II. Definitions
- Sepsis
- Sepsis 3 Definition (2016)
- Life threatening organ dysfunction resulting from dysregulated host response to infection
- Since organ dysfunction is part of the Sepsis 3 definition, Sepsis is now equivalent to severe Sepsis
- Older definition (Sepsis 1/2)
- Systemic Inflammatory Response Syndrome (SIRS) AND an infectious source
- Sepsis with organ dysfunction was considered severe Sepsis
- Sepsis 3 Definition (2016)
- Severe Sepsis
- Sepsis AND organ dysfunction, hypoperfusion or Hypotension
- No longer distinct from Sepsis definition (2016 Sepsis 3 guidelines)
- Septic Shock
- Sepsis AND Hypotension refractory to fluid Resuscitation (typically 30 ml/kg Ideal Body Weight)
- Sepsis with circulatory, cellular and metabolic dysfunction that is associated with a higher risk of mortality
- Organ Dysfunction
- Organ function unable to sustain homeostasis
- Hypoperfusion
- Lactic Acidosis, Oliguria or acutely Altered Mental Status
III. Epidemiology: United States
- Incidence: 1.7 Million per year (2024)
- Prevalence: 3-5 cases per 1000 (>500 cases per 100,000)
- In-Hospital Mortality: 350,000/year
- Worldwide mortality rate 20% (rates vary widely 10 to 36%, some estimates as high as 52%)
IV. Pathophysiology
- Inflammatory response (and Antagonizing anti-inflammatory response)
- Endothelial damage
- Increased vascular permeability
- Coagulation Pathway activation
- Impaired tissue oxygenation
- Decreased Vasopressin, Thyroxine, Cortisol and Growth Hormone
V. Risk Factors
- Age over 65 years (60 to 85% of all Sepsis cases)
- Sepsis risk >13 fold increased risk
- Sepsis mortality risk >2 fold increased risk
- Malnutrition
- Chronic comorbidity (Hazard Ratio >=2)
- Immunosuppression
- Recent surgery
- Postoperative Infection is responsible for one third of Sepsis cases
- Recent hospitalization
- Indwelling catheter or other device
- History of prior Sepsis
VI. Signs: Sepsis
- Constitutional changes
- Body Temperature abnormality
- Fever
- Most common presenting symptom
- However, absence of fever does not exclude Sepsis
- Hypothermia (<36 C): Poor prognostic sign
- Fever
- Diaphoresis
- Rigors
- Myalgias
- Malaise
- Body Temperature abnormality
- Cardiovascular changes
- Occurs with myocardial depression and intravascular fluid redistribution
- Hypotension (seen on presentation in 40% of Sepsis cases)
- Systolic Blood Pressure <90 mmHg or
- Mean arterial pressure <65 mmHg or
- Systolic Blood Pressure drop >40 mmgHg from baseline
- Hypotension at presentation confers a 2 fold increased mortality risk
- Cold and clammy skin
- Mottling of skin
- Decreased Capillary Refill 3 seconds or greater
- Tachycardia
- Decreased Urine Output (<0.5 ml/kg)
- Respiratory Findings
- Hypoxia, Dyspnea or Tachypnea
- Pharyngitis, Dysphagia or Stridor
- Cough, Pleuritic Chest Pain
- Abnormal lung auscultation (consolidation)
- Gastrointestinal findings
- Abdominal Pain, distention and rigidity (peritoneal signs)
- Decreased Bowel Sounds
- Upper Gastrointestinal Bleeding (significant blood loss in Sepsis is rare)
- Vomiting
- Diarrhea
- Genitourinary Findings
- Dysuria, frequency, Hematuria, pyuria
- Costovertebral Angle Tenderness
- Pelvic Pain
- Vaginal Discharge or Vaginal Bleeding
- Neurologic changes
- Dermatologic changes
- Direct Bacterial Infection (responsible for Sepsis)
- Vasculitis, microembolic, or Disseminated Intravascular Coagulation (DIC) induced lesions
- Ecchymosis
- Bullae
- Petechiae or Purpura
- Consider Neisseria Meningitidis
- Consider Rocky Mountain Spotted Fever
VII. Diagnosis: Criteria (2015 Sepsis-3 definitions)
- Precautions
- Although SOFA has been preferred for Sepsis definition, it misses more cases of Sepsis than SIRS
- For Sepsis, Test Sensitivity is 82% for SIRS, while SOFA Score is 66% and qSOFA is 46%
- qSOFA is no longer recommended as a Sepsis screening tool due to low Test Sensitivity
- SIRS has poor Test Specificity for Sepsis
- For Sepsis, Test Specificity is 24% for SIRS, while SOFA Score is 75% and qSOFA is 82%
- SIRS has a particularly high False Positive Rate
- SOFA Score appears inadequate alone (in combination with infection) to diagnose Sepsis
- SOFA Score has been validated only to identify life threatening organ dysfunction
- SOFA Score is useful in prognosis
- SOFA Score worsening of >=2 at least doubles mortality, and increases overall mortality 10%
- References
- Although SOFA has been preferred for Sepsis definition, it misses more cases of Sepsis than SIRS
- Sepsis
- Infection AND
- Organ Dysfunction
- qSOFA Score or SOFA Score 2 or more is consistent with Sepsis
- SOFA Score (or qSOFA Score) are recommended to replace SIRS Criteria in Sepsis-3 Guidelines
- Previously: Systemic Inflammatory Response Syndrome (SIRS criteria) positive (2 of 4 present)
- However, SOFA Score has a much lower Test Sensitivity than SIRS for Sepsis
- Septic Shock
- Infection and SOFA Score or qSOFA Score >=2 (or SIRS) AND
- Full fluid Resuscitation trial (e.g. 40-60 ml/kg or 2 Liters in an adult patient or wedge pressure 12-20 mmHg) AND
- Lactic Acid >2 mmol/L AND
- Hypotension despite what should be adequate fluid Resuscitation
