Sepsis Algorithm and Differential Diagnosis

Table of Contents

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)

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

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)

NICE Sepsis Guidance — 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
  - Meta-analysis (Crit Care Med 2011; 39:386–391)
    - Use of albumin solutions for the resuscitation of patients with sepsis was associated with lower mortality compared with other fluid resuscitation regimens.
  - SAFE study (N Engl J Med 2004;350:2247)
    - Similar outcomes for saline and albumin
  - ALBIOS Trial (N Engl J Med 2014; 370:1412)
    - No improved survival at 28 and 90 days when with albumin added to crystalloid

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

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
- Mortality rates increase as lactate increases (Ann Emerg Med. 2005;45:524)
- As lactate increases from 2 to 8 mg/dL, mortality increases from 1090% (Crit Care Med 1992;20:80)
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

Early Identification of Sepsis

Initial Resusctitation

Maximize Circulation

Maximize Tissue Oxygen Delivery

Supportive Therapy

Protocols

References

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