Treating severe sepsis and septic shock

Effective treatment of sepsis is possible only if the full surgical sanitation of the focus of infection and adequate antimicrobial therapy. Inadequate starting antimicrobial therapy is a risk factor for death in patients with sepsis. Maintenance of the patient's life, prevention and elimination of organ dysfunctions are possible only with the purposeful intensive therapy.

Its main goal is the optimization of O ₂ transport in conditions of its increased consumption, which is typical for severe sepsis and septic shock. This direction of treatment is realized through hemodynamic and respiratory support.

Hemodynamic support

Infusion therapy

Infusion therapy is one of the initial measures for maintaining hemodynamics and, above all, CB. Its main tasks in patients with sepsis:

• restoration of adequate tissue perfusion,
• correction of homeostasis disorders,
• normalization of cellular metabolism,
• decrease in the concentration of mediators of the septic cascade and toxic metabolites.

In sepsis with PON and septic shock, they try to reach the following values of important indicators quickly (within the first 6 hours):

• hematocrit> 30%,
• diuresis 0.5 ml / (kghh),
• blood saturation in the superior vena cava or right atrial> 70%,
• mean BP> 65 mm. Gt; Art.
• CVP 8-12 mm. Gt; Art.

Maintaining the listed values at the specified level increases the survival of patients (category of evidence B). Monitoring hemodynamics with the help of the Swan-Ganz catheter and RISCO-technology (transpulmonary thermodilution and pulse wave shape analysis) broadens the possibilities of monitoring and evaluating the effectiveness of hemodynamic therapy, however, no evidence of an increase in survival rates has been obtained with their use.

The value of optimal preload is selected individually, since it is necessary to take into account the degree of endothelial damage and the state of lymph drainage in the lungs, the diastolic function of the ventricles, as well as changes in intrathoracic pressure. The volume of infusion therapy is chosen in such a way that DZLK does not exceed plasma CODE (prevention of AL) and there is an increase in CB. Additionally, the parameters characterizing the gas exchange function of the lungs (paO ₂ and paO ₂ / FiO ₂ ) and changes in the radiographic pattern are taken into account .

For infusion therapy in the context of the targeted treatment of sepsis and septic shock, crystalloid and colloidal solutions are used with almost identical results.

All infusion media have both advantages and disadvantages. To date, given the results of experimental and clinical studies, there is no reason to prefer any particular type.

• For example, to adequately correct the venous return and the level of preload, it is necessary to introduce a volume of crystalloids 2-4 times larger than colloids, which is associated with the distribution of solutions in the body. In addition, the infusion of crystalloids is associated with a greater risk of edema of the tissues, and their hemodynamic effect is shorter, than in colloids. At the same time, crystalloids are cheaper, do not affect the coagulation potential and do not provoke anaphylactoid reactions. On the basis of the foregoing, the qualitative composition of the infusion program is determined depending on the characteristics of the patient, taking into account the degree of hypovolemia, the phase of the ICE syndrome, the presence of peripheral edema and serum albumin concentration, the severity of acute pulmonary injury.
• Plasma substitutes (dextrans, gelatin preparations, hydroxyethyl starch) are shown with a pronounced deficiency of bcc. Hydroxyethyl starches with a degree of substitution of 200 / 0.5, 130 / 0.4 and 130 / 0.42 have a potential advantage over dextran because of the lower risk of evasion through the membrane and the absence of clinically significant effects on hemostasis.
• The introduction of albumin in critical conditions may increase the risk of death. The growth of RCD during its infusion is transient in nature, and then further extubation of albumin takes place in conditions of increased permeability of the capillary bed (syndrome of "capillary leakage"). Perhaps, transfusion of albumin will be useful only at its concentration in serum less than 20 g / l and absence of signs of "leakage" into interstitium.
• The use of cryoplasm is indicated with coagulopathy of consumption and a decrease in the coagulation potential of the blood.
• Wide use of donor erythrocyte mass should be limited due to the high risk of various complications (APL, anaphylactic reactions, etc.). According to most experts, the minimum concentration of hemoglobin in patients with severe sepsis is 90-100 g / l.

Correction of hypotension

Low perfusion pressure requires the immediate inclusion of drugs that increase vascular tone and / or inotropic cardiac function. Dopamine or norepinephrine is the first choice for correction of hypotension in patients with septic shock.

