Compliance with Surviving Sepsis Guidelines (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

• Compliance with the Surviving Sepsis Campaign Bundle is Variable, But Generally Low in Most Studies (Crit Care Med, 2010) [MEDLINE] (Lancet Infect Dis, 2012) [MEDLINE]
• Study of Surviving Sepsis Compliance and Outcomes (Crit Care Med, 2015) [MEDLINE]
  • Increased Compliance with Sepsis Performance Bundles was Associated with a 25% Relative Risk Reduction in Mortality Rate
  • Every 10% Increase in Compliance and Additional Quarter of Participation in the Surviving Sepsis Campagin Initiative was Associated with a Significant Decrease in the Odds Ratio for Hospital Mortality

Using Informational Handoffs

Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

• For Adults with Sepsis/Septic Shock, Using a Handoff Process of Critically Important Information at Transitions of Care is Recommended (Weak Recommendation, Very Low Quality of Evidence)
  • For Adults with Sepsis/Septic Shock, There is Insufficient Evidence to Make a Recommendation Regarding the Use of Any Specific Structured Handoff Tool Over Usual Handoff Processes (No Recommendation)

Family Support

Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

• For Adults with Sepsis/Septic Shock and Their Families, Screening for Economic and Social Support (Including Housing, Nutritional, Financial, and Spiritual Support) and Providing Relevant Referrals is Recommended (Best Practice)

Setting Goals of Care

Rationale

• Patients with Sepsis and Multiple Organ Failure Have a High Mortality Rate
  • A Percentage of Patients Who Survive an Episode of Sepsis Will Have a Poor Quality of Life

Clinical Efficacy

• Australian Prospective, Randomized Control Trial of End-of-Life Care Planning in Elderly Patients (BMJ, 2010) [MEDLINE]
  • Advance Care Planning Improved End-of-Life Care, Improved Patient/Family Satisfaction, and Decreased Stress, Anxiety, and Depression in Surviving Relatives
• Systematic Review of Studies of Interventions to Improve Communication in the Intensive Care Unit (Chest, 2011) [MEDLINE]
  • The Use of Printed Information and Structured Communication by the Usual ICU Team/Ethics Consultation/Palliative Care Consultation Improved Family Emotional Outcomes, Decreased the ICU Length of Stay, and Decreased Treatment Intensity
  • Evidence that the Interventions Decreased Costs was Inconclusive
• Systematic Review of Palliative Care Interventions and Advance Care Planning on ICU Utilization (Crit Care Med, 2015) [MEDLINE]
  • Despite a Wide Variation in Study Type and Quality, Advance Care Planning in Patients at High Risk for Death Decreased the Risk of ICU Admission (by 37%)
  • Despite a Wide Variation in Study Type and Quality, Palliative Care Interventions in the ICU Decreased ICU Length of Stay (26% Relative Risk Reduction)

Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

• For Adults with Sepsis/Septic Shock, Discussing Goals of Care and Prognosis with Patients/Families is Recommended (Best Practice Statement)
  • For Adults with Sepsis/Septic Shock, Addressing Goals of Care Early (within 72 hr) is Recommended (Weak Recommendation, Low Quality of Evidence)
  • For Adults with Sepsis/Septic Shock, There is Insufficient Evidence to Make Any Recommendation Regarding Specific Standardized Criterion to Trigger Goals of Care Discussion (No Recommendation)
  • For Adults with Sepsis/Septic Shock, Principles of Palliative Care (Which May Include Palliative Care Consultation Based on Clinician Judgement) Should Be Integrated into the Treatment Plan, When Appropriate, to Address Patient/Family Symptoms and Suffering (Best Practice Statement)
  • For Adults with Sepsis/Septic Shock, Routine Formal Palliative Care Consultation for All Patients is Not Recommended (Weak Recommendation, Low Quality of Evidence)

Sepsis Performance Improvement

Rationale

• Sepsis Performance Improvement Efforts are Associated with Improved Outcome (Crit Care Med, 2015) [MEDLINE]
• Systematic Review and Meta-Analysis of Sepsis Performance Improvement Programs (PLoS One, 2015) [MEDLINE]: n = 50 observational studies
  • Sepsis Performance Improvement Programs were Associated with Increased Adherence to Sepsis Resuscitation and Management Bundles, as Well as Decreased Mortality Rate in Sepsis/Severe Sepsis/Septic Shock

Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

• For Hospitals and Health Systems, Use of a Performance Improvement Program is Recommended for Sepsis (Including Sepsis Screening for Acutely Ill High-Risk Patients) (Strong Recommendation, Moderate Quality Evidence)
• For Hospitals and Health Systems, Standard Operating Procedures for Sepsis Treatment are Recommended (Strong Recommendation, Very Low Quality Evidence)

Triage

Clinical Efficacy

• Study of Association Between Intensive Care Unit (ICU) Admission and Mortality in Patients with Pneumonia (JAMA, 2015) [MEDLINE]
  • Among Medicare Beneficiaries Hospitalized with Pneumonia, ICU Admission of Patients for Whom the Decision Appeared to Be Discretionary was Associated with Improved Survival and No Significant Difference in Costs
• French Randomized ICE-CUB 2 Trial of Systematic Intensive Care Unti Triage in Critically Ill Elderly Patients (JAMA, 2017) [MEDLINE]
  • In Critically Ill Elderly Patients, Systematic ICU Admission Increased ICU Use But Did Not Decrease the 6-Month Mortality Rate

Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

• For Adults with Sepsis/Septic Shock Who Require Intensive Care Unit Admission, Admission to the Intensive Care Unit within 6 hrs is Recommended (Weak Recommendation, Low Quality of Evidence)

Infection Prevention

Recommendations (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]

• Selective Oral and Digestive Decontamination Should Be Introduced and Investigated as a Means to Decrease the Risk of Ventilator-Associated Pneumonia (Grade 2B Recommendation)
• Oral Chlorhexidine Gluconate Decontamination Should Be Used as a Means to Decrease the Risk of Ventilator-Associated Pneumonia in ICU Patients with Sepsis (Grade 2B Recommendation) (see Chlorhexidine Gluconate)

Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

• No Recommendations Made

Center for Medicare and Medicaid Services (CMS) Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) Management Bundle

Background

• CMS Introduced the SEP-1 Sepsis Management Quality Measure in October, 2015 to Track Provider/Hospital Performance in the Management of Sepsis (Emerg Med Clin North Am, 2017) [MEDLINE]
  • While SEP-1 was Meant to Reflect Best Evidence and Practice, its Use is Currently Controversial
    • In Addition, the Clinical Definitions of Sepsis (Below) Do Not Represent the Current State of the Art (i.e. SOFA Scoring) in Terms of Categorizing Sepsis Patients
  • SEP-1 is Currently “Hospital Compare”, Meaning that Individual Cases are Not Reimbursed Differently Depending on Adherence to the Metric: hospital performance is compared with other institutions and publicly reported

SEP-1 Sepsis Definitions

• Severe Sepsis: including all of the following
  • Documentation of Suspected or Possible Source of Infection
  • ≥2 Systemic Inflammatory Response Syndrome (SIRS) Manifestations
    • Heart Rate >90 bpm
    • Respiratory Rate >20 breaths/min
    • Temperature <96.8 or >100.9 Degrees F
    • White Blood Cell <4k, >12k, or Bands >10%
  • Organ Dysfunction (Any of the Following) Criteria
    • Systolic Blood Pressure <90 or Mean Arterial Pressure <65 or a Systolic Blood Pressure Decrease of >40 mm Hg
    • Acute Respiratory Failure as Evidenced by a New Need for Invasive or Noninvasive Mechanical Ventilation
    • Serum Creatinine >2.0 or Urine Output <0.5 mL/kg/hrs for 2 hrs
    • Serum Bilirubin >2 mg/dL
    • Platelet Count <100,000
    • International Normalized Ratio >1.5 or Activated Partial Thromboplastin Time >60 sec (in a Non-Anticoagulated Patient)
    • Serum Lactate >2 mmol/L
• Septic Shock: including both of the following
  • Documentation of Severe Sepsis
  • Hypotension Persisting in the Hour After the Intravenous Fluid Bolus as Evidenced By Either
    • Systolic Blood Pressure <90 or Mean Arterial Pressure <65 or a Systolic Blood Pressure Decrease of >40 mm Hg
    • Tissue Hypoperfusion Present with Initial Serum Lactate Level ≥4 mmol/L

