What Is the Role of Protein C in Sepsis?

The incidence of sepsis is high, with more than 18 million severe sepsis cases worldwide each year, and 750,000 patients with sepsis in the United States each year, and this number is increasing at a rate of 1.5% to 8.0% per year. Sepsis is a dangerous condition with a high mortality rate. About 14,000 people die every day from complications worldwide, and about 215,000 people die each year in the United States. According to foreign epidemiological surveys, the mortality rate of sepsis has exceeded that of myocardial infarction, which has become the main cause of death for non-heart disease patients in the intensive care unit. In recent years, despite considerable progress in anti-infective treatment and organ function support technology, the mortality rate of sepsis is still as high as 30% to 70%. The cost of sepsis treatment is high, medical resources are consumed, it seriously affects the quality of human life, and it has caused a huge threat to human health. Therefore, in 2001, the European Critical Society, the American Critical Society and the International Sepsis Forum launched the "surviving sepsis campain (SSC)". In 2002, several organizations in Europe and the United States jointly initiated and signed the "Barcelona Declaration", and Further develop evidence-based medical evidence based on sepsis research and continuously update the SSC guidelines for sepsis treatment to improve the treatment of sepsis and reduce sepsis mortality. The SSC guidelines were first developed in 2003 and then revised again in 2008. ^[1]

Zhang Dan	(Deputy Chief Physician)	Department of Emergency Medicine, the First Affiliated Hospital of Chongqing Medical University
Liu Jinglun	(Attending physician)	Department of Emergency Medicine, the First Affiliated Hospital of Chongqing Medical University

Sepsis refers to systemic inflammatory response syndrome (SIRS) caused by infection. It is clinically confirmed that bacteria are present or there are highly suspected infections. Although sepsis is caused by infection, once it occurs, its occurrence and development follow its own pathological processes and rules, so in essence, sepsis is the body's response to infectious factors.

Western Medicine Name: Sepsis
English name: sepsis

Affiliated Department: Internal Medicine-
Main cause: Bacterial infections
Contagious: Contagious

Introduction to sepsis disease

Classification of sepsis diseases

Sepsis can be divided into sepsis, severe sepsis, and septic shock according to the severity of sepsis. Severe sepsis refers to sepsis with organ dysfunction, poor tissue perfusion, or hypotension. Septic shock, which refers to severe sepsis, is still accompanied by uncorrectable persistent hypotension after sufficient fluid resuscitation, and is also considered to be a special type of severe sepsis.

Causes of sepsis

Sepsis can be caused by infection of any part. It is clinically common in pneumonia, peritonitis, cholangitis, urinary system infection, cellulitis, meningitis, abscess and so on. The pathogenic microorganisms include bacteria, fungi, viruses, and parasites, but not all patients with sepsis have positive blood culture results of pathogenic microorganisms that cause infection. Only about 45% of patients with septic shock can obtain positive blood culture results. .

Sepsis often occurs in patients with severe illness, such as severe burns, multiple injuries, and after surgery. Sepsis is also common in patients with chronic diseases such as diabetes, chronic obstructive bronchus, leukemia, aplastic anemia, and urinary stones. ^[2]

Pathogenesis of sepsis

The underlying pathogenesis of sepsis is unknown, involving complex systemic inflammatory network effects, genetic polymorphisms, immune dysfunction, coagulation disorders, tissue damage, and the host's abnormal response to different infectious pathogenic microorganisms and their toxins. On the one hand, it is closely related to the multi-system and multi-organ pathophysiological changes, and the pathogenesis of sepsis still needs to be further elucidated.

1. Bacterial endotoxin: Studies have shown that bacterial endotoxin can induce sepsis, uncontrolled inflammatory reactions, immune dysfunction, high metabolic status and multiple organ damage in the pathophysiology of sepsis can be directly caused by endotoxin Or indirectly.

2. Inflammatory mediators: Infectious factors in sepsis are caused by the activation of the body's mononuclear macrophage system and other inflammatory response cells, which produce and release a large number of inflammatory mediators. During sepsis, endogenous inflammatory mediators, including vasoactive substances, cytokines, chemokines, oxygen free radicals, acute-phase reactive substances, biologically active lipids, plasma enzyme system products, and fibrinolytic pathways, etc. The effect forms a network effect and causes extensive damage to various systems and organs throughout the body. At the same time, certain cytokines, such as tumor necrosis factor (TNF) -, may play an important role in the occurrence and development of sepsis.

