Sepsis Algorithm and Differential Diagnosis

Early Identification of Sepsis

SIRS (Systemic Inflammatory Response Syndrome)

  • Inflammatory response to a non-infectious insult (pancreatitis, burn, surgery…)
    • Temperature (<36 or >38°C)
    • Tachycardia (HR >90)
    • Tachypnea (RR > 20 or PaCO2 < 32)
    • WBC (>12,000, <4,000 or >10% bands)
Roadmap to Sepsis
Roadmap to Sepsis

Sepsis

  • Systemic, deleterious inflammatory response to infection
  • Diagnosis: Infection (documented or suspected) and some of the following:
    • General variables
      • Fever (> 38.3°C)
      • Hypothermia (core temperature < 36°C)
      • Heart rate > 90
      • Tachypnea
      • Altered mental status
      • Significant edema or positive fluid balance (> 20 mL/kg over 24 hr)
      • Hyperglycemia (plasma glucose > 140mg/dL in the absence of diabetes)
    • Inflammatory variables
      • Leukocytosis (WBC count > 12,000)
      • Leukopenia (WBC count < 4000)
      • Normal WBC count with greater than 10% immature forms (bands)
      • Plasma C-reactive protein more than two standard deviations (sd) above the normal value
      • Plasma procalcitonin more than two standard deviations (sd) above the normal value
    • Hemodynamic variables
      • Arterial hypotension (SBP < 90mm Hg, MAP < 70mm Hg, or an SBP decrease > 40mm Hg in adults or less than two 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 > 0.5mg/dL
      • Coagulation abnormalities (INR > 1.5 or aPTT > 60 s)
      • Ileus (absent bowel sounds)
      • Thrombocytopenia (platelet count < 100,000)
      • Hyperbilirubinemia (plasma total bilirubin > 4mg/dL)
    • Tissue perfusion variables
      • Hyperlactatemia (High Lactate)
      • Decreased capillary refill or mottling
Clinical and laboratory findings in sepsis
Clinical and laboratory findings in sepsis

Sepsis induced hypotension

  • SBP < 90 mm Hg or MAP < 70 mm Hg or
  • SBP decrease > 40mm Hg in the absence of other causes of hypotension.

Severe sepsis

  • Sepsis + organ dysfunction
  • Definition: Sepsis induced tissue hypoperfusion or organ dysfunction with any of the following thought to be due to the infection
    • Sepsis-induced hypotension
    • Lactate above upper limits of laboratory normal
    • Urine output <0.5 mL/kg/hr for more than two hours 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 mg/dL
    • Bilirubin >4 mg/dL
    • Platelet count <100,000
    • Coagulopathy (INR >1.5)
  • Mortality rate: 25-30%

Septic Shock:

  • Mortality rate: 40-70%
    • Severe sepsis + hypotension, not responsive to fluid resuscitation
    • Sepsis induced hypotension persisting despite adequate fluid resuscitation (30ml/kg)
Sepsis Algorithm and Differential Diagnosis
Sepsis Algorithm and Differential Diagnosis

Initial Resusctitation

Initial Resuscitation

  • ABCs / IV / O / Monitor / SaO22
  • Labs: CBC, CMP, PT/PTT, BCx x 2, lactate, UA, UCx, Foley
  • Fluid resuscitation (30ml/kg Normal Saline bolus to start)
  • Early broad spectrum antibiotics
  • Consider central line +/- CVP monitoring

Oxygenation

  • Goal: maximize O2 delivery to tissue
  • Supplemental oxygen for all patients
  • Consider Intubation?
    • Altered mental status and unable to protect airway
    • Persistent hypoxia despite (SaO2 < 90%) despite O2 supplementation (non-rebreather mask)
    • Severe hypotension/shock
    • Respiratory failure

Resuscitation End Goal

Maximize Tissue Oxygen delivery as measured by:
□ ScvO2 > 70%
□ Lactate clearance (LC) ≥10%

Goals

  • CVP 8–12 mm Hg
  • MAP ≥ 65 mm Hg
  • Urine output ≥ 0.5 mL/kg/hr
  • Superior vena cava oxygenation saturation (ScvO) 70% or mixed venous oxygen saturation (SvO2) 65%

Target

  • Target: Normalizing lactate (in patients with elevated lactate)