Dopamine (dopamine) at a dose of <10 μg / (kg-min) increases blood pressure, primarily due to the increase in CB, and minimally affects the systemic vascular resistance. In large doses, its α-adrenergic effect predominates, which leads to arterial vasoconstriction, and at a dose of <5 μg / (kg-min) dopamine stimulates the dopaminergic receptors of the renal, mesenteric and coronary vessels, which leads to vasodilation, increased glomerular filtration, and Na + excretion.

Norepinephrine increases mean blood pressure and increases glomerular filtration. Optimization of systemic hemodynamics under its effect leads to an improvement in kidney function without the use of low doses of dopamine. Recent studies have shown that its isolated use compared with a combination with large doses of dopamine leads to a statistically significant reduction in mortality.

Adrenaline is an adrenergic drug with the most pronounced adverse hemodynamic effects. It has a dose-dependent effect on heart rate, mean BP, CB, left ventricular function, delivery and consumption of O ₂. However, simultaneously there are tachyarrhythmias, worsening of the organ blood flow, hyperlactatemia. Therefore, the use of epinephrine is limited to cases of complete refractoriness to other catecholamines.

Dobutamine - drug of choice for larger and CB delivery and consumption of O ₂ under normal or elevated level of preload. Due to the predominant effect on beta 1-adrenergic receptors, it contributes more to the above indices than dopamine.

 

In experimental studies, it has been shown that catecholamines, in addition to circulatory support, can regulate the course of systemic inflammation, influencing the synthesis of key mediators with a distant effect. Under the influence of adrnalin, dopamine, norepinephrine and dobutamine, activated macrophages reduce the synthesis and secretion of TNF-a.

The choice of adrenergic drugs is carried out according to the following algorithm:

• cardiac index 3.5-4 l / (min. ² ), SvO ₂ > 70% - dopamine or norepinephrine,
• cardiac index <3.5 l / (min. ² ), SvO ₂ <70% - dobutamine (if systolic blood pressure <70 mm Hg - together with norepinephrine or dopamine).

[1], [2], [3], [4], [5], [6], [7], [8],

Respiratory support

Lungs are one of the first target organs involved in the pathological process in sepsis. Acute respiratory failure is one of the leading components of multi-organ dysfunction. Its clinical and laboratory manifestations in sepsis correspond to APL, and in the progression of the pathological process, ARDS. Indications for carrying out mechanical ventilation for severe sepsis are determined depending on the severity of parenchymal respiratory failure (APL or ARDS). Its criterion is the respiratory index:

• <200 - shows intubation of the trachea and respiratory support,
• > 200 - Indications are determined individually.

If, with spontaneous breathing with oxygen support, the patient is conscious, there is no high cost of breathing and pronounced tachycardia (heart rate <120 per minute), the normal venous return value S 0 > ₂ > 90%, then one can refrain from his transfer to mechanical ventilation. However, it is necessary to closely monitor the patient's condition. The optimum value of S O ₂ is about 90%. It can be supported by various methods of gas supply (facial masks, nasal catheters) in non-toxic concentrations (FiO ₂ <0.6). Non-invasive artificial ventilation is contraindicated in sepsis (category of evidence B).

Avoid high-volume ventilation (DO = 12 ml / kg) regimens, since secretion of cytokines with light increases in such cases, which leads to weight gain of the PON. It is necessary to adhere to the concept of safe ventilation, which is possible under the following conditions (category of evidence A):

• TO <10 ml / kg,
• non-inverted ratio of inspiration and expiration,
• peak pressure in the respiratory tract <35 cm of water. Art.
• FiO ₂ <0.6.

Selection of the parameters respiratory cycle is performed to achieve adequate ventilation its criteria RAO ₂ > 60 mm Hg, SpO ₂ > 88-93% rvO ₂ 35-45 mm Hg, SvO ₂ > 55%.

One of the effective methods for optimizing gas exchange is ventilator ventilation in the abdominal position (Prone Positioning) (category of evidence B). This position is effective in patients in the most serious condition, although its effect on the reduction in mortality in the long-term period is statistically unreliable.

Nutritional support

Conducting artificial nutritional support is an important element of treatment, one of the mandatory measures, since the development of the PON syndrome in sepsis, as a rule, is accompanied by manifestations of hypermetabolism. In a similar situation, the covering of energy needs occurs due to the destruction of its own cellular structures (autokannibalism), which aggravates organ dysfunction and enhances endotoxicosis.