Inclusion and Exclusion Criteria

• SEP-1 Inclusion Criteria
  • Discharge Age >17 and Any of the Following Diagnoses
    • International Classification of Diseases-10-CM Principal or Other Diagnosis Code of Sepsis
    • Severe Sepsis
    • Septic Shock
  • Transfer Inclusions
    • Transfer from Urgent Care
    • Transfer from Psychiatric or Rehabilitation Units (Only if Part of Your Hospital)
    • Transfer from Dialysis Center (with Some Exceptions)
    • Transfer from Same-Day Surgery Center within Your Hospital
    • Transfer from Any Clinic
    • Transfer from Any Skilled Nursing Facility
• SEP-1 Exclusion Criteria
  • Comfort Care within 3 hrs of Presentation for Severe Sepsis or 6 hrs for Septic Shock
  • Administrative Contraindication to Care (eg, Patient Refusal)
  • Length of Stay >120 Days
  • Transfer Exclusions
    • Transfer from Another Acute Care Facility
    • Transfer from Long-Term Acute Care (Not Nursing Home)
    • Transfer from Any Acute Rehabilitation Facility
    • Transfer from Any Outside Psychiatric Hospital
    • Transfer from Cardiac Catheterization Laboratory in an Outside Hospital
    • Transfer from Same-Day Surgery in an Outside Hospital
    • Patients Brought to the Emergency Department as Part of a Mass Casualty
  • Severe Sepsis with Expiration within 3 hrs of Presentation
  • Septic Shock with Expiration within 6 hrs of Presentation
  • Patients Receiving Intravenous Antibiotics >24 hrs Before Presentation of Severe Sepsis

SEP-1 Required Clinical Actions for Included Patients with Severe Sepsis

• General Comments
  • Clock Begins with Physician Documentation of Severe Sepsis
  • Time 0: last criteria and infection documented
  • All Elements of the Bundle are Equally Weighted and All Must Be Performed to Pass the Bundle
• Must Meet All of Within 3 hrs of Presentation
  • Initial Serum Lactate Measurement
  • Broad-Spectrum or Other Antibiotics Administered
  • Blood Cultures Drawn Before Antibiotics
• And Within 6 hrs of Presentation
  • Repeat Serum Lactate Measurement (if Initially Elevated)

SEP-1 Required Clinical Actions for Included Patients with Septic Shock

• General Comments
  • Clock Begins with Physician Documentation of Septic Shock
  • Time 0 is with Any of the Following
    • Systolic Blood Pressure <90 mm Hg
    • Mean Arterial Pressure <65 mm Hg
    • Serum Lactate ≥4 mmol/L
  • All Elements of the Bundle are Equally Weighted and All Must Be Performed to Pass the Bundle
• Must Meet All of Within 3 hrs of Presentation
  • All Above Severe Sepsis 3 hr Timeframe Interventions
  • Resuscitation with 30 mL/kg Crystalloid Fluid
• If Hypotension Persists After Fluid Administration Must Receive Within 6 hrs of Presentation
  • Vasopressors
• If Hypotension Persists After Intravenous Fluids or Initial Lactate ≥4 mmol/L, Must Receive Within 6 hrs of Presentation
  • Repeat Volume Status and Tissue Perfusion Assessment Via
    • Focused Examination Including Vital Signs, Cardiopulmonary Examination, Capillary Refill, Peripheral Pulse Evaluation, and Skin Examination or Any Two of the Following
      • Central Venous Pressure Measurement
      • Central Venous Oxygen Measurement
      • Bedside Cardiovascular Ultrasound
      • Passive Leg Raise or Fluid Challenge

