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.B.B.S. [2]

Overview

The goals for the treatment of sepsis per the Surviving Sepsis Campaign include 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. In addition, hospital length of stay may be shortened.

Improving speed of treatment

Electronic alerts in the electronic health record may or may not improve outcomes.

Medical Therapy

• The delay in administering therapy is associated with outcomes among septic patients.
• For every hour delay in the administration of appropriate antibiotic therapy there is an associated 7% rise in mortality.

Fluid therapy

Guidelines

The 2012 Surviving Sepsis Campaign (SSC) recommendations proposed (see details below):

• Fluid challenge of at least 30 ml/kg of crystalloid in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia.
• However, due to variable patient response to treatment, the SSC guidelines also state that “more rapid administration and greater amounts of fluid may be needed in patients with sepsis-induced tissue hypoperfusion.”

The SSC guidelines also targeted a mean arterial pressure (MAP) of at least 65 mmHg and a central venous pressure (CVP) of

• At least 8 mmHg in the non mechanically-ventilated patient
• At least 12-15 mmHg in the mechanically-ventilated patient

In National Institute for Health and Care Excellence (NICE) guideline No. 51 (PMID 27441326), as proposed by the National Guideline Centre (UK), a systematic review of randomized controlled trials concluded that patients over 16 years with severe sepsis or septic shock requiring fluid resuscitation should receive

• “crystalloids containing sodium in the range 130–154 mmol/litre with a bolus of 500 ml over less than 15 minutes.”
• The patient should then be reassessed and, if fluid status has not improved, receive a second bolus.
• If the patient’s status does not improve following the second bolus, the guidelines recommend consultation of a specialist.

Evidence

Regarding underlying evidence, a systematic review of randomized control trials concluded:

• Strict adherence to early goal directed therapy of septic shock is not necessary. However, principles of early identification and fluid resuscitation, prompt administration of antibiotics, and adequate monitoring of patient parameters should be considered in treatment of patients with severe sepsis and septic shock.

A second systematic review of ProCESS, ProMISe, and ARISE randomized controlled trials, concluded:

• Early goal directed therapy remains the gold standard for treatment of severe sepsis and septic shock given that EGDT has proven internal and external validity.
• While non-inferior outcomes may be able to be achieved using alternative treatment strategies, there is a lack of sufficient evidence backing other protocols.

A third meta-analysis concluded:

• In patient populations with higher mortality, EGDT or lactate level and central venous pressure normalization are viable therapies.
• Newer evidence challenges the need for strict adherence to six hour bundle goals in populations with lower mortality.

Another meta-analysis by the recent trialists of the three most recent trials found that low mortality was achieved even in the control groups in all three studies which was based on the standard care at each institution. The amount of fluid administered in these three trials was 30 ml/kg prior to enrollment and then ranged from 1.9-2.6 L in the first three hours prior to diagnosis of septic shock. Approximately 1.7-3.3 L of additional fluid was given once the septic shock protocol was initiated in both the control and EGDT groups. Total fluids at 9 hours averaged between 4.0 - 5.5 L.

Regarding the speed fluid administration, only two trials revealed an explicit protocol. These showed the fluids being administered in 500-1,000mL boluses every 30 minutes.

Regarding type of fluids, a meta-analysis concluded "among the patients with sepsis, fluid resuscitation with crystalloids compared to starch resulted in reduced use of RRT; the same may be true for albumin versus starch." A more recent trial of patients with diverse diagnoses found no difference.

Excessive fluid therapy

Positive fluid balance may be associated with worse outcomes in most, but not all studies. For example, a retrospective review of patient in Vasopressin in Septic Shock Trial (VASST) determined positive fluid balance initially at 12 hr and cumulatively at 4 days resulted in higher mortality.

De-escalation and removal of fluids

Avoidance of fluid overload may be avoid be careful restriction of fluids after the initial 30 ml/kg bolus according to a randomized controlled trial. Expert opinion suggests positive fluid balance should be addresses within three days of resuscitation.

Hemodynamic monitoring

Regarding the monitoring of fluid administration, few randomized controlled trials used an explicit protocol. These showed the fluids being administered in 500-1,000mL boluses every 30 minutes interspersed with more frequent patient reassessment than is currently required by both the Surviving Sepsis and CMS protocols. The patients in these studies were reevaluated at the time of each bolus administration (every 30 minutes.)

