Sepsis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2];

Overview

The "Surviving Sepsis Campaign" was an international effort organized by physicians that developed and promoted widespread adoption of practice improvement programs grounded in evidence-based guidelines. The goal was to improve diagnosis and treatment of sepsis. Included among the guidelines were sepsis screening for high-risk patients; taking bacterial cultures soon after the patient arrived at the hospital; starting patients on broad-spectrum intravenous antibiotic therapy before the results of the cultures are obtained; identifying the source of infection and taking steps to control it (e.g., abscess drainage); administering intravenous fluids to correct a loss or decrease in blood volume; and maintaining glycemic (blood sugar) control. These and similar guidelines have been tested by a number of hospitals and have shown potential for decreasing hospital mortality due to sepsis.

Medical Therapy

The delay in administering therapy after sepsis has been recognized, is the main problem in the adequate management of septic patients. For every hour delay in the administration of appropriate antibiotic therapy there is an associated 7% rise in mortality. A large international collaboration was established to educate people about sepsis and to improve patient outcomes with sepsis, entitled the "Surviving Sepsis Campaign".

Early Goal Directed Therapy (EGDT)

Early Goal Directed Therapy (EGDT), developed at Henry Ford Hospital by E. Rivers, MD, is a systematic approach to resuscitation that has been validated in the treatment of severe sepsis and septic shock. It is meant to be started in the Emergency Department. The theory is that one should use a step-wise approach, having the patient meet physiologic goals, to optimize cardiac preload, afterload, and contractility, thus optimizing oxygen delivery to the tissues.

Although initial studies reported benefit from EGDT, the more recent ProCESS and ARISE trials failed to demonstrate any benefit. However, the outcomes in the control groups of these trials were much more favorable than in the earlier trials. The extent of protocol-based care in the 'usual care' of the control groups is not known.

In Early Goal Directed Therapy:

• Fluids are administered until the central venous pressure (CVP), as measured by a central venous catheter, reaches 8-12 cm of water (or 10-15 cm of water in mechanically ventilated patients).
• If the mean arterial pressure is less than 65 mmHg or greater than 90 mmHg, vasopressors or vasodilators are given as needed to reach the goal.
• The central venous saturation (ScvO2), i.e. the oxygen saturation of venous blood as it returns to the heart as measured at the superior vena cava, is optimized. If the ScvO2 is less than 70%, blood is given to reach a hemoglobin of 10 g/dl and then inotropes are added until the ScvO2 is optimized. Elective intubation may be performed to reduce oxygen demand if the ScvO2 remains low despite optimization of hemodynamics.
• Urine output is also monitored, with a goal of 0.5 mL/kg/h. In the original trial, mortality was cut from 46.5% in the control group to 30.5% in the intervention group. The Surviving Sepsis Campaign guidelines recommends EGDT for the initial resuscitation of the septic patient with a level B strength of evidence.

GENESIS Project

The protocol per the GENESIS Project is:

• Measure serum lactate
• Obtain blood cultures and administer broad-spectrum antibiotic within 3 hours of emergency department admission
• If hypotensive or serum lactate 4 mmol/L
  • 20 mL/kg of crystalloid
  • If needed, add vasopressors to keep mean arterial pressure >65 mm Hg
  • If needed, aim for central venous pressure 8 mm Hg
  • If needed, aim for central venous oxygen saturation 70%

Standard treatment of infants with suspected sepsis consists of supportive care, maintaining fluid status with intravenous fluids, and the combination of a beta-lactam antibiotic (such as ampicillin) with an aminoglycoside such as gentamicin.

