Severe sepsis and septic shock are common complications in critically ill medical and surgical patients, with millions of cases worldwide each year and a growing trend, and a mortality rate of more than 25%. Facing the challenge of severe sepsis and septic shock, the European Society of Critical Care Medicine (ESICM), the Society of Critical Care Medicine (SCCM) and the International Sepsis Forum (ISF) launched a global initiative to save sepsis in Barcelona, Spain, in October 2002 – the Surviving Sepsis Campaign (SSC). The Surviving Sepsis Campaign (SSC) was launched in Barcelona, Spain, calling on medical professionals, health institutions and governmental organizations worldwide to give high priority to severe sepsis and septic shock, and organizing experts to develop internationally recognized guidelines for the treatment of severe sepsis and septic shock, which are updated annually. In this paper, based on the newly revised 2008 guidelines for the treatment of severe sepsis and septic shock [1] (hereinafter referred to as the guidelines), we introduce several therapeutic advances in severe sepsis and septic shock, taking into account the current hot issues of clinical concern, and append the recommendation level of the guidelines and the quality of evidence to the therapeutic opinions.
Level 1 is a strong recommendation, indicating that the beneficial effects (low risk of treatment, low burden on medical staff, low cost of care) are significantly better than the negative effects (high risk of treatment, high burden on medical staff, high cost of care). level 2 is a general recommendation, indicating that the beneficial effects may be better than the negative effects, but there is still uncertainty about the balance between benefits and risks. The level of recommendation is determined more by clinical importance than by the level of quality of evidence.
The quality of evidence is divided into: A randomized controlled studies (RCTs); B RCTs with deficient design or rigorous observational studies; C general observational studies; D case series or expert opinion.
I. Resuscitation treatment (resuscitation)
1.Early resuscitation goals (initial resuscitation goals)
Resuscitation is an important basis for the treatment of severe sepsis and septic shock. Early resuscitation goal-oriented treatment can improve the survival rate of patients with septic shock. The guidelines clearly state that resuscitation of septic patients with hypotension or elevated blood lactate >4 mmol/L should be performed immediately rather than delayed until after admission to the ICU. Resuscitation goals should be achieved within the first 6 hours: (1) central venous pressure (CVP): 8-12 mmHg; (2) mean arterial pressure (MAP): ≥65 mmHg; (3) urine output: ≥0.5 mL?kg-1?hr-1. (4) central venous (superior vena cava) oxygen saturation ScvO2 or mixed venous oxygen saturation SvO2 ≥70% or ≥65 (1C) (1C)
If CVP has reached 8-12 mmHg within 6 hours of early fluid resuscitation and ScvO2 or SvO2 has not reached 70% or 65%, infusion of concentrated red blood cells to achieve a red blood cell pressure (Hct) ≥ 30% and/or infusion of dobutamine (maximum dose to 20 μg?kg- 1?min- 1) may be given to achieve resuscitation goals (2C). In patients with severe infection or septic shock, achieving these resuscitation goals within 6 hours of the onset of severe infection may reduce patient morbidity and mortality.
2.Fluid therapy
Rehydration is the first step of resuscitation therapy. Crystalloid or colloid fluids can be used, and there is no evidence to show which fluid resuscitation is better (1B). The goal of treatment is to achieve a CVP of at least 8 mmHg, and 12 mmHg in mechanically ventilated patients (1C). Fluid shock therapy with continuous fluid replacement until hemodynamics (e.g., arterial pressure, heart rate, urine output) improve is recommended (1D). When administering fluid shock therapy to a patient suspected of having hypovolemia, at least 1000 ml of crystalloid fluid or 300-500 ml of colloid fluid should be administered within the first 30 minutes (1D). However, when only cardiac filling pressure (CVP or pulmonary artery wedge pressure) increases without hemodynamic improvement, the rate of fluid replacement should be reduced (1D).
3.Boosting drugs (vasopressors)
Some patients do not achieve resuscitation goals by correcting shock with adequate rehydration and require treatment with vasopressors. In addition, when facing a life-threatening hypotensive state, even if hypovolemia has not been corrected, vasopressors should be used to maintain life and organ perfusion and keep the mean arterial blood pressure above 65 mmHg. (1C)
The guidelines recommend that the preferred antihypertensive agents are norepinephrine or dopamine (administered via central venous catheter) (1C). Epinephrine, phenylephrine, and vasopressin therapy are not recommended as first choices (2C). If patients do not respond well to norepinephrine or dopamine therapy, epinephrine is recommended as an alternative (2B). A randomized, double-blind prospective multicenter study (n = 280) demonstrated comparable efficacy of blood pressure maintenance with norepinephrine versus epinephrine in critically ill patients with severe sepsis or acute circulatory collapse [2].