A meta-analysis of randomized controlled trials using early goal directed therapy found no significant benefit of the mandated use of central venous catheterization and central hemodynamic monitoring in all patients.

Methods of assessing fluid responsiveness

Various methods are available and have been reviewed.

Pulse contour analysis

Analysis of the pulse contour, whether assesses invasively by photo-plethysmography or nonivasively, can estimate cardiac output and other parameters. The accuracy of non-invasive photo-plethysmography is unclear. Commercial products include the invasive PICCO or the non-invasive ClearSight or Nexfin by Edwards.

Bioimpedance and bioreactance

Commercial products include the NICOM by Cheetah Medical.

Antibiotics

Timing

While a systematic review found there was no significant mortality benefit from administering antibiotics within 3 hours of emergency department triage ( OR 1.16, 0.92 to 1.46, p = 0.21) or within 1 hour of shock recognition (OR 1.46, 0.89 to 2.40, p = 0.13) in severe sepsis and septic shock, several concerns exist:

• The meta-analysis reported heterogeneity as insignificant (p = 0.09) with Cochran Q test. However, this is a significant result per the Cochrane collaboration's interpretation of the Cochran Q test.
• The study grouped patients by time to administration of antimicrobial therapy, but did not consider time to administration of appropriate antimicrobial therapy- likely lessening the effect of early therapy.
• One article contributed the majority of the sample size for the 1h group- with said sample including patients with higher sepsis severity scores, higher rates of septic shock, and higher rates of mortality- leading to a potential underestimation of the impact of early antibiotic use.

The two largest studies in the meta-analysis both found positive correlations between delays in antibiotics and mortality.

Delivery method

Continuous infusion may be more effective.

Steroids

Corticosteroids may reduce mortality among patients with septic shock according to a systematic review by the Cochrane Collaboration.

The subsequent HYPRESS randomized controlled trial of patients with severe sepsis showed now benefit.

Transfusion

In septic shock, leukoreduced erythrocyte transfusion is associated with similar clinical outcomes (90 day mortality and ischemic events) among patients who are administered erythrocyte transfusion at a hemoglobin threshold of 7 g/dL compared to those who receive it at a higher threshold of 9 g/dL.

Protocolized therapy

Several protocols have been recommended and studied. Compliance with bundles of care is associated with reduced mortality.

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:
  • Administer 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.

2012 Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)

2012 Bundle

TO BE COMPLETED WITHIN 3 HOURS:

Measure lactate level Obtain blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L

TO BE COMPLETED WITHIN 6 HOURS:

Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥4 mmol/L (36 mg/dL): - Measure central venous pressure (CVP). Target CVP: ≥8 mm Hg. - Measure central venous oxygen saturation (ScvO2). Target ScvO2: ≥70%. Remeasure lactate if initial lactate was elevated. Target lactate: normalization.

Initial Resuscitation

Initial Resuscitation

1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L). Goals during the first 6 hrs of resuscitation:

• Central venous pressure 8–12 mm Hg
• Mean arterial pressure (MAP) ≥ 65 mm Hg
• Urine output ≥ 0.5 mL/kg/hr
• Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively. (Grade 1C)

2. In patients with elevated lactate levels targeting resuscitation to normalize lactate. (Grade 2C)

Screening for Sepsis and Performance Improvement

1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy. (Grade 1C)

2. Hospital–based performance improvement efforts in severe sepsis.

Diagnosis

1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s). (Grade 1C) At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted. (Grade 1C)

2. Use of the 1,3 beta-D-glucan assay (Grade 2B), mannan and anti-mannan antibody assays (Grade 2C), if available and invasive candidiasis is in differential diagnosis of cause of infection.