3. Immune dysfunction: sepsis is mainly characterized by the loss of delayed allergic reactions, inability to clear pathogens, and susceptibility to iatrogenic infections. The mechanism of sepsis immune dysfunction, on the one hand, is an important regulatory cell of the immune system, T cell dysfunction, inflammatory mediators drift to the anti-inflammatory response, reducing inflammatory factors, and increasing anti-inflammatory factors; on the other hand, it is manifested as immune paralysis That is, the apoptotic cells are not reactive with immunity, and T cells do not respond to specific antigen stimulation to proliferate or secrete cytokines.

4. Intestinal bacteria / endotoxin translocation: Since the 1980s, people have noticed that the body s largest bacteria and endotoxin reservoir-intestinal dysfunction caused by stress occurs, which in turn causes intestinal bacteria / endotoxin The infection caused by toxin translocation is closely related to the subsequent sepsis and multiple organ dysfunction. Studies have shown that stress response after severe injury can cause damage to the intestinal mucosal barrier, intestinal flora ecological imbalance, and decreased immune function of the intestine, leading to intestinal bacteria / endotoxin translocation, triggering the body's excessive inflammation and organ damage.

5. Coagulation dysfunction: The coagulation system plays an important role in the pathogenesis of sepsis. It and inflammatory reactions promote each other and constitute a key factor in the occurrence and development of sepsis. Endotoxin and TNF can activate the exogenous coagulation pathway by inducing macrophages and endothelial cells to release tissue factors, and coagulation factor XII activated by endotoxin can further activate the endogenous coagulation pathway, eventually leading to diffuse intravascular coagulation ( DIC).

6. Gene polymorphism: The clinical manifestations and prognosis of different individuals who are commonly infected with the same pathogenic bacteria are very different, suggesting that genetic factors such as gene polymorphism also affect the human body's susceptibility and tolerance to shock shock, and clinical manifestations are diverse Sex and drug treatment response differences are important factors. ^[3]

Clinical manifestations of sepsis

1. The performance of SIRS refers to the following clinical manifestations with 2 or more items: (1) body temperature> 38 ° C or <36 ° C; (2) heart rate> 90 beats / min; (3) respiratory rate> 20 beats / Min or PaCO 2 <32mmHg; (4) peripheral blood leukocytes> 12 × 109 / L or <4 × 109 / L or immature cells> 10%.

2. Patients with sepsis generally have one or more manifestations of SIRS. The most common are fever, tachycardia, shortness of breath, and increased peripheral white blood cells. However, the "International Septic Symposium" in 2001 considered that the SIRS diagnostic criteria were too sensitive and not very specific, and summarized the performance of sepsis into three categories: (1) symptoms and signs of primary infection; (2) The manifestation of SIRS; (3) Shock and progressive multiple organ dysfunction manifested after the progress of sepsis. ^[4]

Diagnosis of sepsis

1. Because the previous diagnostic indicators of "infection + SIRS manifestations" are considered too sensitive, the clinical diagnosis of adult sepsis requires a definite infection or suspicious infection plus the following indicators:

(1) General condition: fever (> 38.3 ) or hypothermia (<36 ); rapid heart rate (> 90 beats / min) or> 2 standard deviations above normal age; rapid breathing (> 30 beats / Points); changes in consciousness; obvious edema or fluid positive balance> 20 ml / kg, duration more than 24h; hyperglycemia (blood glucose> 7.7mmol / L) without history of diabetes.

(2) Inflammation indicators: leukopenia (> 12 × 109 / L or leukocytopenia (<4 × 109 / L) or normal white blood cells but immature cells> 10%; plasma C-reactive protein> normal value 2 standard deviations; plasma Procalcitonin> 2 standard deviations from normal.

(3) Hemodynamic indexes: hypotension (systolic blood pressure <90 mmHg, mean arterial pressure <70 mmHg or adult systolic blood pressure drop> 40 mmHg, or 2 standard deviations below normal age); mixed venous blood Oxygen saturation (SvO2)> 70%; cardiac index (CI)> 3.5 L / min / m2.