- Mean arterial pressure <65 mmHg (<80 mmHg if prior Hypertension) or
- Vasopressor (Dopamine, Norepinephrine, Epinephrine) required for pressure support
VIII. Diagnosis: Criteria for other definitions (not included in 2015 Sepsis definitions)
- Severe Sepsis
- Infection and SOFA Score or qSOFA Score >=2 (or SIRS) AND
- Markers of poor organ perfusion (tissue hypoperfusion precedes Hypotension)
- Increased serum lactate (>4 mmol/L cut-off)
- Capillary Refill 3 seconds or greater
- Mottled skin
- Urine Output <0.5 ml/kg for 1 hour or more (or renal replacement therapy)
- Abrupt onset of Altered Level of Consciousness or abnormal EEG
- Disseminated Intravascular Coagulation
- Acute Lung Injury or ARDS
- Platelet Count <100,000/ml
- Cardiac dysfunction (based on Echocardiogram)
- Refractory Septic Shock
- Septic Shock AND
- High Vasopressor dose required to maintain Mean arterial pressure <60 mmHg (<80 mmHg if prior Hypertension)
- Dopamine >15 mcg/kg/min OR
- Norepinephrine or Epinephrine >0.25 mcg/min
- Multiple Organ Dysfunction Syndrome (MODS)
- Most severe Sepsis with progressive organ dysfunction
- Parameters demonstrating progressive organ dysfunction
- Serum Creatinine
- Serum Bilirubin
- PO2 to FIO2 ratio
- GCS Score
- Platelet Count
IX. Differential Diagnosis
- Hypovolemia
- Acute blood loss
- Acute Myocardial Infarction
- Acute Pancreatitis
- Transfusion Reaction
- Diabetic Ketoacidosis
- Adrenal Insufficiency
- Acute Pulmonary Embolism
- Consider evaluation early in course
X. Evaluation: Predictors of positive Blood Cultures (each doubles risk)
- Age over 30 years
- Heart Rate >90 bpm
- Temperature >37.8 C (>100 F)
- White Blood Cell Count >12,000
- Central venous catheter
- Hospital stay >10 days
XI. Evaluation: Sources
- Most common organisms
- Bacteria are responsible for most Sepsis cases
- Gram-positive Bacteria (25 to 50% of all Sepsis cases)
- Gram Negative Bacteria (30 to 60% of all Sepsis cases)
- Escherichia coli (most common overall)
- KlebsiellaPneumoniae
- Pseudomonas aeruginosa
- Most common sources (80% of cases)
- Respiratory infection
- Pneumonia is most common cause of Sepsis (43% of all Sepsis cases)
- Organism less likely to be obtained on culture
- Genitourinary infection
- Urinary Tract Infection or Pyelonephritis (16% of all Sepsis cases)
- Consider Septic Abortion in pregnancy or Chorioamnionitis in postpartum patients
- Organism most likely to be identified on culture
- Gastrointestinal infection
- Skin and Soft Tissue Infection
- Respiratory infection
- Occult sources
- Meningitis (1% of cases)
- Consider Lumbar Puncture
- Bacterial Endocarditis (1% of cases)
- Consider Echocardiogram
- Acute Sinusitis
- Consider Sinus CT
- Cholecystitis
- Consider RUQ Ultrasound
- Meningitis (1% of cases)
XII. Labs
- Cultures
- Obtain within 45 minutes of presentation
- Do not delay Antibiotics if cultures cannot be obtained within 45 minutes
- If surgical source culture is required, percutaneous, minimally invasive approach is preferred
- Consult with local surgery or Interventional Radiology
- Sources
- Blood Culture
- Rigors, high fever, and appetite loss are most predictive of positive Blood Cultures
- https://www.journalofhospitalmedicine.com/jhospmed/article/127086/prediction-rule-bacteremia
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841330/
- Urine Culture
- CSF Culture (if indicated)
- Central Line or PICC Line (if present, draw a culture through the line prior to removal)
- Blood Culture
-
Complete Blood Count
-
Leukocytosis (>12,000) or Leukopenia (<4000)
- Neutrophil predominance is typical
- Neutropenia is uncommon (except for chronic Alcoholism and the elderly)
-
Thrombocytopenia
- Typically precedes DIC
- Platelet Count drop >30% is associated with increased ICU-mortality
-
Hemolytic Anemia (microangiopathic)
- Present in DIC
-
Leukocytosis (>12,000) or Leukopenia (<4000)
- Coagulation Studies (INR, PTT)
- Coagulopathy in DIC
- Chemistry panel
- Hyperglycemia (Sepsis-induced Insulin Resistance)
- Acute Renal Failure
- Liver Function Tests
-
Thyroid Stimulating Hormone
- Consider in refractory cases
- Serum Lactate (Lactic Acid)
- Marker of poor organ perfusion (see definition of severe Sepsis above)
- Obtain on all septic patients, when obtaining Blood Cultures and for those admitted with infection
- Serum Lactate >4 mmol/L is associated with increased mortality
- Higher serum lactates should be met with more aggressive management
- Measurement of serial Lactic Acid levels should be performed on the same machine
- Most accurate methods are with Arterial Blood Gas machine (even for venous sample)
- Weingart and Orman in Majoewsky (2013) EM:Rap 13(10):5
- Recheck elevated Lactic Acid level in 2 hours after first draw, then every 4-6 hours until stabilized
- Urinalysis
-
Procalcitonin (controversial)
- See Procalcitonin
- Emergency medicine literature highlights low efficacy and does not recommend
- Some hospitalist guidelines recommend Procalcitonin to guide Antibiotic management and duration
XIII. Imaging
- Chest XRay
-
CT Abdomen and Pelvis
- Indicated for intraabdominal or pelvic findings or suspected GI Source
