Introduction
Methods
• Underlying methodology | |
A | RCT |
B | Downgraded RCT or upgraded observational studies |
C | Well-done observational studies |
D | Case series or expert opinion |
• Factors that may decrease the strength of evidence | |
1. | Poor quality of planning and implementation of available RCTs suggesting high likelihood of
bias |
2. | Inconsistency of results (including problems with subgroup analyses) |
3. | Indirectness of evidence (differing population, intervention, control, outcomes, comparison) |
4. | Imprecision of results |
5. | High likelihood of reporting bias |
• Main factors that may increase the strength of evidence | |
1. | Large magnitude of effect (direct evidence, relative risk (RR) > 2 with no plausible
confounders) |
2. | Very large magnitude of effect with RR > 5 and no threats to validity (by two levels) |
3. | Dose response gradient |
What should be considered | Recommended Process |
---|---|
Quality of evidence | The lower the quality of evidence the less likely a strong recommendation |
Relative importance of the outcomes | If values and preferences vary widely, a strong recommendation becomes less likely |
Baseline risks of outcomes | The higher the risk, the greater the magnitude of benefit |
Magnitude of relative risk including benefits, harms, and burden | Larger relative risk reductions or larger increases in relative risk of harm make a strong
recommendation more or less likely respectively |
Absolute magnitude of the effect | The larger the absolute benefits and harms, the greater or lesser likelihood respectively
of a strong recommendation |
Precision of the estimates of the effects | The greater the precision the more likely is a strong recommendation |
Costs | The higher the cost of treatment, the less likely a strong recommendation |
Initial resuscitation (first 6 hours)
|
Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: • Indicates a strong recommendation or “we recommend”; ○ indicates a weak recommendation or “we suggest” |
• Begin resuscitation immediately in patients with hypotension or elevated serum lactate
> 4mmol/l; do not delay pending ICU admission.(1C)
|
• Resuscitation goals:(1C)
|
– Central venous pressure (CVP) 8–12 mm Hg* |
– Mean arterial pressure ≥ 65 mm Hg |
– Urine output ≥ 0.5 mL.kg-1.hr-1 |
– Central venous (superior vena cava) oxygen saturation ≥ 70%, or mixed
venous ≥ 65% |
○ If venous O2 saturation target not achieved: (2C)
|
– consider further fluid |
– transfuse packed red blood cells if required to hematocrit of ≥ 30%
and/or |
– dobutamine infusion max 20 μg.kg-1.min-1
|
* A higher target CVP of 12–15 mm Hg is recommended in the presence of mechanical
ventilation or pre-existing decreased ventricular compliance. |
Diagnosis
|
• Obtain appropriate cultures before starting antibiotics provided this does not significantly
delay antimicrobial administration.(1C)
|
– Obtain two or more blood cultures (BCs) |
– One or more BCs should be percutaneous |
– One BC from each vascular access device in place > 48 h |
– Culture other sites as clinically indicated |
• Perform imaging studies promptly in order to confirm and sample any source of infection;
if safe to do so.(1C)
|
Antibiotic therapy
|
• Begin intravenous antibiotics as early as possible, and always within the first hour
of recognizing severe sepsis (1D) and septic shock (1B). |
• Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens
and with good penetration into presumed source.(1B)
|
• Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid
toxicity & minimise costs.(1C)
|
○ Consider combination therapy in Pseudomonas infections.(2D)
|
○ Consider combination empiric therapy in neutropenic patients.(2D)
|
○ Combination therapy no more than 3–5 days and deescalation following susceptibilities.(2D)
|
• Duration of therapy typically limited to 7–10 days; longer if response slow,
undrainable foci of infection, or immunologic deficiencies.(1D)
|
• Stop antimicrobial therapy if cause is found to be non-infectious.(1D)
|
Source identification and control
|
• A specific anatomic site of infection should be established as rapidly as possible(1C)
and within first 6 hrs of presentation(1D). |
• Formally evaluate patient for a focus of infection amenable to source control measures
(eg: abscess drainage, tissue debridement).(1C)
|
• Implement source control measures as soon as possible following successful initial