Contraindicated Medications

Sepsis is considered an absolute contraindication to the use of the following medications:

• Etanercept
• Sitagliptin And Metformin Hydrochloride

2008 Surviving Sepsis Campaign International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)

Initial Resuscitation (DO NOT EDIT)

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1. The guideline committee recommends the protocolized resuscitation of a patient with sepsis-induced shock, defined as tissue hypoperfusion (hypotension persisting after initial fluid challenge or blood lactate concentration equal to or greater than 4 mmol/L). This protocol should be initiated as soon as hypoperfusion is recognized and should not be delayed pending intensive care unit (ICU) admission. During the first 6 hours of resuscitation, the goals of initial resuscitation of sepsis-induced hypoperfusion should include all of the following as one part of a treatment protocol: Central venous pressure (CVP) 8–12 mm Hg Mean arterial pressure (MAP) >65 mm Hg Urine output >0.5 mL/kg/hour Central venous (superior vena cava) or mixed venous oxygen saturation >70% or >65%, respectively. (Grade 1C) 2. The guideline committee suggests that during the first 6 hours of resuscitation of severe sepsis or septic shock, if central venous oxygen saturation (SCVO2) or mixed venous saturation (SvO2) of 70% or 65% respectively is not achieved with fluid resuscitation to the CVP target, then transfusion of packed red blood cells to achieve a hematocrit of >30% and/or administration of a dobutamine infusion (up to a maximum of 20 micrograms/kg/min) be utilized to achieve this goal. (Grade 2C)

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Antibiotic Therapy (DO NOT EDIT)

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1. The guideline committee recommends that intravenous antibiotic therapy be started as early as possible and within the first hour of recognition of septic shock (Grade 1B) and severe sepsis without septic shock (Grade 1D). Appropriate cultures should be obtained before initiating antibiotic therapy, but should not prevent prompt administration of antimicrobial therapy. (Grade 1D) 2a. The guideline committee recommends that initial empirical anti-infective therapy include one or more drugs that have activity against all likely pathogens (bacterial and/or fungal) and that penetrate in adequate concentrations into the presumed source of sepsis. (Grade 1B) 2b. The guideline committee recommends that the antimicrobial regimen be reassessed daily to optimize activity, to prevent the development of resistance, to reduce toxicity, and to reduce costs. (Grade 1C) 2c. The guideline committee suggests combination therapy for patients with known or suspected Pseudomonas infections as a cause of severe sepsis. (Grade 2D) 2d. The guideline committee suggests combination empiric therapy for neutropenic patients with severe sepsis. (Grade 2D) 2e. When used empirically in patients with severe sepsis, the guideline committee suggests that combination therapy should not be administered for more than 3 to 5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known. (Grade 2D) 3. The guideline committee recommends that the duration of therapy typically be 7 to 10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, or who have immunologic deficiencies including neutropenia. (Grade 1D) 4. If the presenting clinical syndrome is determined to be due to a noninfectious cause, the guideline committee recommends antimicrobial therapy be stopped promptly to minimize the likelihood that the patient will become infected with an antibiotic resistant pathogen or will develop a drug related adverse effect. (Grade 1D)

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Source Control (DO NOT EDIT)

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1a. The guideline committee recommends that a specific anatomic diagnosis of infection requiring consideration for emergent source control - for example necrotizing fasciitis, diffuse peritonitis, cholangitis, intestinal infarction – be sought and diagnosed or excluded as rapidly as possible (Grade 1C) and within the first 6 hours following presentation. (Grade 1D) 1b. The guideline committee further recommends that all patients presenting with severe sepsis be evaluated for the presence of a focus of infection amenable to source control measures, specifically the drainage of an abscess or local focus of infection, the debridement of infected necrotic tissue, the removal of a potentially infected device, or the definitive control of a source of ongoing microbial contamination. (Grade 1C) 2. The guideline committee suggests that when infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and non-viable tissues has occurred. (Grade 2B) 3. The guideline committee recommends that when source control is required, the effective intervention associated with the least physiologic insult be employed, for example, percutaneous rather than surgical drainage of an abscess. (Grade 1D) 4. The guideline committee recommends that when intravascular access devices are a possible source of severe sepsis or septic shock, they be promptly removed after establishing other vascular access. (Grade 1C)

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Fluid Therapy (DO NOT EDIT)