-
Echocardiogram
- Indicated for suspected endocarditis with septic emboli (e.g. IVDA)
- Bedside Ultrasound
XIV. Management: Sepsis Decision Pathway
- Indications
- Modified SIRS Criteria 2 or more AND suspected infection
- Step 1: Emergency Department triage measures
- Serum Lactic Acid
- Mean arterial pressure
- Triage may also draw rainbow lab tubes and one Blood Culture bottle and set aside
- Triage Sepsis alert in the EMR significantly reduces time to fluids and Antibiotics
- Hayden (2016) Am J Emerg Med 34(1): 1-9 +PMID:26386734 [PubMed]
- Step 2: Mean Arterial Pressure <65 mmHg
- Immediate rooming
- Initial stabilization
- Initiate 30 cc/kg IV crystalloid bolus within 3 hours (with first liter within 30 minutes)
- Obtain 2 sets of Blood Cultures as well as specific source cultures
- Initiate broad spectrum Antibiotics
- Reassess mean arterial pressure and consider IVC Ultrasound
- Go to Steps 3a-d
- Step 3a: Mean Arterial Pressure <65 mmHg despite 2 Liters crystalloid in Step 2 (Septic Shock)
- Obtain Central Line access
- Empiric second round of fluid Resuscitation (or base on IVC Ultrasound)
- Age <75 AND no history of CHF: Give 4 L IV fluids within first 6 hours
- Age >75 OR history of CHF: Give 3 L IV fluids within first 6 hours
- Start Vasopressors (e.g. Norepinephrine)
- Target mean arterial pressure (MAP) >65 mmHg
- Disposition to Intensive Care Unit
- Step 3b: Mean Arterial Pressure >65 mmHg AND Serum Lactic Acid 4 mmol/L or more (Severe Sepsis)
- Obtain 2 peripheral IVs
- A single large gauge IV (e.g. 16 to 18g) may be sufficient
- Central Line access may be considered (optional)
- Initiate 2 Liter crystalloid bolus
- Empiric second round of fluid Resuscitation (or base on IVC Ultrasound)
- Age <75 AND no history of CHF: Give 4 L IV fluids within first 6 hours
- Age >75 OR history of CHF: Give 3 L IV fluids within first 6 hours
- Obtain 2 sets of Blood Cultures as well as specific source cultures
- Initiate broad spectrum Antibiotics
- Admit to Intensive Care unit
- Repeat serum Lactic Acid after fluid Resuscitation
- Obtain 2 peripheral IVs
- Step 3c: Mean Arterial Pressure >65 mmHg AND Serum Lactic Acid 2-4 mmol/L (Sepsis)
- Initiate 2 Liter crystalloid bolus
- Obtain specific source cultures
- Consider 2 sets of Blood Cultures (per hospital policy, discuss with admitting hospitalist)
- Initiate targeted Antibiotics for suspected source
- Repeat serum Lactic Acid after initial crystalloid bolus
- Serum lactate clearance >10% (percent drop in lactate from first value)
- Admit to regular medical ward
- Serum lactate clearance <10% (percent drop in lactate from first value)
- Repeat crystalloid bolus 1 Liter
- Admit to Intensive Care
- Serum lactate clearance >10% (percent drop in lactate from first value)
- Step 3d: Mean Arterial Pressure >65 mmHg AND Serum Lactic Acid <2 mmol/L (Uncomplicated Sepsis)
- Antibiotics as indicated
- Fluid Resuscitation as indicated
- References
- Berg and Orman in Herbert (2015) EM:Rap 15(8): 8-11
XV. Management: Antibiotic Overall Approach
- Appropriate Antibiotic choice and delivery
- Establish Emergency Department first dose protocols
- Based on local sensitivities and infectious disease recommendations
- Simultaneous Antibiotics without delay is ideal (obtain additional IV sites if needed)
- Vancomycin dosing should be calculated based on weight
- Dose: 15-20 mg/kg total body weight (up to 2 grams)
- Establish Emergency Department first dose protocols
- Start Antibiotics as early as possible (within 1 hour of Septic Shock, within 3 hours of Sepsis without shock)
- Early Antibiotic delivery is most critical in severe Sepsis and Septic Shock
- Mortality increases with each hour of Antibiotic delay
- Kumar (2006) Crit Care Med 34(6): 1589-96 [PubMed]
- Gaieski (2010) Crit Care Med 38(4): 1045-53 [PubMed]
- Seymour (2017) N Engl J Med 376(23):2235-44 [PubMed]
- Consider source, but start broad spectrum Antibiotic
- Source not identified in 20-30% of cases
- Re-evaluate Antibiotic selection daily (esp. as cultures and sensitivity results are returned)
- Inappropriate Antibiotic selection is associated with a 34% increase in mortality
- Empiric therapy without obvious source (broad spectrum coverage)
- Vancomycin 15-20 mg/kg (up to 2 g) every 12 hours AND
- MRSA accounts for 1 in 20 causes of Sepsis in critically ill patients
- However, broad spectrum Antibiotic (see below) should be infused first, before the 2 hour Vancomycin infusion starts
- Choose one of the following broad spectrum Antibiotic
- Piperacillin-Tazobactam (Zosyn, if low Prevalence ESBL) OR
- Imipenem 1 g IV every 8 hours (or Meropenem or Doripenem) OR
- Cefepime 2 g IV every 8 hours with Metronidazole
- Consider adding Aminoglycoside (e.g. Gentamicin)
- Vancomycin 15-20 mg/kg (up to 2 g) every 12 hours AND
- Remove obvious source within 6 hours (source control)
- Remove infected lines
- Abscess Incision and Drainage
- Necrotic tissue Debridement (e.g. Necrotizing Fasciitis)
- Culture the tip of infected device
- Consider risk factors for multi-drug resistance
- Recent Antibiotics
- Recent wound care
- Hospitalization in last 3 months