(4) Parameters of organ dysfunction: oxygenation index (PaO2 / FiO2) <300; acute oliguria (urine volume <0.5 ml / kg / h); creatinine increase 44.2 mol / L; abnormal coagulation function (international standardized ratio> 1.5 or activated partial thromboplastin time> 60s); intestinal palsy: disappearance of bowel sounds; thrombocytopenia (<100 × 109 / L); hyperbilirubinemia (total bilirubin> 70mmol / L).

(5) Tissue perfusion parameters: hyperlactic acidemia (> 3 mmol / L); prolonged capillary refilling time or skin spots.

It should be noted that the new diagnostic criteria do not emphasize that the above 5 or more of them must be added to the infection before they can be diagnosed as sepsis, but more emphasis on the use of abnormal indicators combined with the specificity of clinical specialties. The condition changes to make a more clinical diagnosis of sepsis.

2. Severe sepsis: Sepsis with manifestations of organ dysfunction.

3. Septic shock: Unexplained causes of acute circulatory failure characterized by hypotension are a special type of severe sepsis. include:

(1) Systolic blood pressure <90mmHg or systolic blood pressure reduced from the original base value> 40mmHg for at least 1 hour, or rely on infusion and medication to maintain blood pressure, mean arterial pressure <60mmHg;

(2) Capillary refill time> 2s;

(3) Cold limbs or skin patches;

(4) Hyperlactic acidemia;

(5) decreased urine output. ^[5]

Monitoring and treatment of sepsis

1. Monitoring: Accurately understanding the disease status of patients with sepsis is an indispensable part in the treatment of septic shock. Among them, indicators that can reflect the body's hemodynamics and microcirculation perfusion are particularly important, so master the monitoring indicators commonly used in sepsis. Methods and clinical significance are important skills for doctors.

(1) Central venous pressure (CVP) and pulmonary artery entrapment (PAWP). CVP and PAWP reflect right ventricular end-diastolic pressure and left ventricular end-diastolic pressure, respectively, and are indicators of preload pressure. Central venous catheters should be placed as early as possible in patients with severe sepsis, and pulmonary artery floating catheters should be placed according to the condition.

(2) Central venous oxygen saturation (ScvO2) and mixed venous oxygen saturation (SvO2). In the early stages of severe sepsis and septic shock, even if the body's blood pressure, heart rate, urine output, and CVP are within the normal range at this time, hypoperfusion of systemic tissue perfusion has occurred, and ScvO2 and SvO2 can be earlier Reflect this perfusion state of the tissue. Studies have shown that SvO2 <70% in severe sepsis and septic shock indicates a significant increase in mortality.

(3) Blood lactic acid. Blood lactic acid is a sensitive indicator of whether the tissue is in a state of hypoperfusion and hypoxia. For example, when the lactic acid level is higher than 4mmol / L, the mortality rate is significantly increased. And dynamic monitoring of blood lactate changes or calculation of lactate clearance is more valuable for assessing disease status.

(4) Tissue oxygen metabolism. Hypoperfusion of gastrointestinal blood flow caused by sepsis can cause ischemia and hypoxia of mucosal cells, increase H + release and CO2 accumulation. Gastrointestinal mucosa pH (pHi) is an indicator that reflects the gastrointestinal tissue oxygenation status.

2. Early fluid resuscitation:

In sepsis, due to abnormal vasoconstriction and diastolic function and increased permeability, the body's blood volume decreases and tissues and organs appear hypoperfusion in the early stage. Therefore, effective fluid resuscitation in a timely manner has become a key measure for sepsis treatment. There is evidence that early fluid resuscitation helps improve the prognosis of patients with septic shock. The sepsis treatment guidelines also propose an early target-guided treatment (EGDT) strategy for sepsis, suggesting that within 6 hours: (1) central venous pressure (CVP) 8-12mmHg; (2) Mean arterial pressure (MAP) 65mmHg; (3) Urine output 0.5ml / kg / h; (4) ScvO2 70% or SvO2 65%

3 Controlling infection:

(1) Obtain biological evidence. If possible, take biological samples and perform bacterial / fungal cultures before using antibiotics. The samples include blood, sputum, urine, wound secretions, etc. The culture results are helpful for targeted antibiotic treatment. However, not all biological specimens of sepsis will produce positive results.

