Sepsis

Sepsis, severe sepsis, and septic shock are inflammatory conditions that develop during generalized bacterial infection. In severe sepsis and septic shock, tissue perfusion is critically reduced. The main causes of sepsis are gram-negative microorganisms, staphylococci, and meningococci. The disease often begins with chills, fever, hypotension, and oliguria. Acute multiple organ failure may develop. Treatment of sepsis involves aggressive infusion therapy, antibiotics, supportive care, monitoring of glycemia, glucocorticoids, and activated protein C.

Sepsis has been known since ancient times as “putrefaction of the blood” (Avicenna).

Currently, sepsis refers to complications of the purulent process, inflammatory complications of surgical interventions and traumatic injuries, in which the severity of systemic manifestations is directly proportional to the prevalence of the inflammatory process or the area of the lesion, i.e. there is a direct dependence of the reaction of the macroorganism on the source of infection.

Sepsis is characterized by the continuous or periodic entry of microorganisms from a purulent focus into the blood, microbial or tissue intoxication with the development of severe multi-organ disorders and often the formation of new foci of purulent inflammation in various organs and tissues.

A characteristic feature of sepsis is the loss of the body's ability to fight pathogens outside the infectious focus.

The number of patients with sepsis has increased 4-6 times in recent years.

Mortality in sepsis remains high and amounts to 20-69%.

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What causes sepsis?

Most cases of septic shock are caused by hospital-acquired gram-negative bacilli or gram-positive cocci, often in patients with compromised immune systems and chronic illnesses. Rarely, Candida or other fungi are the cause. A unique form of shock caused by staphylococcal and streptococcal toxins is called toxic shock.

Septic shock is more common in neonatology, in patients over 35 years of age and in pregnant women. Predisposing factors include diabetes mellitus, cirrhosis, leukopenia, especially oncological diseases or treatment with cytotoxic drugs; the presence of artificial materials used for invasive diagnostic or therapeutic procedures, including endotracheal tubes, vascular and urinary catheters, drainage tubes, etc.; previous treatment with antibiotics or glucocorticoids. Sources of infection may be the lungs and the urinary, biliary and gastrointestinal tracts.

Pathophysiology of sepsis

The pathogenesis of sepsis is not fully understood. Bacteria or their components (e.g. toxin) cause activation of tissue macrophages with production of proinflammatory mediators, including tumor necrosis factor (TNF) and interleukin 1 (IL-1). These cytokines promote activation of the endothelium, increase in vascular wall porosity and extravasation of neutrophils and macrophages, simultaneously activating the coagulation and anticoagulation system, formation of microthrombi consisting of platelets and fibrin on the surface of damaged endothelium. In addition, cytokines promote release of a large number of other mediators, including leukotrienes, lipoxygenase, histamine, bradykinin, serotonin and IL-2. They are counteracted by anti-inflammatory mediators, such as IL-4 and IL-10, as a result of activation of the feedback mechanism.

In the initial phase, arteries and arterioles dilate, peripheral arterial resistance decreases; cardiac output usually increases. This condition is described as "warm shock." Later, cardiac output may decrease, blood pressure drops (against the background of the same or increased peripheral resistance), and characteristic signs of shock appear.

With increased cardiac output, vasoactive mediators cause shunting of blood flow around the capillaries (redistribution effect). Impaired microcirculation as a result of shunting and formation of microthrombi leads to decreased delivery of oxygen and nutrients, impaired removal of carbon dioxide and metabolic products. Decreased perfusion causes dysfunction and sometimes damage to one or more organs, including the kidneys, lungs, liver, brain, and heart.

Coagulopathy develops as a result of intravascular coagulation with consumption of most coagulation factors, in addition, acute fibrinolysis may develop.

Sepsis - Causes and Pathogenesis

Symptoms of sepsis

Sepsis usually presents with fever, tachycardia, and tachypnea; blood pressure remains normal. There are signs of a generalized infectious process. In the development of severe sepsis or septic shock, the first symptom may be a disturbance in mental status. Blood pressure usually falls, the skin becomes paradoxically warm, and oliguria (less than 0.5 ml/kg/h) appears. Later, the extremities become cool and pale with peripheral cyanosis and mottling, then signs of organ damage appear.

