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Definition

Sepsis is a systemic, deleterious host response to infection, manifested as multi system organ dysfunction plus hypotension, that is not readily reversible with fluid resuscitation.

Diagnostic Criteria For Sepsis (Documented/Suspected Infection Plus Inflammatory variables Plus One of The Organ Dysfunction)

General variables

• Fever > 38.3°C
• Hypothermia ( core temperature < 36°C )
• Heart rate > 90/min–1 or > 2 SD above the normal value for age
• Tachypnea
• Altered mental status
• Edema
• Positive fluid balance ( > 20 mL/kg over 24 hr)
• Hyperglycemia ( plasma glucose > 140 mg/dL or 7.7 mmol/L ) in the absence of diabetes

Inflammatory variables

• Leukocytosis ( WBC count > 12,000 µL–1 )
• Leukopenia ( WBC count < 4000 µL–1 )
• Immature WBCs forms are > 10% with normal count
• Plasma C-reactive protein > 2 SD above the normal value
• Plasma procalcitonin > 2 SD above the normal value

Hemodynamic variables

• Arterial hypotension after 30 ml/kg fluid bolus ( SBP < 90 mm Hg, MAP < 70 mm Hg, or an SBP decrease > 40 mm Hg in adults or < 2 SD below normal for age )

Organ dysfunction variables

• Arterial hypoxemia ( Pao2/Fio2 < 300 )
• Acute oliguria ( urine output < 0.5 mL/kg/hr for at least 2 hrs despite adequate fluid resuscitation )
• Creatinine increase > 0.5 mg/dL or 44.2 µmol/L
• Coagulation abnormalities ( INR > 1.5 or aPTT > 60 Sec )
• Ileus ( absent bowel sounds )
• Thrombocytopenia ( platelet count < 100,000 µL–1 )
• Hyperbilirubinemia ( plasma total bilirubin > 4 mg/dL or 70 µmol/L )

Tissue perfusion variables

• Hyperlactatemia > 1 mmol/L
• Decreased capillary refill or mottling

Diagnostic Criteria for Severe Sepsis (sepsis induced hypoperfusion or organ dysfunction)

Includes any one of the following caused due to the infection:

• Sepsis-induced hypotension
• Lactate above upper limits laboratory normal
• Urine output < 0.5 mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation
• Acute lung injury with Pao2/Fio2 < 250 in the absence of pneumonia as infection source
• Acute lung injury with Pao2/Fio2 < 200 in the presence of pneumonia as infection source
• Creatinine > 2.0 mg/dL (176.8 μmol/L)
• Bilirubin > 2 mg/dL (34.2 μmol/L)
• Platelet count < 100,000 μL
• Coagulopathy (international normalized ratio > 1.5)

Management

Characterize the symptoms: ❑ Fever ❑ Hypothermia ❑ Altered mental status ❑ Mottling ❑ Ileus ❑ Oliguria

Examine the patient: ❑ Tachycardia ❑ Tachypnea ❑ Edema ❑ Hyperglycemia ❑ Hypotension after an initial 30 ml/Kg bolus ❑ Decreased capillary refill

Order labs: ❑ Random blood sugar (RBS) ❑ Complete blood count (CBC) ❑ Plasma C reactive protein (CRP) ❑ Plasma procalcitonin ❑ Pulse oximetry ❑ Urinalysis/Renal function tests ❑ PT/INR ❑ Liver function tests ❑ Serum lactate ❑ Central venous pressure (CVP)

Consider alternative diagnosis: ❑ Infections ❑ Acute pancreatitis ❑ Diabetic ketoacidosis Lower gastrointestinal bleeding Myocardial infarction

Initial resuscitation: Goals to achieve in first 6 hours ❑ CVP 8-12 mm Hg ❑ Mean arterial pressure (MAP) ≥ 65 mm Hg ❑ Urine output ≥ 0/5 mL/Kg/hr ❑ Central venous O2 sat. 70% ❑ If lactate levels elevated, target is normalization

Diagnosis: ❑ Perform 2 sets of blood cultures (aerobic and anaerobic) atleast, before starting antibiotics Drawn percutaneously Drawn through each vascular access device present for > 48 hours ❑ Perform 1,3 beta-D_glucan assay, mannan, anti-mannan antibody assay if available ❑ Perform imaging studies as appropriate to locate a source

Antimicrobial therapy: ❑ Initiate within 1st hour of diagnosis Reassess regimen daily ❑ Use low procalitonin levels for prognosis ❑ Usual duration of therapy 10 days ❑ Longer in neutropenics, slow responders, undrainable foci, immunologically compromised

Choice of antibiotics

'Unknown organism ❑ Empiric therapy with broad spectrum antbiotic with good tissue penetrance