- Consider initial Antibiotics that may be given as IV bolus
- Some beta-lactams, Cephalosporins and Aminoglycosides may be administered IV bolus
- Larger molecule Antibiotics (e.g. Vancomycin, Quinolones) may not be given IV bolus
- Risk of adverse reactions
- References
- Lin and Spaulding in Herbert (2016) EM:Rap 16(3): 6-7
- Garrelts (1992) Pharmacoeconomics 1(2): 116-23 +PMID:10172048 [PubMed]
- Avoid delay in subsequent Antibiotic doses
- Antibiotic second dose delays are common in transition from the Emergency Department to admission
- Leisman (2017) Crit Care Med 45(6): 956-65 +PMID:28328652 [PubMed]
-
Antibiotic course
- Typical total Antibiotic course: 7 to 10 days
- Longer Antibiotic duration indications
- Bacterial Endocarditis
- Osteomyelitis
- Endovascular device infections
- Orthopedic hardware infections
XVI. Management: Antibiotics - Empiric by Site of Infection and Risk Factors
- Unknown source
- See empiric therapy described above
-
Lung Infection
- Evaluate Pleural Fluid
- Drain empyema if present
- Community Acquired Pneumonia without risk for multidrug resistance or Pseudomonas
- See Pneumonia Management
- Empiric Antibiotic Regimen
- Ceftriaxone AND Azithromycin OR
- Ceftriaxone AND Doxcycline OR
- Fluoroquinolone (Levofloxacin, Moxifloxacin)
- Pneumonia with risk for Multi-drug resistance or Pseudomonas
- Pseudomonas or Multi-Drug Resistance Indications
- Chronic Lung Disease (e.g. Cystic Fibrosis, COPD, Bronchiectasis)
- Frequent Antibiotics or Corticosteroids
- Gram Negative Rods on Sputum Gram Stain
- Hospital-Acquired Pneumonia
- Empiric Antibiotic Regimen
- Fluoroquinolone (e.g. Ciprofloxacin) AND
- Piperacillin-Tazobactam 4.5 g IV q6-8h OR Cefepime OR Carbapenem (e.g. Meropenem) OR Aztreonam
- Add Vancomycin for MRSA if cavitary Pneumonia or empyema
- Pseudomonas or Multi-Drug Resistance Indications
- Evaluate Pleural Fluid
- Urinary tract source
- See Acute Pyelonephritis
- Cover organisms associated with complicated Urinary Tract Infection
- Enterococcus
- Pseudomonas aeruginosa
- Staphylococcus aureus
- Empiric Antibiotics if no risk for multidrug resistance
- Ceftriaxone OR
- Fluoroquinolone (e.g. Ciprofloxacin, Levofloxacin)
- Avoid Fluoroquinolones if local Escherichia coli resistance rates >10%
- Empiric Antibiotics if risk of multidrug resistance (or Extended-Spectrum Beta-Lactamase, indwelling Foley Catheter)
- Cefepime OR
- Piperacillin/Tazobactam (Zosyn) 4.5 g every 6-8 hours OR
- Carbapenem (e.g. Meropenem, especially for ESBL organisms) AND Vancomycin OR
- Levofloxacin AND Gentamicin 7 mg/kg every 24 hours
- Other Antibiotics are preferred over fluouroquinolones in UTI with Sepsis due to increasing resistance
- Imaging indications
- Evaluate for obstruction (Nephrolithiasis)
- Intra-abdominal or pelvic source suspected
- Empiric Antibiotic coverage
- First-line single agents (choose one)
- Piperacillin-Tazobactam (Zosyn) 4.5 g every 6-8 hours OR
- Imipenem/Cilastin (Primaxin) 250-500 mg IV every 6-8 hours OR
- Meropenem 1 g IV every 8 hours OR
- Cefepime 2 g IV every 12 hours AND Metronidazole 500 mg IV every 6-8 hours
- Alternatives regimens (e.g. beta lactam Anaphylaxis)
- Vancomycin AND Aztreonam AND Metronidazole
- Prior guidelines added additional Gram Negative coverage (no longer recommended)
- Gentamicin 7 mg/kg every 24 hours OR
- Ciprofloxacin 400 mg IV every 12 hours
- First-line single agents (choose one)
- Early surgical Consultation
- Consider percutaneous or open drainage of infection source
- Empiric Antibiotic coverage
-
Meningitis Suspected
- See Bacterial Meningitis Management
- Vancomycin 15-20 mg/kg (up to 2 g) every 12 hours AND
- Ceftriaxone 2 g every 12 hours (or Cefotaxime)
- Consider Ampicillin 2 g every 4 hours (for listeria if Immunocompromised or over age 50 years)
- Consider adding Dexamethasone 10 mg every 6 hours (for pneumococcal Meningitis)
- Consider adding Acyclovir 10 mg/kg every 8 hours (if herpes Encephalitis suspected, Delirium, focal deficits)
- Consider adding Rifampin
- Alternative regimen (e.g. Beta Lactam Anaphylaxis)
- Vancomycin AND Moxifloxacin AND Trimethoprim-Sulfamethoxazole
-
Skin and Soft Tissue Infection or Necrotizing Fasciitis
- See Cellulitis
- See Necrotizing Fasciitis
- Empiric Antibiotics
- Vancomycin 15-20 mg/kg (up to 2 g) every 12 hours OR Linezolid AND
- Piperacillin/Tazobactam (Zosyn) 4.5 g every 6-8 hours OR Carbapenem OR Cefepime with Metronidazole
- Add Clindamycin 900 mg every 8 hours (esp. if toxin release, e.g. Necrotizing Fasciitis, gangrene)
- Surgical Consultation indications
- Necrotizing Fasciitis suspected
- Deep abscess
- Post-splenectomy
- Ceftriaxone 2 g IV every 24 hours (every 12 hours if Meningitis) OR
- Piperacillin-Tazobactam (Zosyn) 4.5 g IV every 6-8 hours OR
- Carbapenem (e.g. Meropenem) OR
- Clindamycin OR
- Fluoroquinolone (e.g. Levofloxacin OR Moxifloxacin)
- Do not use in Dog Bite (risk of Capnocytophagia, with Fluoroquinolone resistance)
-
Febrile Neutropenia
- See Febrile Neutropenia
- Cefepime OR
- Piperacillin-Tazobactam (Zosyn) 4.5 g IV q6-8 hours OR
- Carbapenem OR
- Ceftazidime (Fortaz) OR
- Aztreonam AND Vancomycin OR