resuscitation.(1C)
|
Exception: infected pancreatic necrosis, where surgical intervention best delayed. (2B)
|
• Choose source control measure with maximum efficacy and minimal physiologic upset.(1D)
|
• Remove intravascular access devices if potentially infected.(1C)
|
Fluid therapy
|
Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: • Indicates a strong recommendation or “we recommend”; ○ indicates a weak recommendation or “we suggest” |
• Fluid-resuscitate using crystalloids or colloids.(1B)
|
• Target a CVP of ≥ 8 mm Hg (≥ 12 mm Hg if mechanically
ventilated).(1C)
|
• Use a fluid challenge technique while associated with a haemodynamic improvement.(1D)
|
• Give fluid challenges of 1000 ml of crystalloids or 300–500 ml of
colloids over 30 min. More rapid and larger volumes may be required in sepsis-induced tissue hypoperfusion.(1D)
|
• Rate of fluid administration should be reduced if cardiac filling pressures increase
without concurrent hemodynamic improvement.(1D)
|
Vasopressors
|
• Maintain MAP ≥ 65 mm Hg.(1C)
|
• Norepinephrine or dopamine centrally administered are the initial vasopressors of choice.(1C)
|
○ Epinephrine, phenylephrine or vasopressin should not be administered as the initial
vasopressor in septic shock.(2C)
|
– Vasopressin 0.03 units/min maybe subsequently added to norepinephrine with anticipation
of an effect equivalent to norepinephrine alone. |
○ Use epinephrine as the first alternative agent in septic shock when blood pressure
is poorly responsive to norepinephrine or dopamine.(2B)
|
• Do not use low-dose dopamine for renal protection.(1A)
|
• In patients requiring vasopressors, insert an arterial catheter as soon as practical.(1D)
|
Inotropic therapy
|
• Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac
filling pressures and low cardiac output.(1C)
|
• Do not increase cardiac index to predetermined supranormal levels.(1B)
|
Steroids
|
○ Consider intravenous hydrocortisone for adult septic shock when hypotension remains
poorly responsive to adequate fluid resuscitation and vasopressors.(2C)
|
○ ACTH stimulation test is not recommended to identify the subset of adults with septic
shock who should receive hydrocortisone.(2B)
|
○ Hydrocortisone is preferred to dexamethasone.(2B)
|
○ Fludrocortisone (50 μg orally once a day) may be included if an alternative
to hydrocortisone is being used which lacks significant mineralocorticoid activity. Fludrocortisone is
optional if hydrocortisone is used.(2C)
|
○ Steroid therapy may be weaned once vasopressors are no longer required.(2D)
|
• Hydrocortisone dose should be < 300 mg/day.(1A)
|
• Do not use corticosteroids to treat sepsis in the absence of shock unless the patient's
endocrine or corticosteroid history warrants it.(1D)
|
Recombinant human activated protein C (rhAPC)
|
○ Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical
assessment of high risk of death (typically APACHE II ≥ 25 or multiple organ failure) if there
are no contraindications.(2B,2Cforpost-operativepatients) |
• Adult patients with severe sepsis and low risk of death (eg: APACHE II<20 or one
organ failure) should not receive rhAPC.(1A)
|
Blood product administration
|
Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: • Indicates a strong recommendation or “we recommend”; ○ indicates a weak recommendation or “we suggest” |
• Give red blood cells when hemoglobin decreases to < 7.0 g/dl (< 70 g/L)
to target a hemoglobin of 7.0–9.0 g/dl in adults.(1B)
|
– A higher hemoglobin level may be required in special circumstances (e. g.: myocardial
ischaemia, severe hypoxemia, acute haemorrhage, cyanotic heart disease or lactic acidosis) |
• Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used
for other accepted reasons.(1B)
|
• Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless
there is bleeding or planned invasive procedures.(2D)
|
○ Do not use antithrombin therapy.(1B)
|
• Administer platelets when: (2D)
|
– counts are < 5000/mm3 (5 × 109/L)
regardless of bleeding. |
– counts are 5000 to 30,000/mm3 (5–30 × 109/L)
and there is significant bleeding risk. |
– Higher platelet counts (≥ 50,000/mm3 (50 × 109/L))
are required for surgery or invasive procedures. |
Mechanical ventilation of sepsis-induced acute lung injury (ALI)/ARDS
|
• Target a tidal volume of 6 ml/kg (predicted) body weight in patients with ALI/ARDS.(1B)
|
• Target an initial upper limit plateau pressure < 30 cm H2O.