Neutropenic pt with severe sepsis (goal is to cover Acinetobacter & Pseudomonas spp) ❑ Use combination empirical therapy

Severe infections + resp failure + septic shock ❑ Extended spectrum beta lactam and aminoglycoside/fluoroquinolone

Streptococcus pneumoniae ❑ Beta lactam + macrolide

Culture specific organism ❑ Shift to appropriate anti-bacterial, antiviral or antifungal

Remove source/foci of infection: ❑ Use minimally invasive process ❑ Source removal best done in first 12 hours ❑ Remove intravascular access devices if they are a possible source ❑ Oral chlorhexidine gluconate to reduce oral contamination as a risk factor for ventilator associated pneumonia

Hemodynamic support Fluid therapy: ❑ Administer crystalloids, use albumin when demand for fluids is too high ❑ Use dynamic variables (change in pulse pressure, stroke volume) and static variables (arterial pressure,heart rate) to assess status Vasopressors (to achieve target MAP 65 mm Hg): ❑ Place arterial line as soon as feasible ❑ Administer norepinephrine as 1st choice drug ❑ Use epinephrine - when additional agent needed ❑ Use vasopressin 0.03 units/minute to raise MAP or decrease norepinephrine usage ❑ Selective dopamine (absolute or relative bradycardia) and phenylephrine usage Inotropic therapy: ❑ Trial of dobutamine infusion 20 μg/Kg if cardiac output low with elevated cardiac filling pressure

Corticosteroids: ❑ Use continuous flow IV hydrocortisone 200 mg/day if shock doesn’t improve with fluids & vasopressor ❑ Taper when vasopressors no longer required

Blood products: ❑ Transfuse blood when hemoglobin < 7.0 g/dL ❑ Transfuse platelets if < 10,000/mm3 or < 20,000/mm3 in those with high risk

'Mechanical ventilation for sepsis induced ARDS': ❑ Target tidal volume of 6 mL/Kg ❑ Target plateau pressure ≤ 30 mm Hg ❑ Use PEEP (positive end expiratory pressure) to avoid alveolar collapse ❑ Raise patients bed to 30-45° ❑ Attempt weaning when all foll. criteria are met: ❑ Pt arousable ❑ Hemodynamics stable ❑ No new complications ❑ Low ventilatory/fiO2 requirements ❑ Extubate when weaning successful

Other supportive therapy Sedation & neuromuscular blockade: ❑ Use minimal sedation/neuromuscular blockade in mechanically ventilated patients Glucose control: ❑ Blood glucose target value should be ≤ 180 mg/dL ❑ Use insulin infusion and 1-2 hourly monitoring to achieve target Renal replaement therapy: ❑ May be used for management of fluid balance in hemodynamically unstable patients ❑ Use for septic patients with acute renal failure DVT prophylaxis: ❑ Do pharmacoprophylaxis with low molecular weight heparin (LMWH), if no contraindications present ❑ Use pneumatic compression devices whenever possible Stress ulcer prophylaxis ❑ Consider prophylaxis if risk factors are present Feeding: ❑ Enteral & oral feeding preferred over total parenteral feeding (TPN) ❑ Adjust calorie requirement in subsequent days, as tolerated Goals of care: ❑ Discuss goals or care, patient aspirations and future directives with family with 72 hours of admission

Do's

• Patients who are suspected of being severely infected, should be routinely screened for sepsis.

• Administer antimicrobial therapy within 1 hour of diagnosis of sepsis.

• Delay intervention, if source/foci of infection is peri-pancreatic necrosis.

Dont's

• Antimicrobial Therapy:

• • Do not use empiric combination therapy for more than 3-5 days.

• • Do not use antimicrobial agents in severely inflamed patients, from a non-infectious cause.

• Fluid therapy:

• • Do not use hydroxyethyl starch for resuscitation of severe sepsis and septic shock.

• Vasopressors:

• • Do not use low dose vasopressin/dopamine/phenylephrine as monotherapy.

• • Do not use low dose dopamine for renal protection.

• Corticosteroids:

• • Do not use corticosteroids in absence of shock.

• Blood products:

• • Do not use erythropoietin as a specific treatment of anemia associated with sepsis.

• • Do not use antithrombin.

• • Do not use fresh frozen plasma to correct clotting abnormalities in the absence of bleeding or planned invasive procedure.

• Other supportive therapy:

• • Do not use following therapies as their role is not clear:

IV immunoglobulins

IV selenium

• • Do not use pulmonary artery catheters routinely.

• • Do not use bicarbonate therapy as prophylaxis of hypoperfusion induced lactic acidosis if pH > 7.15.