- Ciprofloxacin AND Clindamycin
- Indications to ADD Vancomycin
- Septic Shock
- Pneumonia
- Catheter Related Bloodstream Infection
- Skin or Soft Tissue Infection
- Severe Mucositis
- Vascular Device Infection
- Vancomycin 15-20 mg/kg (up to 2 g) IV every 12 hours AND
- Piperacillin-Tazobactam (Zosyn) 4.5 g IV q6-8 hours (or Aztreonam 2 g IV q8 hours) AND
-
Illicit Drug use
- Include Vancomycin in regimen (to cover MRSA)
- Petechial rash
- Include Ceftriaxone 2 g IV q12 hours
- Cover Neisseria Meningitidis and Rocky Mountain Spotted Fever (also consider DIC)
-
Acute Diarrheal Syndrome
- Metronidazole 500 mg IV every 6 hours AND
- Vancomycin 250 mg orally every 6 hours (OR enema 1 g/500 ml rectally every 8 hours)
XVII. Monitoring: Serum Lactate
- Serial serum lactate levels can help guide Resuscitation and response to management
- Consider obtaining at presentation and again at 3 and 6 hours
- Lactate clearance can drive goal directed therapy
- Jones (2010) JAMA 303(8):739-46 [PubMed]
- Indications for more aggressive Sepsis management and monitoring with serial serum lactate levels
- Serum lactate >4 mmol/L
- Hypotension despite 2 Liters of IV fluids
- Hypotension responsive to IV fluids (may be a harbinger of later more severe episodes)
XVIII. Management: Stabilization - General Measures
- ABC Management
- Surviving Sepsis Guidelines in 2018
- Criticism that prior 3 and 6 hour bundles have been compressed into 1 hour
- Weak evidence to support the aggressive changes and increased risk of adverse effects
- Swaminathan, Spiegel, Farkas in Herbert (2018) EM:Rap 18(10): 1-2
- Precautions: ProCESS Trial results (2014)
- Pragmatic aggressive care (fluids, Antibiotics, pressors)
- As effective as Early Goal Directed Therapy (with Svo2 monitoring)
- Emphasis
- Aggressive fluid hydration starting with 30 cc/kg bolus (4.4 Liters on average)
- Early Antibiotics
- Vasopressors (44%)
- Central Lines (>50% of cases)
- However, specialized Sepsis catheters with Svo2 monitoring are not required
- Did not improve outcomes beyond otherwise aggressive care
- References
- Pragmatic aggressive care (fluids, Antibiotics, pressors)
- Oxygenation
- Maintain Oxygen Saturation >90%
- Maintain superior vena cava Oxygen Saturation (Scvo2) >70%
- Maintain mixed venous Oxygen Saturation (Svo2) >65%
- Advance to High Flow Oxygen as needed to maintain adequate oxygenation
- Ventilation (BIPAP or Mechanical Ventilation)
- Indicated for septic patients with Oxygen Saturation <90% or significant Tachypnea despite High Flow Oxygen
- Use a low threshold for intubation of the elderly patient with severe Sepsis
- Be alert for transient Hypotension with intubation in Sepsis (consider Push Dose Pressor)
- Lung Protective Ventilator Strategy (using ARDSPEEP and FIO2 Tables)
- Tidal Volumes 6 cc/kg of Ideal Body Weight (up to 8 cc/kg/IBW)
- Maintain median inspiratory plateau pressure (IPP) <30 cm H2O in ventilated patients
- Central venous access indications (e.g. internal jugular venous catheterization)
- Vasopressor delivery (Norepinephrine, Epinephrine)
- Unreliable Intravenous Access
- Monitoring (controversial - see above)
- Monitoring may be done instead non-invasively (e.g. follow IVC Ultrasound)
- Sepsis catheters (e.g. Vigileo) can monitor Central Venous Oxygen Saturation (ScvO2)
- ProCESS Trial showed no added benefit to otherwise aggressive Sepsis management (see above)
XIX. Management: Stabilization - Volume Resuscitation
- Crystalloid selection
- Lactated Ringers is preferred instead of NS
- May also consider Plasma-Lyte after several liters of NS have been given
- However, several Antibiotics (Ceftriaxone and Zosyn) cannot be run in same line as LR
- Consider using Normal Saline until dual Intravenous Access, or initial Antibiotics completed
- Normal Saline (NS) increases acidosis in contrast to Lactated Ringers (LR)
- NS in the large quantities used for Sepsis, may have adverse renal and inflammatory effects
- Lactated Ringers is preferred instead of NS
- Crystalloid volume
- Start with 1 liter of isotonic crystalloid (NS or LR) in first 30 minutes
- Improved survival when crystalloid bolus started within first 30 minutes
- Liesman (2016) Ann Emerg Med 68(3): 298-311 +PMID:27085369 [PubMed]
- Typical total initial crystalloid bolus of 30cc/kg (2-3L in 70-100 kg adult) within first 3 hours
- Typical total crystalloid fluid over first 24-48 hours may approach 5-7 Liters
- Overall Crystalloid Total: 2-4 Liters initially of NS or LR (up to 10 L have been used in some cases)
- Hemodynamic effects of fluid boluses lasts only one hour
- Start with 1 liter of isotonic crystalloid (NS or LR) in first 30 minutes
- Goals
- Inferior Vena Cava Ultrasound with <50% collapse on inspiration
- Passive Leg Raise Maneuver (fluid responsiveness)
- Increased Pulse Pressure (difference between systolic Blood Pressure and diastolic Blood Pressure)
- Serial serum lactate decrease (see above)
- Improved Capillary Refill
- Central Venous Pressure >8 (>12 if on mechanical Ventilator)
- Central venous oxygen level >70 mmHg
- Urine Output >0.5 ml/kg/h
- Systolic Blood Pressure >90 mmHg or mean arterial pressure >65-70 mmHg
