavity. SBP is precipitated by inadequate perfusion, which compromises intestinal integrity. Bacteria penetrate the intraperitoneal fluid directly through the intestinal wall. Inadequate treatment of SBP leads to mortality in 60-90% of cases, and even with potent antibiotic therapy, the fatality rate remains high at approximately 40%.

Classically, the diagnosis of SBP is established by the presence of a triad of signs: fever, abdominal pain, and encephalopathy. However, SBP differs from peritonitis of other etiologies in that Temperature elevation, abdominal pain, and tenderness to Palpation are often very mild. Approximately 25% of patients with SBP present only with extra-abdominal signs, and in 5% of patients, SBP is asymptomatic. The diagnosis is confirmed if bacteria are identified on a Gram-stained smear or recovered in culture. An absolute leukocyte count in peritoneal fluid exceeding 500 per mm³ should serve as a trigger for initiating empirical therapy, especially if polymorphonuclear leukocytes predominate.

Gram-negative microorganisms are most commonly found in the small intestine, but 15% of SBP patients exhibit polymicrobial infection, and 5% have anaerobes. *Escherichia coli* is the most likely pathogen, with pneumococci also being prevalent.

In most cases, adequate treatment involves The Use of an aminoglycoside combined with ampicillin or penicillin.

Intracranial hypertension caused by cerebral edema is another cause of altered consciousness in ALF. Clinical examination rarely detects cerebral edema, nor does CT, although the latter is very useful for ruling out other causes of depressed consciousness.

Elevated intracranial pressure resulting from liver failure does not respond to therapies effective for Other forms of cerebral edema. Surgical decompression and dexamethasone are futile in this Setting. Hyperventilation is useful only for a short duration, and while mannitol (0.5-1 g/kg) may temporarily reduce edema, it does not improve survival probability. Death due to brain herniation can occur suddenly and unexpectedly (such herniation is found at autopsy in 80% of fatal ALF cases).

Gastrointestinal hemorrhage is frequently the direct cause of death in ALF patients. The risk of bleeding is often compounded by coagulopathy. Antacids, sucralfate, and H₂-blockers effectively prevent acute stress ulcers; however, H₂-blockers carry risks in ALF due to altered drug metabolism and adverse CNS effects.

Between 10% and 20% of ALF patients die from bacterial infection. By depleting opsonins and Complement levels and suppressing phagocytosis, liver failure predisposes patients to infection. Nearly 80% of ALF patients develop severe infectious complications, which are accompanied by bacteremia in 25% of cases. Fever and leukocytosis are uncommon (observed in only 30% of cases).

Given The Central Role of the liver in maintaining hemostasis, it is unsurprising that hemorrhage causes the death of one-third of patients with fulminant hepatic failure. The high incidence of bleeding and clotting disorders is explained by the fact that nearly all coagulation factors are produced by the liver (with the exception of factor VIII and von Willebrand factor). Furthermore, Kupffer cells play a key role in protecting the circulation from activated clotting proteins. The liver is also responsible for producing major anticoagulant proteins (antithrombin III, and proteins C and S). Thrombocytopenia occurs and is typically associated with disseminated intravascular coagulation (DIC). Vitamin K effectively increases the production of certain factors (II, VII, IX, X). Because renal function is also frequently impaired in ALF, volume overload is a frequent complication when fresh frozen plasma is used to correct clotting factor deficiencies.

Renal failure, which develops in half of ALF patients, can be of two types: acute tubular necrosis and hepatorenal syndrome (HRS). Blood urea nitrogen is an unreliable indicator of renal function in ALF because hepatic synthesis of urea from ammonia is sharply reduced in these patients. Hepatorenal syndrome is a unique form of oliguric renal failure observed in patients with severe hepatic dysfunction. This syndrome is characterized by an elevated serum creatinine level, oliguria, and unresponsiveness to fluid challenge and Diuretics. Urinary sodium levels are typically very low (below the normal value of 10 mmol/L). In ALF, nephrotoxic medications and hypovolemia—which may result from ongoing gastrointestinal bleeding, excessive removal of ascitic fluid, or the overuse of diuretics—should be avoided. The Role of low-dose ('renal') dopamine in the therapeutic regimen remains incompletely defined.