Consider chest wall compliance when assessing plateau pressure.(1C)
|
• Allow PaCO2 to increase above normal, if needed to minimize
plateau pressures and tidal volumes.(1C)
|
• Positive end expiratory pressure (PEEP) should be set to avoid extensive lung collapse
at end expiration.(1C)
|
○ Consider using the prone position for ARDS patients requiring potentially injurious
levels of FiO2 or plateau pressure, provided they are not put at risk from positional changes.(2C)
|
• Maintain mechanically ventilated patients in a semi-recumbent position (head of the
bed raised to 45 °) unless contraindicated(1B),
between 30 –45
(2C). |
○ Non invasive ventilation may be considered in the minority of ALI/ARDS patients with
mild-moderate hypoxemic respiratory failure. The patients need to be hemodynamically stable, comfortable,
easily arousable, able to protect/clear their airway and expected to recover rapidly.(2B)
|
• Use a weaning protocol and a spontaneous breathing trial (SBT) regularly to evaluate
the potential for discontinuing mechanical ventilation.(1A)
|
– SBT options include a low level of pressure support with continuous positive airway
pressure 5 cm H2O or a T-piece. |
– Before the SBT, patients should: |
– be arousable |
– be haemodynamically stable without vasopressors |
– have no new potentially serious conditions |
– have low ventilatory and end-expiratory pressure requirement |
– require FiO2 levels that can be safely delivered with a face mask or nasal cannula |
• Do not use a pulmonary artery catheter for the routine monitoring of patients with
ALI/ARDS.(1A)
|
• Use a conservative fluid strategy for patients with established ALI who do not have
evidence of tissue hypoperfusion.(1C)
|
Sedation, analgesia, and neuromuscular blockade in sepsis
|
• Use sedation protocols with a sedation goal for critically ill mechanically ventilated
patients.(1B)
|
• Use either intermittent bolus sedation or continuous infusion sedation to predetermined
end points (sedation scales), with daily interruption/lightening to produce awakening. Re-titrate if
necessary.(1B)
|
• Avoid neuromuscular blockers (NMBs) where possible. Monitor depth of block with train
of four when using continuous infusions.(1B)
|
Glucose control
|
• Use IV insulin to control hyperglycemia in patients with severe sepsis following stabilization
in the ICU.(1B)
|
• Aim to keep blood glucose < 150 mg/dl (8.3 mmol/L) using a validated
protocol for insulin dose adjustment.(2C)
|
• Provide a glucose calorie source and monitor blood glucose values every 1–2 hrs
(4 hrs when stable) in patients receiving intravenous insulin.(1C)
|
• Interpret with caution low glucose levels obtained with point of care testing, as these
techniques may overestimate arterial blood or plasma glucose values.(1B)
|
Renal replacement
|
○ Intermittent hemodialysis and continuous veno-venous haemofiltration (CVVH) are considered
equivalent.(2B)
|
○ CVVH offers easier management in hemodynamically unstable patients.(2D)
|
Bicarbonate therapy
|
• Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing
vasopressor requirements when treating hypoperfusion-induced lactic acidemia with pH ≥ 7.15.(1B)
|
Deep vein thrombosis (DVT) prophylaxis
|
• Use either low-dose unfractionated heparin (UFH) or low-molecular weight heparin (LMWH),
unless contraindicated.(1A)
|
• Use a mechanical prophylactic device, such as compression stockings or an intermittent
compression device, when heparin is contraindicated.(1A)
|
○ Use a combination of pharmacologic and mechanical therapy for patients who are at
very high risk for DVT.(2C)
|
○ In patients at very high risk LMWH should be used rather than UFH.(2C)
|
Stress ulcer prophylaxis
|
• Provide stress ulcer prophylaxis using H2 blocker(1A) or proton
pump inhibitor(1B). Benefits of prevention of upper GI bleed must be weighed against
the potential for development of ventilator-associated pneumonia. |
Consideration for limitation of support
|
• Discuss advance care planning with patients and families. Describe likely outcomes
and set realistic expectations.(1D)
|
I. Management of Severe Sepsis
A. Initial Resuscitation
-
Central venous pressure (CVP): 8–12 mm Hg
-
Mean arterial pressure (MAP) ≥ 65 mm Hg
-
Urine output ≥ 0.5 mL.kg−1.hr −1
-
Central venous (superior vena cava) or mixed venous oxygen saturation ≥ 70% or ≥ 65%, respectively (Grade 1C)