Nutritional support is considered as a method of preventing severe exhaustion (protein-energy deficiency) against the background of pronounced increase in cata- and metabolism. The inclusion of enteral nutrition in the intensive care complex prevents the movement of intestinal microflora, dysbacteriosis, increases the functional activity of enterocytes and the protective properties of the intestinal mucosa. These factors reduce the degree of endotoxicosis and the risk of secondary infectious complications.

Calculation of nutritional support:

• energy value - 25-35 kcal / (kg of body weight x day),
• the amount of protein is 1.3-2.0 g / (kg body weight x day),
• the amount of carbohydrates (glucose) is less than 6 g / kg / day,
• the amount of fats is -0.5-1 g / kg / day,
• dipeptides of glutamine 0.3-0.4 g / kg / day,
• vitamins - standard daily kit + vitamin K (10 mg / day) + vitamins B ₁ and B ₆ (100 mg / day) + vitamins A, C, E,
• microelements - a standard daily kit + Zn (15-20 mg / day + 10 mg / day in the presence of a liquid stool),
• Electrolytes - Na +, K +, Ca2 +, respectively, balance calculations and concentrations in the plasma.

The early onset of nutritional support (24-36 hours) is more effective than on the 3-4th day of intensive care (category of evidence B). Especially - with enteral tube feeding.

In severe sepsis, the benefits of enteral or parenteral nutrition are not the same duration of organ disorders and the timing of respiratory and inotropic support, equal levels of mortality. Given the foregoing, early enteral nutrition is a cheaper alternative to parenteral. The use of mixtures enriched with dietary fiber (prebiotics) for the nutrition of feed significantly reduces the frequency of diarrhea in patients with severe sepsis.

For effective protein synthesis in the body, it is important to observe the metabolic ratio "total nitrogen, g - non-protein calories, kcal" = 1- (110-130). The maximum dose of carbohydrates is 6 g / (kg of body weight), as the administration of large doses threatens hyperglycemia and activation of catabolism in skeletal muscles. Fatty emulsions are recommended to be administered around the clock.

Contraindications to nutritional support:

• decompensated metabolic acidosis,
• individual intolerance of nutritional support,
• sharp unrestored hypovolemia,
• refractory shock - a dose of dopamine> 15 μg / (kghmin) and systolic blood pressure <90 mm Hg,
• severe non-occlusive arterial hypoxemia.

Control of glycemia

An important aspect of the complex treatment of severe sepsis is a constant control of the concentration of glucose in the blood plasma and insulin therapy. A high level of glycemia and the need for its correction are factors of an unfavorable outcome in sepsis. Taking into account the above circumstances, patients maintain normoglycemia (4.5-6.1 mmol / l), for which an insulin infusion (0.5-1 U / h) is performed with an increase in the glucose concentration above the permissible values. Depending on the clinical situation, glucose concentration is monitored after 1-4 hours. When performing this algorithm, a statistically significant increase in the survival of patients was noted.

[9], [10], [11], [12], [13],

Glucocorticoids

The results of modern studies on the effectiveness of glucocorticoids in patients with septic shock are summarized in the following statements:

• it is inappropriate to use hormones in high doses [methylprednisolone 30-120 mg / (kghsut) once or 9 days, dexamethasone 2 mg / (kghsut) 2 days, betamethasone 1 mg / (kghsut) 3 days] - increased risk of hospital infections, survival,
• the use of hydrocortisone in a dose of 240-300 mg per day for 5-7 days accelerates the stabilization of hemodynamic parameters, allows the elimination of vascular support and improves survival in patients with concomitant relative adrenal insufficiency (category of evidence B).

It is necessary to abandon the chaotic empirical appointment of prednisolone and dexamethasone - there are no grounds for extrapolating new information on them. In the absence of laboratory evidence of relative adrenal insufficiency, hydrocortisone at a dose of 300 mg per day (for 3-6 injections) is administered

• with refractory shock,
• if high doses of vasopressors are necessary to maintain effective hemodynamics.