Acute Respiratory Failure frequently occurs in ALF patients, with direct causes including aspiration, Pneumonia, Pulmonary Atelectasis, and ventilation-perfusion mismatch. The latter arises from the loss of the liver's ability to activate vasodilatory humoral substances. Altered consciousness, abdominal distension, and restricted respiratory excursion caused by an enlarged and congested liver can lead to pulmonary parenchymal atelectasis and hypoxemia. Pulmonary edema may also develop as a result of fluid overload, hypoalbuminemia, impaired myocardial contractility, and increased vascular permeability.

Ascites frequently occurs in ALF, and intraperitoneal fluid can also track into the thoracic cavity via pleuroperitoneal pathways, producing symptoms of pleural effusion. This can further impair ventilation and increase the work of breathing. Typically, diuretics combined with sodium and water restriction are sufficient to reduce ascites to an acceptable level. The administration of spironolactone or potassium-sparing diuretics, either alone or in combination with saluretics, is also effective.

Intensive care for liver failure involves halting hepatic necrosis, improving the function of the failing liver, supporting and replacing hepatic function using active detoxification Methods, and correcting other vital functions and Homeostasis.

It is known that if hepatonecrosis is halted, liver cells can regenerate within 10–15 days. However, during this period, it is essential to substitute hepatocyte function as fully as possible to sustain the body's life.

Intensive care should begin with measures aimed at eliminating the etiological factor. Hepatocyte damage occurs due to the impairment of cell membranes and cellular edema. The stabilization of membranes—and consequently the protection of hepatocytes from further destruction—is facilitated by the administration of glucocorticoids, specifically prednisolone up to 300 mg, hydrocortisone up to 1500 mg, and dexamethasone up to 64 mg per day. The reduction of hepatocyte edema can be achieved by increasing the oncotic and Osmotic Pressure of Blood Plasma. For this purpose, a 10% albumin solution is prescribed intravenously at 200–300 ml/day, along with single-group concentrated blood plasma up to 400 ml/day, especially since these patients invariably exhibit hypoproteinemia, while dietary proteins must be excluded. Mannitol is also prescribed at 1-1,5 g/kg via intravenous drip as a 15% solution, with the daily dose not exceeding 140-180 g.

Restoring the functional capacity of hepatocytes promotes the improvement of hepatic blood flow. This is achieved by eliminating hypovolemia and intestinal paresis, draining the thoracic lymphatic duct, improving myocardial contractility, and administering drug therapy (euphylline 10 ml of a 2.4% solution, complamin 2 ml of a 15% solution intramuscularly twice a day, droperidol—after hemodynamic stabilization, rheopolyglucukin, and rheogluman to improve blood rheological properties, etc.).

To reduce hepatic hypoxia, Oxygen therapy (oxygen inhalation, Hyperbaric Oxygenation, etc.) is used in combination with antihypoxants (gamma-hydroxybutyric acid, barbiturates, vitamin E). Its efficacy can be enhanced by agents that improve oxygen utilization by liver cells (pama-comic acid, cytochrome C, cocarboxylase, alpha-Lipoic Acid or berlithion, coenzyme A, gutilin and diphosphopyridine nucleotide, succinic acid, or reamberin).

To prevent the breakdown of endogenous tissue proteins, it is necessary to support the liver's energy metabolism. This is achieved by intravenous glucose infusion of at least 5 g/(kg·day) as a 10% solution with The addition of Insulin (1 IU per 4-6 g of dry glucose weight).

To bind circulating blood ammonia, preparations of glutamic or malic acid at 7-15 mg, Glutathione 500-1000 mg, and Arginine 25-75 mg/day are prescribed. For the same purpose, glutargin (Ornithine and arginine, which convert ammonia into urea) is administered at 2 to 8 g/day in a diluted form via intravenous infusion.