3. Imaging studies performed promptly to confirm a potential source of infection.

Infection Issues

• At least 2 sets of blood cultures should be drawn before antibiotic therapy (percutaneous and through vascular access). This should be done only if there was no significant delay in antibiotic administration (<45 mins). (Grade 1B) for septic shock, and (Grade 1C) for severe sepsis.
• Broad-spectrum antibiotics should be initiated within the first hour of recognition of severe sepsis or septic shock, with daily reassessment for de-escalation. (Grade 1B)
• Initial broad-spectrum antibiotics should consist of one or more drugs covering all likely sources (bacterial, and/or fungal or viral). With good penetration in sufficient concentrations into tissue of presumed source. (Grade 1B)
• Low procalcitonin levels could be used to re-assess patient status for purposes of discontinuation of broad-spectrum antibiotics, in patients who appear septic but have no evidence of infection. (Grade 2C)
• Combination broad-spectrum antibiotic therapy is recommended for: Neutropenic patients with severe sepsis, and patients with multidrug resistant bacterial pathogens (such as Acinetobacter and Pseudomonas app.) (Grade 2B)
• Patients with severe infections associated with respiratory failure and septic shock, combination broad-spectrum antibiotics is recommended. A broad-spectrum beta lactam with either an aminoglycoside or a fluoroquinolone for P.aeruginosa bacteremia, and broad-spectrum beta lactam with a macrolide for Streptococcus pneumoniae. (Grade 2B)
• Combination broad-spectrum antibiotic therapy should be de-escalated to the most appropriate single therapy as soon as the susceptibility profile is known. Combination therapy should not be administered for more than 3-5 days. (Grade 2B)
• Duration of therapy should typically last 7-10 days; but longer courses could be necessary for patients with slow clinical response, undrainable niche of infection, bacteremia with S.aureus; some fungal or viral infections, or immunological deficiencies. (Grade 2C)
• Antibacterial therapy is not recommended for patients with severe inflammatory states without an infectious source. GRADE: UG

Antimicrobial Regimen

Sepsis, adult

• 1. Sepsis, adult

• 1.1 Empiric antimicrobial therapy

• 1.1.1 History of intravenous drug use with high prevalence of MRSA

• Perferred regimen: Vancomycin 1 g IV q12h

• 1.1.2 Sepsis associated with petechiae

• Perferred regimen: Ceftriaxone 2 g IV q12h

• 1.1.3 Biliary source

• 1. Community-acquired acute cholecystitis of mild-to-moderate severity

• Preferred regimen (1): Cefazolin 1–2 g IV q8h
• Preferred regimen (2): Cefuroxime 1.5 g IV q8h
• Preferred regimen (3): Ceftriaxone 1–2 g IV q12–24 h

• 2. Community-acquired acute cholecystitis of severe physiologic disturbance, advanced age, or immunocompromised state

• Preferred regimen (1):Imipenem-cilastatin 500 mg IV q6h OR 1 g q8h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (2):Meropenem 1 g IV q8h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (3):Doripenem 500 mg IV q8h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (4):Piperacillin-tazobactam 3.375 g IV q6h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (5):Ciprofloxacin 400 mg IV q12h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (6):Levofloxacin 750 mg IV q24h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (7):Cefepime 2 g IV q8–12h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h

• 3. Acute cholangitis following bilio-enteric anastamosis of any severity

• Preferred regimen (1): Imipenem-cilastatin 500 mg IV q6h OR 1 g q8h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (2): Meropenem 1 g IV q8h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (3): Doripenem 500 mg IV q8h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (4): Piperacillin-tazobactam 3.375 g IV q6h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (5): Ciprofloxacin 400 mg IV q12h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (6): Levofloxacin 750 mg IV q24h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h
• Preferred regimen (7): Cefepime 2 g IV q8–12h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h

• 4. Health care-associated biliary infection of any severity

• Preferred regimen (1): Imipenem-cilastatin 500 mg IV q6h OR 1 g q8h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h AND Vancomycin 15–20 mg/kg IV q8–12 h
• Preferred regimen (2): Meropenem 1 g IV q8h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h AND Vancomycin 15–20 mg/kg IV q8–12 h
• Preferred regimen (3): Doripenem 500 mg IV q8h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h AND Vancomycin 15–20 mg/kg IV q8–12 h
• Preferred regimen (4): Piperacillin-tazobactam 3.375 g IV q6h, AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h AND Vancomycin 15–20 mg/kg IV q8–12 h
• Preferred regimen (5): Ciprofloxacin 400 mg IV q12h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h AND Vancomycin 15–20 mg/kg IV q8–12 h
• Preferred regimen (6): Levofloxacin 750 mg IV q24h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h AND Vancomycin 15–20 mg/kg IV q8–12 h
• Preferred regimen (7): Cefepime 2 g IV q8–12h AND Metronidazole 500 mg IV q8–12 h OR 1500 mg q24h AND Vancomycin 15–20 mg/kg IV q8–12 h

• Note: Antimicrobial therapy of established infection should be limited to 4–7 days, unless it is difficult to achieve adequate source control. Longer durations of therapy have not been associated with improved outcome.