Sepsis - Symptoms

Classification of sepsis

There is a classification of sepsis based on the severity of its course.

Sepsis is a generalized infection accompanied by a response of the body, which is called systemic inflammatory response syndrome (SIRS). SIRS is an acute inflammatory reaction with systemic manifestations caused by the release of numerous endogenous inflammatory mediators into the bloodstream. SIRS can also develop with pancreatitis and trauma, including burns. Diagnosis of SIRS is based on the presence of two or more of the following criteria:

• Temperature > 38 °C or < 36 °C
• Heart rate > 90 bpm
• Respiratory rate > 20 times/min or Pa-CO2 32 mmHg.
• Leukocyte count > 12,000 cells/µL or < 4000 cells/µL, or > 10% immature forms.

Sepsis in the USA

Category	Number of cases	Mortality (%)	Number of deaths annually
Sepsis	400,000	15	60,000
Severe sepsis	300,000	20	60,000
Septic shock	200,000	45	90,000

At present, these criteria are considered additional, but not precise enough to be diagnostic.

Severe sepsis is sepsis that is accompanied by signs of damage to at least one organ. Cardiovascular failure is manifested by hypotension, respiratory failure - by hypoxemia, renal - by oliguria and hematological disorders - by coagulopathy.

Septic shock is severe sepsis with organ hypoperfusion and hypotension that is not corrected in response to initial volume support.

The following classifications have been historically developed and are used in practice.

1. Depending on the underlying cause, there are:
   • primary, or cryptogenic, sepsis (extremely rare), when the cause of sepsis remains unknown (entry gate and purulent focus are not found);
   • secondary sepsis, the cause of which is the presence of any purulent focus; depending on the entry point of infection, gynecological, surgical, urological, traumatological, odontogenic sepsis, etc. are distinguished; surgical sepsis is a severe general disease that occurs against the background of an existing local focus of infection and requires surgical intervention and general intensive treatment.
2. According to the type of flow, the following are distinguished:
   • fulminant - develops within 1-3 days after the introduction of infection (it is necessary to distinguish fulminant sepsis from septic shock - a complication that can occur with any form and duration of the purulent process);
   • acute - develops within 4 days to 2 months from the introduction of infection;
   • subacute - from 2 to 6 months;
   • chronic sepsis.

Some authors also distinguish recurrent sepsis, characterized by alternating periods of exacerbations (when all symptoms are clearly expressed) and periods of remission (when it is not possible to identify any noticeable symptoms).

3. Depending on the characteristics of the clinical picture, the following forms of sepsis are distinguished:
   • septicemia (sepsis without metastases);
   • septicopyemia (sepsis with metastases).

According to the classification of the international consensus conference (1991), a distinction is made between purulent-resorptive fever (sepsis) and acute staphylococcal septicopyemia.

In our country, the classification of sepsis proposed by the international consensus conference in 1991 has not received due recognition, apparently due to terminological problems. At present, the following terms are more commonly used.

“The first, frequently encountered option is sepsis as a complication of a surgical infection, when “the worse it is locally (in the purulent focus), the worse the general condition of the patient.”

In this situation, sepsis essentially reflects a certain degree of severity of the patient's condition. In such cases, when formulating a diagnosis, sepsis should take the appropriate place: for example, pancreatic necrosis, retroperitoneal phlegmon, sepsis. This order determines the diagnostic and treatment tactics - the priority is not the attempts at immunomodulation and extracorporeal detoxification, but adequate drainage of the purulent focus.

The second option is sepsis as a rare disease - septicopyemia, when the determining criterion is the occurrence of metastatic pyemic (purulent) foci. Then, in the formulation of the diagnosis, after the word "sepsis" there should be a designation of the primary focus of infection, followed by a list of the localizations of pyemic (secondary) purulent foci."