Early Antimicrobials

  • Blood Cultures
    • 2 sets, at least one peripheral and one via each vascular device
    • Cultures before antibiotics if no significant delay (>45 min)
    • Cultures from other sites (CSF, Urine, body fluids) should also be obtained before antibiotics if no delay
  • Antibiotics
    • Begin broad-spectrum empiric antibiotics within one hour of diagnosis of sepsis to cover likely source and pathogens
    • Each hour delay in antibiotics is associated with a measurable increase in mortality

Antibiotics

□ Blood cultures prior to antibiotics
□ Antibiotics within 1 hour of diagnosis

Source control

  • Evaluate patient for focus of infection amenable to source control (abscess drainage, debridement, device removal etc..)
  • Look for cause of infection that can be surgically controlled (peritonitis, cholangitis, intestinal infarction, necrotizing soft tissue infection etc.)
  • If intravascular access devices are a possible source, they should be removed promptly after other vascular access has been established

Maximize Circulation

Fluids (Preload)

  • Crystalloids
    • Initial fluid of choice
    • Initial fluid challenge: 30ml/kg (2-3L) bolus
    • Additional fluid in boluses (500ml) and reassess after each bolus
  • Goal (maximize preload)
    • Goal → No additional stroke volume from more fluids
    • Empiric IV fluids: Begin with 30ml/kg bolus and continue up to 4-6 L (goal MAP>65)
    • IVC US: Fluid bolus until there is ↓ change in size of IVC with respiration
    • CVP monitoring: Fluid bolus until goal CVP >10 (CVP>14 in intubated pts)
    • ProCESS trial showed no benefit to using invasive monitoring and CVP measurements
    • Caution:
      • Cardiogenic pulmonary edema
      • Non-Cardiogenic pulmonary edema (ARDS) → more fluid worsens prognosis
  • Albumin
    • Indication: Patient has already received a substantial amount of crystalloid (4-6L) → use albumin to help prevent third spacing
    • Dose: 500cc bolus of 5% albumin (or a dose of 25% albumin)
    • Journal club

MAP formula

MAP = (2 x DBP + SBP) / 3

Vasopressors

  • Indication: MAP <65 after adequate fluid loading
  • Goal: Target MAP > 65 mmHg
    • Supplemental endpoints: Blood Pressure, regional/global perfusion, urine output, mental status, lactate
  • Norepinephrine (Levophed-NE)
    • First line drug of choice
    • Dose:
      • Start: 0.5-1 mcg/min (up to 30mcg/min in refractory shock)
    • Increases MAP due to its vasoconstrictive effects, with little change in heart rate and less increase in stroke volume compared with dopamine
    • Norepinephrine vs Dopamine (N Engl J Med 2010;362:779)
      • No overall difference in mortality (52.5% vs 48.5%; p= 0.10)
      • Increased rate of arrhythmias with Dopamine (24.1% vs 12.4%)
      • Increased mortality in patients with cardiogenic shock with Dopamine
  • Epinephrine
    • 2nd line agent to be added to or substituted for Norepinephrine
    • Dose: 2-10 mcg/min IV
  • Vasopressin
    • Dose:
      • 0.04 U/min IV
      • Can be added to Norepinephrine with the intent of raising MAP to target or decreasing Norepinephrine dosage
    • Not recommended as single agent
  • Dopamine
    • Alternative to Norepinephrine only in highly selective patients
    • Dose:
      • Low-dose: 1-5 mcg/kg/minute, increased renal blood flow and urine output
      • Intermediate-dose: 5-15 mcg/kg/min: ↑ renal blood flow, heart rate, cardiac contractility, and Cardiac Output (CO)
      • High-dose: >15 mcg/kg/min alpha-adrenergic effects predominate, vasoconstriction, increased Blood Pressure
  • Phenylephrine
    • Not recommended except in certain circumstances:
      • Patient at risk for arrhythmias (Norepinephrine is associated with serious arrhythmias)
      • Cardiac output is known to be high and blood pressure persistently low
      • Salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve the MAP target
      • No Central line: can be given peripherally temporarily
    • Dose:
      • 40-60 mcg/min IV (Start 100-180 mcg/min IV until Blood Pressure stable)