Although studies have shown a relative lack of vasopressin in patients with septic shock, combined treatment with norepinephrine and vasopressin (0.03 u/min) did not improve the prognosis of patients with sepsis compared with norepinephrine alone.
Low-dose dopamine is not recommended for renoprotective therapy, and neither a large randomized clinical trial nor a Meta-analysis found variability in the effects of low-dose dopamine and placebo when comparing them. (1A)
If a patient requires antihypertensive drug therapy, an arterial catheter should be placed to monitor blood pressure whenever possible to facilitate timely, accurate, continuous, and reproducible blood pressure information for analysis. (1D)
4.Positive inotropic therapy
Dobutamine should be administered intravenously in patients with elevated cardiac filling pressures and reduced cardiac output, thereby suggesting cardiac insufficiency. (1C)
Two large prospective clinical studies of critically ill patients in the ICU found no benefit to the use of dobutamine to increase oxygen delivery to supernormal levels in patients with severe sepsis and opposed therapy to bring cardiac index to supernormal levels. (1B)
Second, anti-infective therapy (antibiotic therapy)
1. Pathogenic diagnosis (diagnosis)
In cases where antibiotic therapy is not clinically delayed, at least two blood specimens should be obtained for pathogenic examination, one by percutaneous puncture and the other from an intravascular catheter left in place for more than 48 hours. In the same situation, other possible foci of infection such as urine, cerebrospinal fluid, wounds, respiratory secretions, etc. should be retained for pathogenic examination. (1C)
To identify potential foci of infection at an early stage, rapid and timely imaging should be performed for the patient, and specimens of infected foci should be obtained as soon as their presence is clearly established. In patients who are unstable and cannot undergo invasive procedures or are simply not transported out of the ICU, bedside ultrasound is the most effective method. (1C)
2.Antibiotic therapy
In case of confirmed septic shock (1B) or severe sepsis without septic shock (1D), antibiotic therapy should be administered intravenously within one hour if possible. Pathogenic specimens should be retained prior to antibiotic administration, but this should not delay the application of antibiotics (1D)
The initial empirical anti-infective therapy should select one or more drugs to cover all possible pathogenic microorganisms (bacterial and/or fungal) and the drug must be able to penetrate into the foci of infection that may lead to sepsis to ensure adequate drug concentrations. (1B)
Guidelines recommend that antibiotic regimens should be evaluated daily to achieve desired clinical outcomes, prevent the development of bacterial resistance, reduce toxicity to the patient, and reduce cost to the patient (1C).
When a patient is known or suspected to have severe sepsis due to Pseudomonas spp. infection, a combination therapy approach should be used (2D). An empirical combination therapy approach should also be performed in patients with neutropenia (2D).
In patients with severe sepsis, combination therapy should be applied empirically for no more than 3 to 5 days. Once definitive drug sensitivity results are available then the most appropriate single antibiotic therapy should be selected in descending steps (2D). The total course of treatment is generally 7 to 10 days; however, patients with a slow clinical response to therapy, incomplete clearance of the infected lesion, or immunodeficiency including neutropenia should be appropriately prolonged (1D).
If a patient’s existing clinical symptoms are determined to be caused by non-infectious factors, antibiotic therapy should be rapidly discontinued to reduce the patient’s risk of infection and drug-related side effects caused by antibiotic-resistant bacteria (1D).
3. Control the source of infection (source control)
For site-specific infections requiring urgent management (e.g., necrotizing fasciitis, diffuse peritonitis, cholangitis, intestinal infarction, etc.), a definitive diagnosis should be made as soon as possible (1C)/within 6 hours of symptom onset (1D).
All patients with sepsis should be evaluated for the need to select appropriate infection source control measures, such as abscess drainage, debridement of infected necrotic tissue, removal of medical devices in the body that may cause infection, and definitive control of microbial sources of infection that are undergoing contamination (1C). However, when peripancreatic tissue necrosis may become a focus of infection, surgical intervention should wait until a clear demarcation between normal peripancreatic tissue and necrotic tissue is present (2B).
When an infected focus requires management, effective interventions with minimal physiological impact, such as percutaneous drainage of the abscess rather than surgical drainage, are preferable (1D). When an intravascular catheter may be the source of infection in severe sepsis or septic shock, immediate removal after establishing new vascular access is recommended (1C) .
C. Adrenocorticosteroids
The expert panel of the 2008 guideline was more controversial about whether to apply adrenocorticosteroids in patients with septic shock, and the recommendation level was lower than before. For adult patients with septic shock, intravenous application of adrenocorticosteroids is only recommended when blood pressure is insensitive to fluid resuscitation and antihypertensive drug therapy (2C).