- Blood Pressure is an unreliable marker of Sepsis severity and response to therapy
- Blood Pressure can be normal or high immediately before decompensated shock
- Patient positioning is also an unreliable marker to predict fluid Resuscitation response
- Technique involves raising legs and observing for increase in Blood Pressure
- Precautions
- Aggressive fluid hydration is key to Sepsis management, even in those at risk of Fluid Overload (CHF, CKD)
- CHF and CKD patients have decreased mortality with aggressive fluid hydration in Sepsis
- Aggressive fluid hydration offers significant benefit even if Lactic Acid 2-4 (intermediate range)
- Levy (2016) Am J Respir Crit Care Med 193(11):1195-6 +PMID:27248586 [PubMed]
- Liu (2016) Am J Respir Crit Care Med 193(11): 1264-70 +PMID:26695114 [PubMed]
- However, as of 2020, nuanced fluid approach is advocated (not part of Sepsis protocol)
- Early Sepsis trials used 20 cc/kg (not 30 cc/kg)
- Intravenous Fluids have a short duration in the intravascular space
- Third spacing of fluids
- Ongoing insensible losses
- Deliver fluids in 500 cc increments with reassessment in those at risk of fluid overloaf (CHF, CKD)
- See Fluid Responsiveness Markers
- Reevaluate with Inferior Vena Cava Ultrasound
- Consider early initiation of Vasopressors (e.g. Norepinephrine) via reliable peripheral IV
- Counters Sepsis-related vasodilation
- Allows for maintenance of mean arterial pressure (MAP) until fluid Resuscitation is adequate
- References
- Weingart and Swaminathan in Herbert (2020) EM:Rap 20(8): 3
- Weingart and Swaminathan in Swadron (2021) EM:Rap 21(11): 4-6
- Limit fluids in later stages of Sepsis management (day 2 to 3)
- Net fluid balance at 72 hours should approach Zero
- Excessive, persistent overhydration is associated with Acute Respiratory Distress Syndrome (ARDS)
- Each liter of Positive Fluid Balance at 72 hours increases mortality
- Avoid Albumin 5% (500 ml bolus) or similar colloid (lack of efficacy)
- Previously indicated for high volume crystalloid Resuscitation (e.g. >4-6 Liters)
- Was postulated to help prevent fluid third spacing
- No benefit to albumin over Isotonic Saline in Sepsis (as of 2014)
- Avoid hyroxyethyl starch
- Initially promoted to correct Metabolic Acidosis from high volume crystalloid Resuscitation
- Hydroxyethyl Starch is associated with increased risk of bleeding and Renal Failure
- Avoid Synthetic colloid gelatin
- Insufficient evidence as of 2022
- Aggressive fluid hydration is key to Sepsis management, even in those at risk of Fluid Overload (CHF, CKD)
- Transfusion: pRBC Indications
- Indications are controversial (follow a restrictive transfusion policy)
- Most current guidelines suggest transfusion for Hemoglobin <7 g/dl (Hematocrit <21)
- Other studies suggest transfusion for Hemoglobin <10 g/dl (Hematocrit <30)
- Goal Hematocrit >30% if Central Venous Oxygen Saturation <70% after restoring mean arterial pressure
- More important after the initial stabilization
- Mortality increases for transfusion for mild Anemia
- Herbert (1999) N Engl J Med 340:409-17 [PubMed]
- Rivers (2001) N Engl J Med 345(19): 1368-77 [PubMed]
- Indications are controversial (follow a restrictive transfusion policy)
- Transfusion: Platelet Indications
- Platelet Count <10,000/ul OR
- Platelet Count <20,000/ul and significant bleeding risk OR
- Platelet Count <50,000/ul if active bleeding, surgery or invasive procedure required
XX. Management: Stabilization - Vasopressors
- Precaution
- Intravenous Fluids should be maximized prior to starting first pressor (>2 L) and second pressor (4 L)
- Vasopressor delay after refractory Hypotension (MAP <65) increases mortality 5% per hour of delay
- Vasopressors ultimately require central venous access
- Vasopressors may be initiated peripherally during stabilization
- Temporize until Central Line access is obtained (typically <1-2 hours)
- Norepinephrine has been used via reliable large bore peripheral IV up to 24 hours
- Complication rates are higher with peripheral Vasopressor (but not life threatening)
- Risk outweighed by the benefit of initiating Vasopressors without delay
- Indicated after failed response to aggressive hydration
- Ricard (2013) Crit Care Med 41(9): 2108-15 [PubMed]
- Temporize until Central Line access is obtained (typically <1-2 hours)
- Peripheral extravasation of Vasopressors may result in severe local tissue necrosis
- Potential with risk of Compartment Syndrome
- Vasopressors in peripheral lines must be observed very closely
- Frequently recheck for extravasation (e.g. every 10-15 min)
- Plan for immediate response to extravasation including available antidote (e.g. Phentolamine)
- Vasopressors may be initiated peripherally during stabilization
- Target perfusion
- Central Venous Pressure (CVP) 8-12 mmHg
- Mean arterial pressure (MAP) >65 mmHg
- Urine Output >0.5 ml/kg/h
- See venous oxygenation goals (Scvo2 or Svo2) above
- First agent
- Norepinephrine (preferred first line)
- Start at 2 to 5 mcg per minute (or 0.2 mcg/kg/min)
- Titrate to 35-90 mcg/min to adequate perfusion parameters including MAP >65 mmHg