Vasopressors

Ensure that patient is adequately hydrated before starting vasopressors

Flow diagram for resuscitation in sepsis-induced hypoperfusion
Flow diagram for resuscitation in sepsis-induced hypoperfusion

Maximize Tissue Oxygen Delivery

Resuscitation end points:

  • Vital sign endpoints (MAP, BP, HR etc…) are not sufficient to gauge adequacy of resuscitation and tissue hypoxia
  • Patients resuscitated to normal VS may continue to have tissue hypoxia as evidenced by decreased lactate clearance and persistently low ScvO (Am J Emerg Med 1996;14(2):218)
  • Goals of resuscitation:
    • Superior vena cava oxygenation saturation (ScvO2) > 70%
    • Lactate clearance (LC) ≥10%

Lactate clearance (LC)

  • Goal: lactate clearance by at least 10%
  • Lactate as predictor of mortality
  • Lactate clearance (↓ lactate ≥ 10%)
    • Alternative to ScvO2 (JAMA 2010;303:739):
      • Lactate clearance may be acceptable alternative to ScvO2 in determining tissue perfusion
      • Lactate clearance of at least 10% over ≥ 2 hours (adequate tissue oxygen delivery) produces a similar short-term survival rate as a protocol using ScvO2 monitoring.
    • Mortality
      • The Shock Society (Shock 2009;32:35-3)
        • i. Mortality was 60% for lactate non-clearance versus 19% for lactate clearance
        • ii. Lactate non-clearance was an independent predictor of death (OR= 4.9)
        • iii. ScvO2 optimization did not reliably exclude lactate non-clearance
      • Nguyen et. al (Crit Care Med 2004;32:1637)
        • i. Lactate clearance had a significant inverse relationship with mortality
        • ii. There was an approximately 11% decrease likelihood of mortality for each 10% increase in lactate clearance
      • Each 10% increase in repeat lactate values was associated with a 9.4% increase in the odds of hospital death (Ann Am Thorac Soc 2013;10:466)

Lactate Clearance (LC)

Lactate clearance can be used in place of ScvO2 to measure adequacy of resuscitation

IV fluids

  • Patient may require additional IV fluids (NS bolus)
  • Reassess using CVP (central venous pressure) or Ultrasound as applicable

Inotropic Support

  • Dobutamine
    • Bedside ECHO/US: Hypodynamic heart?
    • Trial of dobutamine for:
      • Persistent hypoperfusion (with normal MAP and adequate intravascular volume)
      • Myocardial dysfunction
    • Dose: up 5-20 mcg/kg/min
  • Calcium: replete Ca if low

Blood Products

  • Indication: Red blood cell transfusion if hemoglobin concentration decreases to < 7.0 g/dL
  • Target a hemoglobin concentration of 7.0 to 9.0 g/dL
  • Increases O2 delivery to tissues

Mechanical Ventilation/Intubation

  • Decrease work of breathing and pulmonary metabolic load

Supportive Therapy

Corticosteroids

  • Indication:
    • Unable to restore hemodynamic stability with IV fluid resuscitation and vasopressors
  • Dose: Hydrocortisone 100mg q8h (200-300mg/d)
  • Evidence
    • ACTH Stimulation test (not recommended)
      • Low cortisol → cortisol levels < 15mcg/dl
      • “Non-responder” or “inadequate adrenal reserve” → cortisol levels rise less than 9 mcg/dl to corticotropin stimulation test (250 mcg ACTH stimulation test)
      • Option: Check cortisol level before test and 30, 60 min after test
    • French trial (JAMA 2002;288:862-871)
      • All patient mortality decreased with hydrocortisone (61% vs 55%)
      • Mortality benefit was in “non-responders” in septic shock (63% vs 53%)
      • No mortality benefit in “responders”
      • Conclusion: Survival benefit is seen in patients with adrenal suppression and are non-responders to ACTH stimulation test
    • Meta-analysis (BMJ 2004;329:480)
      • Overall, randomized controlled trials show that short-course, high-dose steroids do not improve survival in severe sepsis
      • Low dose (HCT < 300mg/d) and longer duration of treatment (≥5days) improves hemodynamics, reduces time on vasopressor, and reduces 28 day mortality
    • CORTICUS trial (NEJM 2008;358:111-24)
      • Hydrocortisone showed no mortality benefit for patients in septic shock, even for patients with “inadequate adrenal reserve”
      • Hydrocortisone group → shock was reversed more quickly than in the placebo group (2-3 days)
      • Hydrocortisone group