The results of a large multicenter, randomized, controlled study by Annane et al [3] (which included patients with septic shock who were insensitive to fluid resuscitation and antihypertensive drug therapy, n=300) showed that patients with septic shock who did not respond to a pro-adrenocorticotropic hormone test (i.e., relative adrenocortical insufficiency) were treated with hydrocortisone (300 mg/day) and fludrocortisone ( 50ug/day) reduced 28-day mortality without significant side effects; however, another large multicenter, randomized, controlled study led by Sprung [4] (which included septic shock patients who were not sensitive to fluid resuscitation therapy and whose response to boosters was not considered, n=499) found that, regardless of whether patients responded to a pro-adrenocorticotropic hormone test The use of hydrocortisone did not reduce 28-day mortality in patients with septic shock and increased the chance of developing secondary infections, regardless of whether the patients responded to a pro-adrenocorticosteroid test or not.
Based on the findings of Sprung et al, experts do not recommend an ACTH excitation test to identify patients for adrenocorticosteroid therapy (2B); if adrenocorticosteroid therapy is used, hydrocortisone is preferred over dexamethasone (2B); if hydrocortisone is not available, fludrocortisone (50ug/day) may be added if the corticosteroid of choice does not have significant salt corticosteroid effects. In cases where hydrocortisone is not available, oral treatment with fludrocortisone (50ug/day) may be added if the chosen corticosteroid does not have a significant salt corticosteroid effect; if already treated with hydrocortisone, combined or uncombined fludrocortisone (2C) may be chosen; if the patient does not require further treatment with an elevator, discontinuation of adrenocorticosteroids (2D) is recommended.
Expert consensus opinion is that the dose of hydrocortisone used to treat septic shock should not exceed 300 mg/day (1A) and that high-dose hormone therapy is not beneficial in patients with septic shock. In addition, adrenocorticotropic hormones should not be used in patients with sepsis who are not in shock unless the patient requires continued hormone therapy for endocrine disease or other reasons (1D).
Recombinant human activated protein C (recombinant human activated protein C)
Antagonizing the excessive inflammatory response and hypercoagulation has been considered an effective way to treat sepsis, which is characterized by widespread activation of the inflammatory and coagulation systems after infection. After the failure of numerous anti-inflammatory measures and anticoagulant therapy, new ideas suggest that there is a strong link between inflammation and the coagulation system, and that some drugs with both anti-inflammatory and anticoagulant activities may produce better results, and recombinant human activated protein C is a representative of such drugs.
Activated protein C is a natural anticoagulant in the body, which can prevent thrombin synthesis by protein hydrolysis of coagulation factors Va and VIIIa, and neutralize type I fibrinogen activator inhibitors to enhance fibrinolytic capacity. On the other hand, through endothelial cell protein C receptors and inflammatory cell protein kinase receptors, activated protein C is extensively involved in the regulation of the inflammatory state of endothelial cells and exhibits potential anti-inflammatory activity.
The results of the PROWESS study [5] showed that recombinant human activated protein C treatment in patients with severe sepsis, especially with multi-organ insufficiency or APACHE II ≥25, resulted in a decrease in morbidity and mortality. However, the ADDRESS study [6] showed no benefit and an increased risk of severe bleeding with recombinant human activated protein C in patients with severe sepsis with a low risk of death (e.g., only one organ insufficiency or APACHE II <25). Therefore, the guidelines recommend that adult patients with severe sepsis with a high clinical assessment of mortality risk (most APACHE II ≥25 or multiple organ insufficiency) may receive recombinant human activated protein C therapy if there are no contraindications (2B, 2C for patients undergoing surgery within 30 days). In adult patients with severe sepsis at low risk of death (most APACHE II <20 or one organ insufficiency), recombinant human activated protein C therapy is not recommended (1A).
V. Deep vein thrombosis prophylaxis (DVT)
Patients with severe sepsis and septic shock often combine one or more risk factors for deep vein thrombosis, such as advanced age, bed rest, indwelling central venous catheter, recent surgery or severe medical disease, and are at high risk for venous thromboembolic events. Deep vein thrombosis can dislodge and lead to acute pulmonary embolism, increasing the risk of death in patients with sepsis. Prophylactic treatment of sepsis patients with DVT may reduce the incidence of venous thromboembolic events and decrease the morbidity and mortality of septic patients. Guidelines recommend that prophylaxis of DVT in patients with severe sepsis can be done with low-dose plain heparin 2-3 times/day or daily low-molecular heparin, with contraindications such as thrombocytopenia, severe coagulopathy, active bleeding, and recent cerebral hemorrhage (1A). Device prophylaxis, such as graduated compression stockings or intermittent compression devices (unless contraindicated), is recommended for patients with contraindications to heparin (1A). For very high-risk patients, such as those with severe sepsis, history of deep vein thrombosis, trauma or surgery, combined pharmacological and mechanical methods of prophylaxis are recommended, unless contraindicated or impossible to perform (2C). In very high-risk patients, low-molecular-weight heparin is recommended over regular heparin because low-molecular heparin has been shown to be more advantageous in other high-risk patients (2C).