Probably, in conditions of systemic inflammation in septic shock, the effectiveness of hydrocortisone is associated with the activation of the inhibitor of the nuclear factor kB (1kV-a) and the correction of the relative adrenal insufficiency. In turn, inhibition of the activity of transcription nuclear factor (NF-kB) leads to a decrease in the formation of inducible NO-synthetase (NO - the most potent endogenous vasodilator), pro-inflammatory cytokines, COX and adhesion molecules.

Activated Protein C

One of the characteristic manifestations of sepsis is the violation of systemic coagulation (activation of the coagulation cascade and inhibition of fibrinolysis), which ultimately leads to hypoperfusion and organ dysfunction. The effect of activated protein C on the inflammation system is realized in several ways:

• reduction of the accession of selectins to leukocytes, which protects endothelium from damage, which plays a crucial role in the development of systemic inflammation,
• reduction of the release of cytokines from monocytes,
• blocking the release of TNF-a from leukocytes,
• oppression of thrombin generation (it potentiates the inflammatory response).

Anticoagulant, profibrinolytic and anti-inflammatory action

• activated protein C is due to
• degradation of factors Va and VIIIa - suppression of thrombogenesis,
• inhibition of the plasminogen activator inhibitor - activation of fibrinolysis,
• direct anti-inflammatory effect on endothelial cells and neutrophils,
• protection of the endothelium from apoptosis

The introduction of activated protein C [Drotercogin alpha (activated)] at 24 μg / (kghh) for 96 hours reduces the risk of death by 19.4%. Indications for the appointment of sepsis with acute PON and high risk of death (APACHE II> 25 points, dysfunction of 2 or more organs, category of evidence B).

Activated protein C does not reduce mortality in children, patients with monoorganic dysfunction, APACHE II <25, in patients with non-surgical sepsis.

[14], [15], [16], [17]

Immunoglobulins

The use of intravenous immunoglobulins (IgG and IgG + IgM) is associated with their ability to limit the excessive action of pro-inflammatory cytokines, increase the clearance of endotoxins and staphylococcal superantigen, eliminate anergy, enhance the effect of ß-lactam antibiotics. Their use in the therapy of severe sepsis and septic shock is the only immunocorrection method , increasing survival. The best effect was registered with the combination of IgG and IgM [RR = 0.48 (0.35-0.75), category of evidence A]. The standard dosage regimen is 3-5 ml / (kilohsut) 3 days in a row. When using immunoglobulins, the most optimal results were obtained in the early phase of shock ("warm shock") and in patients with severe sepsis (the APACHE II score is 20-25 points).

Prophylaxis of deep vein thrombosis

Prophylaxis of DVT of the lower extremities significantly affects the results of treatment of patients with sepsis (category of evidence A). Both unfractionated and LMWH are used for this purpose. The main advantages of low molecular weight heparins - a lower frequency of hemorrhagic complications, less pronounced effect on the function of platelets, a prolonged action (the possibility of a single injection per day).

Prevention of the formation of stress ulcers of the gastrointestinal tract

This direction plays an important role in the favorable outcome in the treatment of patients with severe sepsis and septic shock, since the lethality during bleeding from stress-ulcers of the gastrointestinal tract is 64-87%. Without carrying out preventive measures in patients in critical condition, stress ulcers occur in 52.8%. However, the use of proton pump inhibitors and histamine H2-receptor blockers reduces the risk by more than 2 times (the first group of drugs is more effective than the second). The main direction of prevention and treatment is maintaining the pH in the range of 3.5-6.0. It should be emphasized that in addition to the above drugs, enteral nutrition plays an important role in the prevention of the formation of stress ulcers.

Extracorporeal cleansing of blood

Various biologically active substances and metabolic products involved in the development of generalized inflammation are the target for detoxification methods, which is especially important in the absence of natural hepatic-renal clearance in conditions of PNS. The methods of renal replacement therapy that are able to affect not only uremic disorders in patients with renal insufficiency, but also have a positive effect on other changes in homeostasis and organ dysfunction that occur in sepsis, shock and PON are considered promising.

To date, there is no evidence to support the use of extracorporeal blood purification methods as one of the main directions of pathogenetic therapy for sepsis and septic shock. Their use is justified in the case of PON with dominance of renal.

[18], [19], [20], [21], [22], [23]

Hemodialysis

The essence of the method is the diffusion of substances of low molecular weight (up to 5x10 ³ Da) through a semipermeable membrane and the removal of excess fluid from the body along the pressure gradient. Hemodialysis is widely used to treat patients with both chronic and arthritis. The diffusion rate of substances exponentially depends on their molecular weight. For example, the excretion of oligopeptides is slower than their synthesis.