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1. The guideline committee recommends fluid resuscitation with either natural/artificial colloids or crystalloids. There is no evidence-based support for one type of fluid over another. (Grade 1B) 2. The guideline committee recommends fluid resuscitation initially target a CVP of at least 8 mm Hg (12 mm Hg in mechanically ventilated patients). Further fluid therapy is often required. (Grade 1C) 3a. The guideline committee recommends that a fluid challenge technique be applied, wherein fluid administration is continued as long as the hemodynamic improvement (for example, arterial pressure, heart rate, urine output) continues. (Grade 1D) 3b. The guideline committee recommends fluid challenge in patients with suspected hypovolemia be started with at least 1000 mL of crystalloids or 300 to 500 mL of colloids over 30 minutes. More rapid administration and greater amounts of fluid may be needed in patients with sepsis induced tissue hypoperfusion (see initial resuscitation recommendations). (Grade 1D) 3c. The guideline committee recommends the rate of fluid administration be reduced substantially when cardiac filling pressures (CVP or pulmonary artery balloon-occluded pressure) increase without concurrent hemodynamic improvement. (Grade 1D)

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Vasopressors (DO NOT EDIT)

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1. The guideline committee recommends mean arterial pressure (MAP) be maintained >65 mm Hg. (Grade 1C) 2. The guideline committee recommends either norepinephrine or dopamine as the first choice vasopressor agent to correct hypotension in septic shock (administered through a central catheter as soon as one is available). (Grade 1C) 3a. The guideline committee suggests that epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock. (Grade 2C) Vasopressin 0.03 units/min may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone. 3b. The guideline committee suggests that epinephrine be the first chosen alternative agent in septic shock that is poorly responsive to norepinephrine or dopamine. (Grade 2B) 5. The guideline committee recommends that low dose dopamine not be used for renal protection. (Grade 1A) 6. The guideline committee recommends that all patients requiring vasopressors have an arterial line placed as soon as practical if resources are available. (Grade 1D)

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Inotropic Therapy (DO NOT EDIT)

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1. The guideline committee recommends a dobutamine infusion be administered in the presence of myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output. (Grade 1C) 2. The guideline committee recommends against the use of a strategy to increase cardiac index to predetermined supranormal levels. (Grade 1B)

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Corticosteroids (DO NOT EDIT)

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1. The guideline committee suggests intravenous hydrocortisone be given only to adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy. (Grade 2C) 2. The guideline committee suggests the adrenocorticotropic hormone (ACTH) stimulation test not be used to identify the subset of adults with septic shock who should receive hydrocortisone. (Grade 2B) 3. The guideline committee suggests that patients with septic shock should not receive dexamethasone if hydrocortisone is available. (Grade 2B) 4. The guideline committee suggests the daily addition of oral fludrocortisone (50 micrograms) if hydrocortisone is not available and the steroid that is substituted has no significant mineralocorticoid activity. Fludrocortisone is considered optional if hydrocortisone is used. (Grade 2C) 5. The guideline committee suggests clinicians wean the patient from steroid therapy when vasopressors are no longer required. (Grade 2D) 6. The guideline committee recommends doses of corticosteroids comparable to >300 mg hydrocortisone daily not be used in severe sepsis or septic shock for the purpose of treating septic shock. (Grade 1A) 7. The guideline committee recommends corticosteroids not be administered for the treatment of sepsis in the absence of shock. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress-dose steroids if the patient's endocrine or corticosteroid administration history warrants. (Grade 1D)

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Recombinant Human Activated Protein C (rhAPC) (DO NOT EDIT)