(2) Use antibiotics. Since it is not possible to obtain the results of bacterial culture soon, empirical antibiotic treatment should be given as soon as possible in the early stage of sepsis. One or more antibiotics. The selected antibiotics should be effective against all possible pathogenic microorganisms (bacteria / fungi) and can reach a sufficient therapeutic concentration. At the same time, the efficacy evaluation should be based on the condition to ensure the efficacy and prevent bacterial resistance. Once the bacterial culture result is obtained, it should be changed to targeted therapy as soon as possible based on drug sensitivity results combined with clinical conditions, and effective narrow-spectrum antibiotics should be used. Reasonable empirical antibiotic treatment and targeted therapy are important measures to avoid antibiotic abuse and antibiotic resistance.

(3) Eliminate the source of infection. While treating sepsis, you should actively look for the cause of the infection, such as surgical infection (such as suppurative cholangitis, abscess formation, intestinal obstruction, suppurative appendicitis, etc.), and timely surgical intervention should be performed to remove the lesion or perform Drainage; if it is an iatrogenic material infection (such as a venous catheter, urinary catheter, or implanted artificial device, etc.), the material should be removed in time and cultured for microorganisms.

4 Vasoactive drugs: The application of vasoactive drugs is best performed in an ICU that facilitates hemodynamic monitoring.

(1) If the patient's blood pressure and organ hypoperfusion status cannot be improved after fluid resuscitation, vasoactive drugs should be given booster therapy, and if the patient faces life-threatening shock, even if its low volume is not corrected At this time, booster therapy should also be given.

(2) For patients with septic shock, norepinephrine and dopamine are the preferred drugs. In addition, dobutamine and vasopressin can also be selected.

(3) For low cardiac output, dobutamine is the drug of choice for myocardial contraction.

It should be noted that if the patient is under severe metabolic acidosis (PH <7.15), the effect of using vasoactive drugs is often poor, and the acidosis needs to be actively corrected.

5. Glucocorticoids: Adrenal insufficiency often exists in patients with severe sepsis and sepsis, so for patients who need to be given booster drugs to maintain blood pressure after fluid resuscitation, a small dose of glucocorticoid therapy can be considered. Hydrocortisone is usually chosen with a daily dose in the range of 200-300 mg.

6. Mechanical ventilation assisted ventilation: For patients with severe sepsis who have acute lung injury / acute respiratory distress syndrome (ALI / ARDS), mechanical ventilation treatment should be performed in time to alleviate tissue hypoxia, and low platform pressure is recommended. , Protective lung ventilation strategies for small tidal volume ventilation and permissive hypercapnia.

7. Blood glucose control: Insulin resistance exists in patients with sepsis, and evidence-based medicine confirms that hyperglycemia in patients with sepsis is a risk factor for poor prognosis. Therefore, the blood glucose of patients with sepsis should be controlled at a reasonable level (<8.3mmol / L), but at the same time, care should be taken to prevent patients from developing hypoglycemia, so blood glucose monitoring should be strengthened. In the past, intensive blood glucose control was emphasized in patients with sepsis, but recent studies have confirmed that intensive blood glucose control does not significantly reduce the overall mortality rate of patients, but rather easily leads to severe hypoglycemia.

8. Recombinant human activated protein C (rhAPC): For patients with septic shock with organ failure, rhAPC can be given after contraindications such as bleeding risk, but at the same time the status of coagulation function should be closely monitored. However, since the later large-scale clinical controlled studies have failed to confirm the efficacy of rhAPC again, the application of rhAPC is still controversial.

In addition, appropriate sedation can be given to strengthen kidney, liver and other organs to prevent the treatment of stress ulcers, deep vein thrombosis, DIC and other complications.

9. Early target-directed therapy and cluster therapy. In order to better implement the sepsis treatment guidelines and standardize the treatment of severe sepsis and septic shock, it is currently recommended to combine the important measures of the aforementioned sepsis treatment guidelines to form a set of measures, that is, early target-guided treatment and Cluster treatment.

(1) Early target-directed therapy (EGDT) means that once clinically diagnosed with severe sepsis and insufficient tissue perfusion, active fluid resuscitation should be performed as soon as possible, and the following goals should be achieved within the first 6 hours of hemodynamic instability : Central venous pressure 8-12 mmHg; Central venous oxygen saturation (ScvO2) 70%; Mean arterial pressure (MAP) 65 mmHg; Urine volume> 0.5 ml / kg / h.