• 1.1.4 Community-acquired pneumonia

• Preferred regimen: (Levofloxacin 750 mg IV q24h OR Moxifloxacin 400 mg IV q24h) AND Piperacillin-Tazobactam 3.375 g IV q4h AND Vancomycin 1 g IV q12h

• 1.1.5 Unclear infection source

• Preferred regimen: (Doripenem 500 mg IV q8h OR Ertapenem 1 g IV q24h OR Imipenem 0.5 g IV q6h OR Meropenem 1 g IV q8h) AND Vancomycin 1 g IV q12h

• 1.1.6 Low prevalence of ESBL and/or carbapenemase-producing aerobic GNB

• Preferred regimen: Piperacillin-Tazobactam 3.375 g IV q4h AND Vancomycin 1 g IV q12h

• 1.1.7 High prevalence of ESBL and/or carbapenemase-producing aerobic GNB

• Preferred regimen: Colistin 2.5 mg/kg single dose followed by 1.5 mg/kg IV q12h AND Meropenem 1 g IV q8h AND Vancomycin 1 g IV q12h

Sepsis, pediatric

• 1. Sepsis, pediatric

• 1.1 Empiric antimicrobial therapy

• 1.1.1 Children aged > 1 month

• Preferred regimen: (Cefotaxime 50 mg/kg IV q8h OR Ceftriaxone 100 mg/kg IV q24h) AND Vancomycin 15 mg/kg IV q6h
• Alternative regimen: Aztreonam 7.5 mg/kg IV q6h AND Linezolid 10 mg/kg IV q8h

• 1.1.2 Children aged < 1 month

• Preferred regimen: Ampicillin 25 mg/kg IV q8h AND Cefotaxime 50 mg/kg q12h ± Vancomycin 15 mg/kg IV q12h (if suspecting MRSA)
• Alternative regimen: Ampicillin 25 mg/kg IV q6h AND Ceftriaxone 75 mg/kg IV q24h ± Vancomycin 15 mg/kg IV q12h (if suspecting MRSA)

Source Control

1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible. (Grade 1C)

2. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred. (Grade 2B)

3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (eg, percutaneous rather than surgical drainage of an abscess).

4. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established.

Infection Prevention

1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; This infection control measure can then be instituted in health care settings and regions where this methodology is found to be effective. (Grade 2B)

1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis. (Grade 2B)

Hemodynamic Support and Adjunctive Therapy

Fluid Therapy of Severe Sepsis

1. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock. (Grade 1B)

2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock. (Grade 1B)

3. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids. (Grade 2C)

4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients. (Grade 1C)

5. Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables.

Vasopressors

1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg. (Grade 1C)

2. Norepinephrine as the first choice vasopressor. (Grade 1B)

3. Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. (Grade 2B)

4. Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage.

5. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents).

6. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). (Grade 2C)

7. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target. (Grade 1C)

8. Low-dose dopamine should not be used for renal protection. (Grade 1A)

9. All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available.

Inotropic Therapy

1. A trial of dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP. (Grade 1C)

2. Not using a strategy to increase cardiac index to predetermined supranormal levels. (Grade 1B)

Corticosteroids

1. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day. (Grade 2C)

2. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. (Grade 2B)

3. In treated patients hydrocortisone tapered when vasopressors are no longer required. (Grade 2D)

4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock. (Grade 1D)

5. When hydrocortisone is given, use continuous flow. (Grade 2D)

Other Supportive Therapy of Severe Sepsis

Blood Product Administration

1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic heart disease, we recommend that red blood cell transfusion occur only when hemoglobin concentration decreases to <7.0 g/dL to target a hemoglobin concentration of 7.0 –9.0 g/dL in adults. (Grade 1B)