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1. The guideline committee suggests that adult patients with sepsis induced organ dysfunction associated with a clinical assessment of high risk of death, most of whom will have Acute Physiology and Chronic Health Evaluation II (APACHE II) ≥25 or multiple organ failure, receive recombinant human activated protein C (rhAPC) if there are no contraindications (Grade 2B except for patients within 30 days of surgery where it is Grade 2C). Relative contraindications should also be considered in decision making. On October 25, 2011 the U.S. Food and Drug Administration (FDA) notified healthcare professionals and the public that Eli Lilly and Company announced a worldwide voluntary market withdrawal of Xigris [drotrecogin alfa (activated)]. In a recently completed clinical trial (PROWESS-SHOCK trial), Xigris failed to show a survival benefit for patients with severe sepsis and septic shock. 2. The guideline committee recommends that adult patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC. (Grade 1A)

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Blood Product Administration (DO NOT EDIT)

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1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease, or lactic acidosis (see recommendations for initial resuscitation), the guideline committee recommends that red blood cell transfusion occur when hemoglobin decreases to <7.0 g/dL (<70 g/L) to target a hemoglobin of 7.0 to 9.0 g/dL (70 to 90 g/L) in adults. (Grade 1B) 2. The guideline committee recommends that erythropoietin not be used as a specific treatment of anemia associated with severe sepsis, but may be used when septic patients have other accepted reasons for administration of erythropoietin such as renal failure-induced compromise of red blood cell production. (Grade 1B) 3. The guideline committee suggests that fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures. (Grade 2D) 4. The guideline committee recommends against antithrombin administration for the treatment of severe sepsis and septic shock. (Grade 1B) 5. In patients with severe sepsis, the guideline committee suggests that platelets should be administered when counts are <5000/mm3 (5 × 109/L) regardless of apparent bleeding. Platelet transfusion may be considered when counts are 5,000 to 30,000/mm3 (5 to 30 × 109/L) and there is a significant risk of bleeding. Higher platelet counts >50,000/mm3 (50 × 109/L) are typically required for surgery or invasive procedures. (Grade 2D)

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Supportive Therapy of Severe Sepsis (DO NOT EDIT)