- Dose range 0.1 to 1 mcg/kg/min
- May be initiated via peripheral access (while awaiting central access)
- Observe closely for extravasation and move to Central Line within 1-2 hours
- With large bore, reliable peripheral IVs, Norepinephrine has been used peripherally for 24 hours
- Add Vasopressin if refractory Hypotension
- Consider for Hypotension despite Norepinephrine 0.3 mcg/kg/min
- Norepinephrine (preferred first line)
- Second agent (added to first)
- Indicated for Hypotension despite fluid bolus and other additional measures listed below
- Vasopressin 0.03 units/minute (previously 0.04 units/min was recommended)
- Indicated for additional Vasopressor support if BP not at goal despite norephinephrine 0.25 to 0.5 mcg/kg/min
- Indicated when bedside Echocardiogram demonstrates good cardiac contractility with adequate inotropy
- Epinephrine
- Dose 20 to 50 mcg/min
- Indicated for combined Vasopressor and inotropic support
- Indicated when bedside Echocardiogram demonstrates poor cardiac contractility (Cardiomyopathy)
- Consider adding to Norepinephrine and Vasopressin when they are insufficient to maintain target pressures
- Agents to generally avoid in most Sepsis cases
- Avoid Dopamine in Sepsis
- Dosing range: 2-20 mcg/kg/min
- Do not use "renal dose" Dopamine - misnomer
- No longer recommended in Sepsis due to less effective than Norepinephrine and arrhythmogenic
- De Backer (2010) N Engl J Med 362(9): 779-89 [PubMed]
- Avoid Phenylephrine in Sepsis
- Lacks inotropic activity and overall efficacy in Sepsis shock when compared with Norepinephrine
- Has been used to bridge Vasopressor use until securing central venous access
- However Norepinephrine can be safely used for hours until central access has been obtained
- Has also been used to avoid Norepinephrine in Tachycardia
- However, Norepinephrine may still be used despite Tachycardia
- References
- Orman and Weingart in Herbert (2016) EM:Rap 16(8):7-8
- Avoid Dopamine in Sepsis
XXI. Management: Stabilization - Additional measures when poor response to Resuscitation efforts
- Early Intensive Care Unit Admission
- ICU admission within 6 hours is preferred (ED boarding >6 hours is associated with increased Sepsis mortality)
-
Corticosteroids
- Hydrocortisone at physiologic dose
- Hydrocortisone 50 mg IV every 6 hours (some give 100 mg as initial dose) for a total of 200 mg/day
- Indicated for severe Sepsis refractory to aggressive fluid Resuscitation and Vasopressor therapy
- Consider if patient is requiring 2 pressors for support (e.g. Norepinephrine and Epinephrine or Vasopressin)
- Benefit may be limited to early administration
- Efficacy (variable evidence)
- Surviving Sepsis Campaign downgraded Corticosteroid recommendation to weak evidence in 2012
- Marked mortality benefit from Corticosteroids in severe Sepsis
- Has short-term benefit in duration and severity
- CORTICUS trial found no benefit to Corticosteroids overall
- However of those who did respond to shock reversal, those on Corticosteroids improved faster
- Sprung (2008) NEJM 358(2): 111-24 [PubMed]
- ADRENAL Study found no significant benefit
- However some argue higher doses given earlier in course are beneficial
- Swaminathan and Weingart in Herbert (2018) EM:Rap 18(8): 9
- Venkatesh (2018) N Engl J Med 378(9): 797-808 [PubMed]
- Hydrocortisone at physiologic dose
- Consider Hypothyroidism
- Consider additional Intravenous Fluids (if suspect still volume down)
- Give additional 1-2 Liters on top of already administered 2 liters
- Occult Hemorrhage (e.g. Gastrointestinal Bleeding)
- Stop bleeding and Consider pRBC transfusion if actively bleeding or Hemoglobin <7.0 mg/dl
- Inotropes (e.g. Dobutamine)
- Consider for inotropic support when inadequate tissue perfusion/oxygenation
- Especially where myocardial dysfunction is suspected
- Consider when perfusion markers fail to improve despite MAP >65 mmHg and Oxygen Saturation >90%
- SvcO2 <70% or
- Lactic Acid fails to improve or
- Serum Creatinine fails to improve
- Approach
- Dobutamine 2.5 mcg/kg/min
- Obtain beside Echocardiogram if available
- Consider for inotropic support when inadequate tissue perfusion/oxygenation
- Other agents (avoid in general)
- Activated Protein C
- Drotecogin Alfa (Xigris)
- No survival benefit
- Removed from the U.S. market in october 2011 (as well as surviving Sepsis guidelines)
- Sodium Bicarbonate
- Not generally recommended
- Acidosis improves with improved perfusion
- Vitamin C
- No benefit in Sepsis or Septic Shock
XXII. Management: Supportive Measures
- See Critical Care
- Nutrition
- Maintain adequate nutrition
- Initiate Enteral Nutrition via oral Gastric Tube or nasal Gastric Tube within first 24-48 hours
- Enteral Nutrition is preferred over Total Parenteral Nutrition
- May consider Parenteral nutrition at 7 days if inadequate Enteral Nutrition
- Dextrose infusions may be used in first 7 days
- Initiate Enteral Nutrition via oral Gastric Tube or nasal Gastric Tube within first 24-48 hours
- Blood Glucose
- Conventional therapy (non-intensive Blood Sugar management: 144-180) is safer in critically ill
- Tight Glucose control is associated with Hypoglycemia and increased mortality