Hemofiltration

Hemofiltration is an effective method of removing substances with a molecular weight of 5x10 ³ - 5x10 ⁴ Da and the only way to remove a large group of biologically active substances and metabolites from the body. The method is based on the convection method of mass transfer. In addition to adequate correction of azotemia, anaphylatoxins C3a, C5a, pro-inflammatory cytokines (TNF-a, IL-1b, 6 and 8), ß2-microglobulin, myoglobin, parathyroid hormone, lysozyme (molecular weight 6000 Da), a- amylase (molecular weight - 36 000-51 000 Da), creatine phosphokinase, alkaline phosphatase, transaminases and other substances. During hemofiltration, amino acids and plasma proteins (including immunoglobulins and circulating immune complexes) are removed.

Hemodiafiltration

Hemodiafiltration is the most powerful way of purifying blood, combines diffusion and convection (those DG and GF). An additional contribution to the detoxification process is the sorption of pathological substances on the filter membrane.

Plasmapheresis

Plasmapheresis (plasma exchange, plasmafiltration) is also considered as a possible way to correct generalized inflammation in patients with sepsis and septic shock. Optimal use of plasma exchange in a constant mode with the removal of 3-5 volumes of plasma and its simultaneous replacement by fresh frozen, albumin, colloidal and crystalloid solutions is considered optimal. With a sieving factor of 1, the C-reactive protein, haptoglobin, C3 complement fragment, 1-antitrypsin, IL-6, thromboxane-B2, granulocyte-stimulating factor, TNF are well removed during plasmafiltration. The use of sorbents to clean the patient's own plasma reduces the risk of infection and reduces the cost of the procedure, since the need to use foreign proteins disappears.

The use of prolonged infusion of sodium selenite (selenase) 1000 μg / day with severe sepsis leads to a decrease in mortality.

Selenium is an indispensable trace element, the significance of which is related to its key role in antioxidant systems of cells. The level of selenium in the blood is maintained in the range of 1.9-3.17 μM / l. The need for selenium is 50-200 mcg per day. And it depends on the availability of other antioxidants and trace elements.

Selenium is a powerful antioxidant, a component of glutathione peroxidase, phospholinidglutathione peroxidase, other oxidoreductases and some transfers. Glutathione peroxidase is the most important link in the endogenous antioxidant.

Recently, the effectiveness of selenium in critical states has been studied. These studies have shown that the main mechanisms of action of selenium are:

• suppression of hyperactivation of NF-kB;
• decreased complement activation;
• its action as an immunomodulator, an antioxidant and an anti-inflammatory agent
• maintenance of peroxide utilization;
• suppression of endothelial adhesion (decreased expression of ICAM-1, VCAM-2,
• E - selectin, P - selectin);
• protection of the endothelium from cystic radicals (using selenoprotein P, preventing the formation of peroxynitrite from O ₂, and NO).

Summarizing the above, it is possible to define specific tasks of intensive therapy of severe sepsis:

• Hemodynamic support of CVP 8-12 mmHg, mean BP> 65 mmHg, diuresis 0.5 ml / (kghh), hematocrit> 30%, saturation of mixed venous blood> 70%.
• Respiratory support peak pressure in the respiratory tract <35 cm H2O, oxygen inspiratory fraction <60%, respiratory volume <10 ml / kg, noninverted inspiratory-to-expiratory ratio.
• Glucocorticoids - "small doses" (hydrocortisone 240-300 mg per day).
• Activated protein C 24 μg / (kghh) for 4 days with severe sepsis (APACHE II> 25).
• Immunocorrection substitution therapy with pentaglobin.
• Prevention of deep vein thrombosis of the lower extremities.
• Prevention of the formation of stress ulcers of the gastrointestinal tract using proton pump inhibitors and histamine H2-receptor blockers.
• Substitution therapy for acute renal failure.
• Nutritional support energy value of nutrition 25-30 kcal / kg body weight x day), protein 1,3-2,0 g / (kg body weight x day), glutamine dipeptides 0,3-0,4 g / (kg x day ), glucose - 30-70% of non-protein calories, subject to the maintenance of glycemia <6.1 mmol / l, fats - 15-50% of non-protein calories.