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Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) 1. The guideline committee recommends that clinicians target a tidal volume of 6 mL/kg (predicted) body weight in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). (Grade 1B) 2. The guideline committee recommends that plateau pressures be measured in patients with ALI/ARDS and that the initial upper limit goal for plateau pressures in a passively inflated patient be <30 cm H2O. Chest wall compliance should be considered in the assessment of plateau pressure. (Grade 1C) 3. The guideline committee recommends that hypercapnia (allowing partial pressure of arterial carbon dioxide [PaCO2] to increase above its pre-morbid baseline, so-called permissive hypercapnia) be allowed in patients with ALI/ARDS if needed to minimize plateau pressures and tidal volumes. (Grade 1C) 4. The guideline committee recommends that positive end-expiratory pressure (PEEP) be set so as to avoid extensive lung collapse at end-expiration. (Grade 1C) 5. The guideline committee suggests prone positioning in ARDS patients requiring potentially injurious levels of fraction of inspired oxygen (FiO2) or plateau pressure who are not at high risk for adverse consequences of positional changes in those facilities who have experience with such practices. (Grade 2C) 6a. Unless contraindicated, the guideline committee recommends mechanically ventilated patients be maintained with the head of the bed elevated to limit aspiration risk and to prevent the development of ventilator-associated pneumonia. (Grade 1B) 6b. The guideline committee suggests that the head of bed is elevated approximately 30 to 45 degrees. (Grade 2C) 7. The guideline committee suggests that noninvasive mask ventilation (NIV) only be considered in that minority of ALI/ARDS patients with mild-moderate hypoxemic respiratory failure (responsive to relatively low levels of pressure support and PEEP) with stable hemodynamics who can be made comfortable and easily arousable, who are able to protect the airway, spontaneously clear the airway of secretions, and are anticipated to recover rapidly from the precipitating insult. A low threshold for airway intubation should be maintained. (Grade 2B) 8. The guideline committee recommends that a weaning protocol be in place, and mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials on a regular basis to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable (without vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-expiratory pressure requirements; and e) FiO2 requirements that could be safely delivered with a face mask or nasal cannula. If the spontaneous breathing trial is successful, consideration should be given for extubation. Spontaneous breathing trial options include a low level of pressure support, continuous positive airway pressure (approximately 5 cm H2O) or a T-piece. (Grade 1A) 9. The guideline committee recommends against the routine use of the pulmonary artery catheter for patients with ALI/ARDS. (Grade 1A) 10. To decrease days of mechanical ventilation and ICU length of stay the guideline committee recommends a conservative fluid strategy for patients with established acute lung injury who do not have evidence of tissue hypoperfusion. (Grade 1C) Sedation, Analgesia, and Neuromuscular Blockade in Sepsis 1. The guideline committee recommends sedation protocols with a sedation goal when sedation of critically ill mechanically ventilated patients with sepsis is required. (Grade 1B) 2. The guideline committee recommends intermittent bolus sedation or continuous infusion sedation to predetermined end points (e.g., sedation scales) with daily interruption/lightening of continuous infusion sedation with awakening and retitration if necessary for sedation administration to septic mechanically ventilated patients. (Grade 1B) 3. The guideline committee recommends that neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as required or continuous infusion with monitoring the depth of blockade with train-of-four monitoring should be used. (Grade 1B) Glucose Control 1. The guideline committee recommends that, following initial stabilization, patients with severe sepsis and hyperglycemia who are admitted to the ICU receive intravenous (IV) insulin therapy to reduce blood glucose levels. (Grade 1B) 2. The guideline committee suggests use of a validated protocol for insulin dose adjustments and targeting glucose levels to the <150 mg/dL range. (Grade 2C) 3. The guideline committee recommends that all patients receiving intravenous insulin receive a glucose calorie source and that blood glucose values be monitored every 1 to 2 hours until glucose values and insulin infusion rates are stable and then every 4 hours thereafter. (Grade 1C) 4. The guideline committee recommends that low glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may overestimate arterial blood or plasma glucose values. (Grade 1B) Renal Replacement 1. The guideline committee suggests that continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure. (Grade 2B) 2. The guideline committee suggests the use of continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients. (Grade 2D) Bicarbonate Therapy 1. The guideline committee recommends against the use of sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH >7.15. (Grade 1B) Deep Vein Thrombosis Prophylaxis 1. The guideline committee recommends that severe sepsis patients receive deep vein thrombosis (DVT) prophylaxis with either (a) low-dose unfractionated heparin (UFH) administered twice daily or three times daily or (b) daily low-molecular weight heparin (LMWH) unless there are contraindications (i.e., thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage). (Grade 1A) 2. The guideline committee recommends that septic patients who have a contraindication for heparin use receive mechanical prophylactic device such as graduated compression stockings (GCS) or intermittent compression devices (ICD) unless contraindicated. (Grade 1A) 3. The guideline committee suggests that in very high-risk patients such as those who have severe sepsis and history of DVT, trauma, or orthopedic surgery, a combination of pharmacologic and mechanical therapy be used unless contraindicated or not practical. (Grade 2C) 4. The guideline committee suggests that in patients at very high risk, LMWH be used rather than UFH as LMWH is proven superior in other high-risk patients. (Grade 2C) Stress Ulcer Prophylaxis (SUP) 1. The guideline committee recommends that stress ulcer prophylaxis (SUP) using H2 blocker (Grade 1A) or proton pump inhibitor (Grade 1B) be given to patients with severe sepsis to prevent upper gastrointestinal (GI) bleed. 2. Benefit of prevention of upper GI bleed must be weighed against potential effect of an increased stomach pH on development of ventilator-associated pneumonia. Selective Digestive Tract Decontamination (SDD) 1. The guideline committee was evenly split on the issue of selective digestive tract decontamination (SDD), with equal numbers weakly in favor and against recommending the use of SDD. The committee therefore chose not to make a recommendation for the use of SDD specifically in severe sepsis at this time. The final consensus on use of SDD in severe sepsis was achieved at the last nominal committee meeting and subsequently approved by the entire committee.

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