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Diagnosis of sepsis

Sepsis is diagnosed in patients with SIRS or organ dysfunction associated with a generalized infectious process. In patients with signs of a systemic inflammatory response, it is necessary to focus on finding the source of the infectious process based on the anamnesis, physical and laboratory examination, including urine (especially if a urinary catheter is present), blood and other physiological fluids. In severe sepsis, the level of procalcitonin and C-reactive protein in the blood is elevated.

In addition, it is necessary to exclude other causes of shock (hypovolemia, myocardial infarction). Even in the absence of myocardial infarction, hypoperfusion can lead to ECG changes similar to ischemia.

It is necessary to perform a complete blood count (CBC), arterial blood gases, chest X-ray, determination of blood electrolytes, lactate or sublingual PCO2, liver function. At the onset of septic shock, the white blood cell count may decrease to less than 4000/μl, and the number of immature neutrophils may increase to 20%. After 1-4 hours, the situation changes, and, as a rule, there is a significant increase in the total white blood cell count to more than 15,000/μl and immature neutrophils to more than 80% (with the dominance of young forms). Early on, a drop in the platelet count below 50,000/μl is observed.

Respiratory failure develops early in the form of hyperventilation with respiratory alkalosis (low PaCO2 and increased arterial pH) aimed at partial compensation of lactic acidosis. As shock increases, metabolic acidosis increases. Early respiratory failure leads to hypoxemia with PaO2 less than 70 mm Hg. Chest X-ray may show diffuse infiltrative shadows. Blood urea nitrogen and creatinine usually increase as a result of renal failure. Bilirubin and transaminases may be elevated even in the absence of signs of liver failure.

Up to 50% of patients with severe sepsis have relative adrenal insufficiency (normal or slightly elevated cortisol levels that do not increase significantly in response to further stress or exogenous ACTH). Adrenal function can be assessed by measuring the serum cortisol level at 8 a.m.; a level of less than 5 mg/dL is considered inadequate. Alternatively, cortisol can be measured before and after injection of 250 mcg synthetic ACTH; an increase of less than 9 mcg/dL is considered inadequate. Most experts recommend glucocorticoid replacement therapy without laboratory testing. The usual method of glucocorticoid replacement for severe sepsis and septic shock is 100 mg of water-soluble hydrocortisone every 8 hours for 2 to 4 days.

Hemodynamic measurements using a pulmonary artery catheter may be necessary when the type of shock is unclear or large volumes of crystalloid are required (>4-5 L of crystalloid over 6-8 hours). In contrast to hypovolemic shock, septic shock is characterized by normal or increased cardiac output with decreased peripheral vascular resistance. Abnormalities in central venous pressure (CVP) or pulmonary artery wedge pressure (PAWP) are unlikely, as is usually seen in hypovolemic or cardiogenic shock. Echocardiography may be helpful in assessing cardiac function.

Sepsis - Diagnosis

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Treatment of sepsis

Overall mortality in septic shock decreases and averages 40% (range 10–90%). Poor outcome is most often associated with limited ability to initiate early intensive care (within 6 hours) due to problems associated with sepsis diagnosis. In severe lactic acidosis and decompensated metabolic acidosis, especially in combination with multiple organ failure, septic shock is likely to be irreversible and fatal.

Patients with septic shock are usually treated in the intensive care unit. They require continuous monitoring of blood pressure, central venous pressure, pulse oximetry, regular arterial blood gases, glycemia, lactatemia, blood electrolytes, renal function, and possibly sublingual PCO2 _. Urine output is the best indicator of renal perfusion and is usually measured by indwelling bladder catheterization.

Saline infusion should be continued until CVP rises to 8 mmHg (10 cm H2O) or PAWP rises to 12-15 mmHg. Oliguria with hypotension is not a contraindication to active infusion therapy. Fluid volumes can significantly exceed the circulating blood volume (CBV) and reach 10 L in 4-12 hours. PAWP or echocardiography can detect left ventricular dysfunction or the early stages of pulmonary edema due to fluid overload.