Lung protective ventilation (NEJM 2000;342:1301-1308)

  • Avoid high tidal volumes and high plateau pressures in ALI/ARDS
  • ARDS-Net protocol:
    • 9% decrease in all-cause mortality in patients with Vt 6-8ml/kg (vs 12ml/kg) while aiming for a plateau pressure of <30 cm H2O
    • Assist-control Mode ventilation
    • Match PEEP to FiO2 requirements
    • Maintain SaO2 88-95%
    • Permissive hypercapnea (allowing PCO2 to increase above normal) can be tolerated to minimize Vt and PPL

Glucose Control

  • Protocolized approach if glucose > 180mg/dl to target upper glucose of < 180 mg/dl
  • NICE-SUGAR Trial (N Engl J Med 2009;360:1283)
    • Conventional glucose control (<180 mg/dl) resulted in lower mortality vs Intensive glucose control (81108 mg/dl) (Mortality 27.5% vs 24.9%; p=0.02)
    • Intensive glucose control protocol also resulted in more episodes of hypoglycemia
  • Oral feedings as tolerated

Bicarbonate

  • Bicarbonate not recommended for pH > 7.15
  • No evidence supports the use of bicarbonate therapy in the treatment of hypoperfusion induced lactic acidemia associated with sepsis

Other Modalities

  • DVT prophylaxis
  • Stress ulcer prophylaxis
  • Sedation/analgesia/paralysis
  • DIC treatment
  • Nutrition

Protocols

Early Goal Directed Therapy

  • General
    • Goal oriented manipulation of cardiac preload, afterload and contractility to achieve a balance between oxygen delivery and oxygen demand
    • Resuscitation to EGDT goals in first six hours decreased in-hospital mortality and mortality at 28 and 60 days
    • Equipment: Central venous catheter capable of measuring central venous oxygen saturation (ScvO2 and A-Line)
  • Maximize Circulation (MAP>65)
    • Fluid bolus (NS)
      • Goal CVP 8-12 (12-15 for mechanical ventilation) or urine output >0.5ml/kg/hr
      • 500-mL bolus of crystalloid every 30 minutes to achieve a CVP of 8-12 mm Hg
    • Vasopressors (NEJM 2010;362:779-789)
      • Indication: fluid challenge fails to restore blood pressure and adequate perfusion (MAP<65)
      • Goal: Vasopressors or vasodilators to achieve MAP 65 mm Hg or SBP 90 mm Hg
      • Recommendation: Norepinephrine (first line agent) or Dopamine
      • Epinephrine should be used as second line agent in conjunction with Norepinephrine if still need BP support
      • Vasopressin can be used as a low-dose background agent (0.04 Units/min) in conjunction with a vasopressor.
      • Inotropic therapy (Dobutamine) if adequate MAP/fluid resuscitation but ongoing hypoperfusion
  • Maximize Oxygenation (Goal ScvO2>70%)
    • PRBC Transfusion to Hct>30%
    • Inotropic agent (Dobutamine) to maximum dose of 20 mcg/kg/min
    • Mechanical ventilation & Sedation

ProCESS (N Engl J Med 2014; 370:1683)

  • Study protocol
    • RCT compared 3 arms of trial:
      • EGDT targets (ScvO2, CVP, MAP, UOP;; central access required) vs
      • A protocol that used some of the EGDT targets (MAP, UOP; protocol-based standard therapy; central access not required) vs
      • Usual care (no protocol used to direct fluid management)
  • Results
    • No mortality difference in the three groups (21 versus 18 versus 19 percent)
    • No significant benefit of the mandated use of central venous catheterization and central hemodynamic monitoring in all patients

References

  1. https://pubmed.ncbi.nlm.nih.gov/23353941/
  2. https://www.nejm.org/doi/full/10.1056/nejmra043632
  3. https://pubmed.ncbi.nlm.nih.gov/1597042/
  4. https://www.nejm.org/doi/full/10.1056/nejmoa010307
  5. https://www.nejm.org/doi/full/10.1056/nejmoa040232
  6. https://www.nejm.org/doi/full/10.1056/nejmoa1401602