To improve lipotransport mechanisms, stabilize energy metabolism in hepatocytes, and protect them from fatty degeneration, Methionine 1 г 6 times a day, lipokain, and intravenous Choline chloride drops at 1-2 g/day are prescribed. In hemolytic and parenchymatous jaundice with elevated unconjugated bilirubin levels, luminal at 0.5 g 2-3 times a day was administered to induce bilirubin conjugation enzymes. Currently, the administration of luminal is considered controversial, as There is a view that sedatives, including barbiturates—which themselves bind to glucuronic acid in the liver—can further deepen hepatic coma.

To normalize metabolism, a complex of Vitamin C, B-group vitamins, vitamin A, retinol, and proteolysis inhibitors (gordox, trasylol, or contrycal at 20 IU per day) is recommended.

Most of the listed vitamins are components of complex medications, such as Essentiale and Heparmefolin. They also contain phospholipids—the primary Structural elements of hepatocyte cell membranes and mitochondria. By regulating lipid and carbohydrate metabolism, these drugs improve the functional state of functioning hepatocytes, including their detoxification function, help preserve and restore hepatocyte structure, and inhibit the development of liver cirrhosis. The administration of Essentiale begins by combining parenteral and oral routes. It is administered intravenously at 10-20 mg 2-3 times a day via infusion at a rate not exceeding 40-50 drops per minute, dissolved in a 5% glucose or dextrose solution, and orally at 2 capsules 2-3 times a day. As the patient's condition improves, treatment is switched exclusively to capsules.

Heptral (ademetionine) is administered at 400-800 mg/day intravenously.

Detected water-electrolyte balance disorders are carefully corrected, bearing in mind the need to avoid sodium administration in the presence of secondary hyperaldosteronism accompanying liver failure, to eliminate excess water using diuretics, and to carefully replenish potassium ions. Acid-base status is also corrected.

To slow down the production of ammonia in the intestines, dietary protein is restricted to 0.5 g/(kg·day) in patients with liver failure. For parenteral Nutrition, Aminosteril N Hepa or Aminosteril Hepa is used—an amino acid formulation rich in branched-chain amino acids, which minimizes encephalopathy. The gastrointestinal tract is cleansed using high cleansing enemas, laxatives, and gastric tube lavage. Intestinal microflora is suppressed by the oral administration of lactulose (Duphalac, Normase) at 30 ml three times a day orally or via enema for adults, and 1 ml/kg internally every 6 hours for children, or neomycin at 500 mg every 6 hours for adults and 50 mg/(kg·day) divided into 4 doses for children.

To prevent gastrointestinal bleeding, blood clotting is normalized by prescribing aminocaproic acid, vikasol, calcium gluconate, and vitamin C. In the event of gastrointestinal bleeding, cimetidine is administered at 300 mg intravenously every 6 hours (for children under 12 years, 5-10 mg/kg every 6 hours), or preferably losec at 40-80 mg/day intravenously (the pH of gastric contents should be 6.0, at which bleeding typically stops). If the bleeding is caused by esophageal varices, a Sengstaken-Blakemore tube is used, along with intravenous vasopressin and sandostatin 0.1 mg subcutaneously three times a day or 25-50 mcg/hour via continuous intravenous infusion diluted in 200 ml of normal saline.

The aforementioned medications are recommended to be administered into the umbilical vein, which is surgically bougaged specifically for this purpose, after which a catheter is inserted so that all infused medications enter the hepatic circulation directly.

Due to the relatively low efficacy of drug therapy (mortality rate of 60-80%) in liver failure, active methods of liver support and replacement—primarily detoxification—are employed. Today, thoracic lymphatic duct drainage, plasmapheresis, hemofiltration, hemisorption, and lymphosorption are considered more effective and are widely used. Some clinics propose liver transplantation as a treatment option for acute liver failure. Since short-term survival after transplantation ranges from 50 to 75%, it should be considered for patients whose condition deteriorates despite maximum intensive care. Transplantation is not recommended for patients in a state of hepatic coma with irreversible brain damage.

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