- Hyperglycemia is associated with apoptosis, ischemia and delayed healing
- Ideally mean Glucose of 150 mg/dl is preferred (range 144-180 mg/dl or 8-10 mmol/L)
- Consider initiating Insulin for Serum Glucose >180 mg/dl (10 mmol/L) targeting above range
- Monitor Serum Glucose every 1-2 hours if initiating Insulin, then every 4 hours
- (2009) N Engl J Med 360:1283-97 [PubMed]
- Maintain adequate nutrition
- Manage Hypocalcemia (based on Ionized Calcium or Corrected Serum Calcium for albumin)
- Replace with Calcium Gluconate or Calcium Chloride if hypocalcemic
-
Stress Ulcer or Peptic Ulcer prophylaxis
- Indications
- Thrombocytopenia
- Multiorgan failure
- Mechanical Ventilation
- Agents (either are equivalent)
- H2 Blocker (e.g. Ranitidine) or
- Proton Pump Inhibitor (e.g. Protonix)
- Reduces gastrointestinal Hemorrhage risk in high risk septic patients
- Does not appear to increase risk of C. Diff or Pneumonia
- Indications
-
DVT Prophylaxis
- DVT occurs in up to 14% of critically ill patients not on prophylaxis
-
DVT Prophylaxis options
- Low molecular-weight Heparin (preferred) or
- Low dose Unfractionated Heparin or
- Mechanical compression devices if Heparin contraindicated
XXIII. Management: End Stage Renal Disease (ESRD) and Sepsis
- Precautions
- Fluid management
- All septic patients with Hypotension or Lactic Acidosis will typically need upwards of 30 cc/kg replacement
- Early intubation may be preferred
- If monitoring (e.g. Ultrasound, CVP) is unreliable or unavailable
- Aim for 3-4 Liter IV fluid Resuscitation (in 500 cc increments)
- Emergency Dialysis may be required to manage Fluid Overload
- Aggressive fluid Resuscitation needed in Sepsis
- Use Inferior Vena Cava Ultrasound to drive fluid Resuscitation
- See Inferior Vena Cava Ultrasound for Volume Status
- Hypotension or Lactic Acidosis
- Vena cava collapses with inspiration: Give 500 cc IV bolus of fluid
- Vena cava does not collapse: Start Vasopressors (e.g. Norepinephrine)
- Repeat cycle of fluid bolus or pressors followed by Ultrasound until Hypotension and Lactic Acidosis resolve
- Once IVC does not collapse with inspiration, move to Vasopressors
- Consider starting Vasopressors earlier to help increase Preload
- Consider monitoring Central Venous Pressure (CVP) to confirm that it remains low following fluid bolus
- All septic patients with Hypotension or Lactic Acidosis will typically need upwards of 30 cc/kg replacement
- Airway management
- Early intubation is preferred over crash airway management
- BIPAP or intubation may be needed with fluid Resuscitation related to Fluid Shifts and Pulmonary Edema (expected)
- Labs
- Serum lactate is an accurate reflection of Sepsis status in ESRD (lactate undergoes Hepatic Clearance)
- References
- Weingart and Orman in Majoewsky (2013) EM:Rap 13(10): 6
XXIV. Management: Pregnancy and Sepsis
- Sepsis Criteria in pregnancy
- SIRS Criteria and qSOFA Criteria do NOT apply to pregnant patients
- No obstetric Sepsis scoring system (MEWS, MOEWS, SOS) has been found accurate enough for clinical use
- Blood Pressure, Heart Rate, Respiratory Rate are unreliable markers of serious infection or instability in pregnancy
- Lactic Acid cutoffs do not apply well to pregnancy, but higher Lactic Acids are associated with worse outcomes
-
General measures
- Left lateral decubitus position
- Aggressive fluid Resuscitation (as with other Sepsis cases)
- Blood Products as needed
- Early antbiotics
- No clear evidence for one Vasopressor over another in pregnancy (Norepinephrine is reasonable)
- References
- Swadron, Schmitz, Bridwell, Carius in Herbert (2019) EM:Rap 19(3): 12-4
XXV. Prognosis
- Positive Blood Culture
- Confers 150% increase in mortality risk
- Mortality
- Severe Sepsis: 25-30%
- Septic Shock: 40-70%
- Longterm outcomes
- Increased risk of readmission and death in the subsequent year after Sepsis discharge
- Significantly decreased physical and cognitive function after Sepsis discharge
- Yende (2016) Crit Care Med 44(8):1461-7 [PubMed]
XXVI. Resources
- Surviving Sepsis Protocol
XXVII. References
- (2016) CALS, 14th ed, 1:46
- Goldberg (2015) Crit Dec Emerg Med 29(3): 9-19
- Guirgis and Khadpe (2017) Crit Dec Emerg Med 31(12): 3-8
- Palizzolo, Dunne and Gaieski (2024) Crit Dec Emerg Med 38(6): 4-13
- Swadron and Goldberg in Majoewsky (2013) EM:RAP 13(6): 2-4
- Weingart and Orman in Majoewsky (2014) EM:RAP 14(8): 3-5
- Orman and Weingart in Majoewsky (2012) EM:RAP 12(10): 4-7
- Khoujah (2013) Crit Dec Emerg Med 27(4):12-21
- Marik (2011) Annals of Intensive Care 1:17
- Angus (2013) N Engl J Med 369(9): 840-51 +PMID:23984731 [PubMed]
- Annane (2005) Lancet 365(9453): 63-78 [PubMed]
- Cunha (2008) Crit Care Clin 24(2): 313-34 [PubMed]
- Dellinger (2013) Crit Care Med 41(2):580-637 [PubMed]
- Evans (2021) Crit Care Med 49(11):e1063-143 +PMID: 34605781 [PubMed]
- Gauer (2013) Am Fam Physician 88(1): 44-53 [PubMed]
- Gauer (2020) Am Fam Physician 101(7): 409-18 [PubMed]
- Jaimes (2004) Clin Infect Dis 38:357-62 [PubMed]
- Lever (2007) BMJ 335(7625): 879-83 [PubMed]
- Singer (2016) JAMA 315(8): 801-10 [PubMed]