(2) Early sepsis bundle includes early serum lactate level measurement; obtain pathogenic specimens before applying antibiotics; emergency department within 3 hours, ICU start broad-spectrum antibiotic treatment within 1 hour; perform EGDT and perform hemodynamics Monitoring, placing a central venous catheter within 1-2 hours, monitoring CVP and ScvO2; controlling hyperglycemia; low-dose glucocorticoid application; lung protection strategies such as mechanical ventilation platform pressure <30mmHg and small tidal volume ventilation; rhAPC can be used when conditions permit. The implementation of early clustering treatment strategy will help improve clinicians' awareness and compliance with sepsis treatment guidelines and achieve better clinical results. However, in recent years, different researchers have raised questions about cluster therapy from different perspectives, and cluster therapy is easy to ignore the individual differences of sepsis patients. As the underlying pathogenesis of sepsis has not yet been elucidated, it is not easy to judge the comprehensive benefits / risks of cluster treatment. It is expected that more clinical medical evidence research and international and domestic cooperative research will evaluate and improve it. ^[6]

Prognosis of sepsis disease

Sepsis is dangerous and has a high mortality rate. About 9% of sepsis patients will have septic shock and multiple organ dysfunction. More than half of the deaths in intensive care units are caused by septic shock and multiple organ dysfunction. Yes, sepsis is the leading cause of death for non-heart patients in the intensive care unit. Studies have shown that patients with organ failure, shock, multiple infections, and serious underlying diseases have a poor prognosis. ^[7]

Prevention of sepsis

The most effective way to treat and prevent sepsis is to treat and prevent it based on the pathogenesis of sepsis, but unfortunately the pathogenesis of sepsis has not yet been fully elucidated. In this case, the cause of the disease All aspects of clinical prevention work should be done well, and efforts to reduce the risk factors that induce infection have an important role in the treatment and prevention of sepsis. With the advancement of medical research, large-scale, multi-center randomized controlled clinical studies will bring more evidence-based medical evidence to the treatment of sepsis. Prevention brings new hope.

Sepsis complications

The complications of sepsis are the clinical manifestations of the various stages of the pathophysiology of sepsis. Common complications include shock, acute lung injury / acute respiratory distress syndrome, deep vein thrombosis, stress ulcers, and metabolic Acidosis, diffuse intravascular coagulation (DIC), and multiple organ dysfunction. Mastering its pathogenesis helps to better prevent its complications.

Attention to sepsis diet

Promote a healthy diet, avoid eating unclean diets that easily cause intestinal infections, and avoid overeating and excessive drinking.

Expert opinion on sepsis

The primary disease, etiology, degree of disease, and scope of affected organs in patients with sepsis can be different. During the diagnosis and treatment of the disease, it is equally important to focus on implementing the guidelines for sepsis treatment, implementing standardized treatment, and emphasizing individualized treatment. The morbidity and mortality of sepsis are high. Attention should be paid to the prevention of infection in vulnerable populations. At the same time, timely and effective early treatment should be given to infected patients, and the prevention and treatment will further develop into sepsis.

The pathological mechanism of sepsis often involves multiple systems throughout the body, causing multiple organ damage. A large amount of evidence-based medical evidence has shown that a single treatment cannot achieve good results, so early cluster treatment is advocated in the treatment of sepsis, and some important measures for the treatment of sepsis are used as soon as possible.

At present, there is no fundamental breakthrough in the treatment of sepsis, because the underlying mechanism of sepsis has not been elucidated, and the current treatment of sepsis is still more focused on correcting the pathophysiological consequences caused by sepsis. The complexity of the pathogenesis of sepsis is that the inflammatory mediators released by the infection mobilize multiple cells and multiple organ systems throughout the body through the neuro-endocrine-immune system, forming a complex network mechanism. This system has cascade amplification, The characteristics of mutual restriction, and finding the key balance point in this network structure for immune conditioning may bring new breakthroughs in the treatment of sepsis.

Sepsis is a complex disease in which environmental factors and genetic factors work together. Studies have shown that genetic factors affect the body's response to inflammation and the outcome of sepsis. With the development of gene detection technology and bioinformatics, breakthroughs in this field will provide new possibilities for early diagnosis, prognostic analysis and gene therapy of sepsis.