2. Not using erythropoietin as a specific treatment of anemia associated with severe sepsis. (Grade 1B)

3. Fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures. (Grade 2D)

4. Not using antithrombin for the treatment of severe sepsis and septic shock. (Grade 1B)

5. In patients with severe sepsis, administer platelets prophylactically when counts are <10,000/mm3 (10 x 109/L) in the absence of apparent bleeding. We suggest prophylactic platelet transfusion when counts are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of bleeding. Higher platelet counts (≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures. (Grade 2D)

Immunoglobulins

1. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock. (Grade 2B)

Selenium

1. Not using intravenous selenium for the treatment of severe sepsis. (Grade 2C)

History of Recommendations Regarding Use of Recombinant Activated Protein C (rhAPC)

1. A history of the evolution of SSC recommendations as to rhAPC (no longer available) is provided.

Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)

1. Target a tidal volume of 6mL/kg predicted body weight in patients with sepsis-induced ARDS ((Grade 1A) vs. 12 mL/kg).

2. Plateau pressures be measured in patients with ARDS and initial upper limit goal for plateau pressures in a passively inflated lung be ≤30 cm H2O. (Grade 1B)

3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration (atelectotrauma). (Grade 1B)

4. Strategies based on higher rather than lower levels of PEEP be used for patients with sepsis-induced moderate or severe ARDS. (Grade 2C)

5. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia. (Grade 2C)

6. Prone positioning be used in sepsis-induced ARDS patients with a Pao2/Fio2 ratio ≤ 100mm Hg in facilities that have experience with such practices. (Grade 2B)

7. That mechanically ventilated sepsis patients be maintained with the head of the bed elevated to 30-45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia. (Grade 1B)

8. That noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks. (Grade 2B)

9. That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria:

• Arousable
• Hemodynamically stable (without vasopressor agents)
• No new potentially serious conditions
• Low ventilatory and end-expiratory pressure requirements
• Low Fio2 requirements which can be met safely delivered with a face mask or nasal cannula

If the spontaneous breathing trial is successful, consideration should be given for extubation. (Grade 1A)

10. Against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS. (Grade 1A)

11. A conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypo perfusion. (Grade 1C)

12. In the absence of specific indications such as bronchospasm, not using beta 2-agonists for treatment of sepsis-induced ARDS. (Grade 1B)

Sedation, Analgesia, and Neuromuscular blockade in Sepsis

1. Continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints. (Grade 1B)

2. Neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade should be used. (Grade 1C)

3. A short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a Pao2/Fio2 < 150 mm Hg. (Grade 2C)

Glucose Control

1. A protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when 2 consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target an upper blood glucose ≤180 mg/dL rather than an upper target blood glucose ≤ 110 mg/dL. (Grade 1A)

2. Blood glucose values be monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter. (Grade 1C)

3. Glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values.

Renal Replacement Therapy

1. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure. (Grade 2B)

2. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients. (Grade 2D)

Bicarbonate Therapy

1. Not using 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 2B)

Deep Vein Thrombosis Prophylaxis

1. Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE). (Grade 1B) This should be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) ((Grade 1B) versus twice daily UFH, (Grade 2C) versus three times daily UFH). If creatinine clearance is <30 mL/min, use dalteparin (Grade 1A) or another form of LMWH that has a low degree of renal metabolism (Grade 2C) or UFH (Grade 1A).

2. Patients with severe sepsis be treated with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible. (Grade 2C)

3. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage) not receive pharmacoprophylaxis (Grade 1B), but receive mechanical prophylactic treatment, such as graduated compression stockings or intermittent compression devices (Grade 2C), unless contraindicated. When the risk decreases start pharmacoprophylaxis. (Grade 2C)

Stress Ulcer Prophylaxis

1. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who have bleeding risk factors. (Grade 1B)

2. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA. (Grade 2D)

3. Patients without risk factors do not receive prophylaxis. (Grade 2B)

Nutrition

1. Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock. (Grade 2C)

2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day), advancing only as tolerated. (Grade 2B)

3. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock. (Grade 2B)

4. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis. (Grade 2C)

Setting Goals of Care

1. Discuss goals of care and prognosis with patients and families. (Grade 1B)

2. Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate. (Grade 1B)

3. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission. (Grade 2C)

Special Considerations in Pediatrics

Initial Resuscitation

1. For respiratory distress and hypoxemia start with face mask oxygen or if needed and available, high flow nasal cannula oxygen or nasopharyngeal CPAP (NP CPAP). For improved circulation, peripheral intravenous access or intraosseus access can be used for fluid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required then cardiovascular instability during intubation is less likely after appropriate cardiovascular resuscitation. (Grade 2C)

2. Initial therapeutic end points of resuscitation of septic shock: capillary refill of ≤2 secs, normal blood pressure for age, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output >1 mL·kg-1·hr-1, and normal mental status. Scvo2 saturation ≥70% and cardiac index between 3.3 and 6.0 L/min/m2 should be targeted thereafter. (Grade 2C)

3. Follow American College of Critical Care Medicine-Pediatric Life Support (ACCM-PALS) guidelines for the management of septic shock. (Grade 1C)

4. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock. (Grade 1C)

Antibiotics and Source Control

1. Empiric antibiotics be administered within 1 hr of the identification of severe sepsis. Blood cultures should be obtained before administering antibiotics when possible but this should not delay administration of antibiotics. The empiric drug choice should be changed as epidemic and endemic ecologies dictate (eg H1N1, MRSA, chloroquine resistant malaria, penicillin-resistant pneumococci, recent ICU stay, neutropenia). (Grade 1D)

2. Clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension. (Grade 2D)

3. Early and aggressive source control. (Grade 1D)

4. Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is preferred for severe disease. (Grade 1A)

Fluid Resuscitation

1. In the industrialized world with access to inotropes and mechanical ventilation, initial resuscitation of hypovolemic shock begins with infusion of isotonic crystalloids or albumin with boluses of up to 20 mL/kg crystalloids (or albumin equivalent) over 5–10 minutes, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses, and level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales exist then inotropic support should be implemented, not fluid resuscitation. In non-hypotensive children with severe hemolytic anemia (severe malaria or sickle cell crises) blood transfusion is considered superior to crystalloid or albumin bolusing. (Grade 2C)

Inotropes/Vasopressors/Vasodilators

1. Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fluid resuscitation. (Grade 2C)

2. Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure be given vasodilator therapies in addition to inotropes. (Grade 2C)

Extracorporeal Membrane Oxygenation (ECMO)

1. Consider ECMO for refractory pediatric septic shock and respiratory failure. (Grade 2C)

Corticosteroids

1. Timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant shock and suspected or proven absolute (classic) adrenal insufficiency. (Grade 1A)

Protein C and Activated Protein Concentrate

No recommendation as no longer available.

Blood Products and Plasma Therapies

1. Similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock (< 70%), hemoglobin levels of 10 g/dL are targeted. After stabilization and recovery from shock and hypoxemia then a lower target > 7.0 g/dL can be considered reasonable. (Grade 1B)

2. Similar platelet transfusion targets in children as in adults. (Grade 2C)

3. Use plasma therapies in children to correct sepsis-induced thrombotic purpura disorders, including progressive disseminated intravascular coagulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura. (Grade 2C)

Mechanical Ventilation

1. Lung-protective strategies during mechanical ventilation. (Grade 2C)

Sedation/Analgesia/Drug Toxicities

1. We recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with sepsis. (Grade 1D)

2. Monitor drug toxicity labs because drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse drug-related events. (Grade 1C)

Glycemic Control

1. Control hyperglycemia using a similar target as in adults ≤ 180 mg/dL. Glucose infusion should accompany insulin therapy in newborns and children because some hyperglycemic children make no insulin whereas others are insulin resistant. (Grade 2C)

Diuretics and Renal Replacement Therapy

1. Use diuretics to reverse fluid overload when shock has resolved, and if unsuccessful then continuous venovenous hemofiltration (CVVH) or intermittent dialysis to prevent > 10% total body weight fluid overload. (Grade 2C)

Deep Vein Thrombosis (DVT) Prophylaxis

No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis.

Stress Ulcer (SU) Prophylaxis

No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis.

Nutrition

Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot. (Grade 2C)

Contraindicated Medications

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

• Etanercept
• Sitagliptin And Metformin Hydrochloride