If hypotension persists after CVP and PAWP have reached target values, dopamine is added to raise BP to at least 60 mmHg. If the required dose of dopamine exceeds 20 mcg/kg/min, another vasopressor (usually norepinephrine) should be added. It should be noted that vasoconstriction caused by high doses of dopamine and norepinephrine increases the risk of organ hypoperfusion and acidosis, and there is no evidence that these drugs improve outcome in patients with septic shock.

Oxygen is supplied via a mask or nasal cannula. The need for endotracheal intubation and mechanical ventilation may arise if respiratory failure develops.

Parenteral antibiotic administration begins after blood, other biological fluids, and wound contents have been collected for Gram staining and culture. Prompt initiation of empirical therapy is essential and may save the patient's life. The choice of antibiotic is based on information about the likely source of infection, clinical data, the microflora characteristic of the department, and its sensitivity to antibiotics, obtained through local monitoring of circulating flora.

When the pathogen is unknown, one option for empirical therapy includes gentamicin or tobramycin 5.1 mg/kg IV once daily in combination with a third-generation cephalosporin (cefotaxime 2 g every 6-8 hours or ceftriaxone 2 g once daily if Pseudomonas is the likely pathogen - ceftazidime 2 g IV every 8 hours). A combination of ceftazidime and ciprofloxacin is possible. Monotherapy with maximum therapeutic doses of ceftazidime (2 g IV every 8 hours) or imipenem (1 g IV every 6 hours) is possible but not recommended.

Vancomycin should be used if the causative agents of the infection may be resistant staphylococci or enterococci. In case of an abdominal source of infection, a drug effective against anaerobes (metronidazole) is prescribed. After receiving the results of culture and sensitivity, correction of antibacterial therapy may be required. The use of antibiotics continues for several days after shock is overcome and the infectious process subsides.

Abscesses should be drained, and necrotic tissues (e.g. intestinal infarction, gangrenous gallbladder, uterine abscesses) should be surgically removed. Deterioration of the patient's condition against the background of antibacterial therapy is a reason to search for an unsanitized purulent focus.

Normalization of glycemia and its strict control improve outcome in critically ill patients, even in patients without diabetes mellitus. Continuous infusion of intravenous insulin (1-4 U/h of regular insulin) should provide glycemia at a level of 80-110 mg% (4.4-6.1 mmol/l). This technique involves frequent determination (i.e., every 1-4 hours) of plasma glucose levels.

Glucocorticoid therapy has shown positive results. Replacement therapy rather than pharmacological doses of glucocorticoids are often used. One protocol recommends hydrocortisone 50 mg intravenously every 6 hours with the addition of fludrocortisone orally 50 mcg once daily during the period of hemodynamic instability and for three more days after hemodynamic stabilization.

Activated protein C (drotrecogin-a) is a recombinant drug with fibrinolytic and anti-inflammatory activity, which has shown its effectiveness in early use in the treatment of severe sepsis and septic shock, but only in patients with a high risk of death, the severity of which was assessed by the APASHEII scale > 25 points. The dosage is 24 mcg / kg / h, used as a continuous infusion for 96 hours. Since the main complication of using this drug is bleeding, it is contraindicated in patients who have previously (less than 3 months ago) suffered a hemorrhagic stroke, spinal cord and brain surgery (less than 2 months ago), severe trauma with a risk of bleeding, as well as in patients with CNS neoplasms. A risk/benefit assessment is also required in patients at risk for severe bleeding (eg, thrombocytopenia, recent gastrointestinal or other intestinal bleeding, receiving heparin, aspirin, or other anticoagulants).

Other treatment approaches for severe sepsis include control of hyperthermia and early treatment of renal failure (eg, continuous venovenous hemofiltration).

Clinical studies of monoclonal antibodies to lipid A fraction of endotoxin of gram-negative bacteria, antileukotrienes, and antibodies to tumor necrosis factor have not shown their effectiveness.

Sepsis - Treatment