VI. Hemofiltration and renal replacement therapy (hemofiltration and renal replacement)
Theoretically, hemofiltration techniques not only remove metabolites and maintain water and electrolyte balance, but also have some ability to remove inflammatory mediators, cytokines, and endotoxins, and can play a positive role in the treatment of sepsis. However, there is no evidence to support the use of hemofiltration therapy in sepsis patients without combined renal failure. The results of a prospective, randomized, controlled, multicenter study [7] showed that continuous static-venous hemofiltration (CVVH) therapy within 24 hours of the first organ insufficiency in patients with sepsis, instead of reducing plasma cytokine levels, worsened the patients’ condition. Another randomized, controlled study [8] also found that early CVVH treatment did not reduce plasma cytokine levels in patients with sepsis, nor did it help patients to develop multi-organ insufficiency due to sepsis.
Therefore, the guidelines only recommend renal replacement therapy for patients with severe sepsis combined with acute renal failure, and the choice of continuous renal replacement therapy is equivalent to intermittent hemodialysis (2B). However, in patients with hemodynamically unstable sepsis, continuous renal replacement therapy can be more convenient for managing fluid balance (2D).
VII. Mechanical ventilation therapy (mechanical ventilation)
For acute lung injury and acute respiratory distress syndrome due to severe sepsis and septic shock, the guidelines recommend small tidal volume ventilation of 6 ml/kg ideal body weight (1B) with restriction of end-inspiratory plateau pressure ≤30 cmH2O (1C), and permissive hypercapnia may be present (1C). Treatment with the lowest positive end-expiratory pressure to prevent end-expiratory lung collapse (1C) is recommended. In the absence of contraindications, mechanically ventilated patients should have their heads elevated to reduce the risk of aspiration and to prevent ventilator-associated pneumonia (1B). When sedation is required in mechanically ventilated septic patients, intermittent sedation or continuous sedation input can be given to achieve the intended sedation goal (i.e., depth of sedation), with minimal use of neuromuscular blocking agents (1B).
VIII. Other
Other treatment measures recommended by the guidelines include.
1. When the patient’s hemoglobin is less than 70 g/L, transfusion of red blood cells is recommended to keep the hemoglobin at 70-90 g/L (1B).
2. In patients with hypoperfusion-induced hyperlactatemia, sodium bicarbonate is not recommended to improve hemodynamics or for reducing the use of elevating agents when the pH is ≥7.15 (1B).
3, Patients with severe sepsis may use H2 receptor blockers (1A) or proton pump inhibitors PPI (1B) to prevent upper gastrointestinal bleeding due to stress ulcers, but also consider that elevated intragastric pH may increase the risk of ventilator-associated pneumonia.
4. The guideline panel was divided on the issue of selective bowel decontamination (SDD), with almost equal numbers in favor of and against the use of SDD, so no recommendation was made for the application of SDD in patients with severe sepsis.
5. For patients with sepsis combined with hyperglycemia who have been initially stabilized, intravenous insulin therapy should be used to control blood glucose (1B). Adjust the insulin dose using an effective protocol to control blood glucose below 150 mg/dl (8.3 mmol/ L) (2C). Monitor blood glucose every 1 to 2 hours until the blood glucose and insulin dosage are stable and then may be monitored every 4 hours (1C). When monitoring peripheral blood glucose levels by rapid bedside tests, caution should be exercised if blood glucose values are low, as arterial or plasma blood glucose values may be lower than those detected (1B).
The essence of sepsis lies in the excessive release of numerous mediators by the body causing uncontrolled inflammatory response, immune dysfunction and abnormal coagulation system, and the principle of rescue and treatment should emphasize prevention over treatment, that is, to enhance the early treatment of its basic pathogenic factors such as trauma, shock and infection to eliminate or reduce the occurrence and development of sepsis. With the further clarification of the pathogenesis and pathophysiological process of sepsis, the deeper understanding of the network system composed of various inflammatory mediators, cytokines and coagulation factors in the body, and the continuous development of new therapeutic techniques and means, the prognosis of severe sepsis and septic shock will also be continuously improved.