Clinical Efficacy

• Kaiser Multicenter Study of Sepsis Bundle (SEP-1 Type) Implementation (30 mL/kg Fluid Resuscitation or at Least 2L, etc) in Patients with Intermediate Lactate Values (Serum Lactate 2-4 mmol/L) (from 2011-2013) (Am J Respir Crit Care Med, 2016) [MEDLINE]: n = 18,122 (in 21 Kaiser hospitals)
  • Full Sepsis Bundle Compliance Increased from 32.2% in 2011 to 44.9% After Bundle Implementation (P < 0.01)
  • Hospital mortality was 8.8% in 2011, 9.3% in 2012, and 7.9% in 2013 (P = 0.02)
  • Treatment After Bundle Implementation was Associated with an Adjusted Hospital Mortality Odds Ratio of 0.81 (95% CI: 0.66-0.99; P = 0.04)
  • The Subgroup of Patients Heart Failure and/or Kidney Disease Accounted for Almost All of the Decrease in Hospital Mortality (P < 0.01), as Compared to Patients without These Disorders (P > 0.40)
    • This Corresponded to Notable Increases in the Fluid Resuscitation Volume in Patients with Heart Failure and/or Kidney Disease After Bundle Implementation
• Examination of Performance and Efficacy of Each of the SEP-1 Bundle Elements in Sepsis and Septic Shock in New York (NEJM, 2017) [MEDLINE]: n = 49,331 (at 149 hospitals)
  • Only 82.5% of Patients Had the 3 hr Sepsis Bundle (Blood Cultures Drawn, Broad-Spectrum Antibiotics, and Serum Lactate Measurement) Completed within 3 hrs
  • Time to Completion of Bundle Elements
    • Median Time for 3 hr Sepsis Bundle (Blood Cultures Drawn, Broad-Spectrum Antibiotics, and Serum Lactate Measurement) Completion was 1.3 hrs (Interquartile Range, 0.65 to 2.35)
    • Median Time to the Administration of Antibiotics was 0.95 hrs (Interquartile Range, 0.35 to 1.95)
    • Median Time to Completion of the Intravenous Fluid Bolus was 2.56 hours (Interquartile Range, 1.33 to 4.20)
  • More Rapid Completion of the 3 hr Sepsis Bundle Early Rapid Antibiotic Administration (But Not the Rapid Completion of an Initial Bolus of Intravenous Fluids) were Associated with Decreased Risk-Adjusted In-Hospital Mortality Rate
• Systematic Review of Evidence Underlying the SEP-1 Sepsis Quality Metric (Ann Intern Med, 2018) [MEDLINE]: n = 20 studies
  • No High or Moderate-Level Evidence Shows that SEP-1 or its Hemodynamic Interventions Improve Survival in Adults with Sepsis
• Study of Sepsis Time 0 and its Impact on Meeting SEP-1 Metric (Infect Control Hosp Epidemiol, 2018) [MEDLINE]
  • Abstractors Agreed on Time 0 in Only 36% of Cases
  • Perceived Pass Rates Ranged from 11-23% of Cases
  • Variability in Time 0 and Perceived Pass Rates Limit the Utility of SEP-1 for Measuring Quality
• Study of Performance on the SEP-1 Metric in the Emergency Department (Ann Emerg Med, 2018) [MEDLINE]
  • Mean Hospital SEP-1 Bundle Compliance was 54% (Interquartile Range 30-75%)
  • Bundle Compliance Improved During Fiscal Year 2016 from 39% to 57%
  • Broad Variation Existed for Each Bundle Component, with Intravenous Fluid Resuscitation and Repeated Lactate Bundle Elements Having the Widest Variation and Largest Gaps in Quality
• Study of Compliance with SEP-1 Bundle and Relationship to Mortality Rate (Crit Care Med, 2018) [MEDLINE]
  • Crude Mortality Rates were Higher in Sepsis Cases Which Failed vs Passed the SEP-1 Bundle, But There was No Difference After Adjusting for Clinical Characteristics and Severity of Illness
  • Delays in Antibiotic Administration were Associated with Higher Mortality, But Only Accounted for a Small Fraction of SEP-1 Failures: the most common reason for failing the measure was omission of the 3 and 6 hr lactate measurement
  • SEP-1 May Not Clearly Differentiate Between High and Low-Quality Care, and Detailed Risk Adjustment is Necessary to Properly Interpret the Associations Between SEP-1 Compliance and Mortality
• University of Chicago Study of Lactate Measurement in Sepsis as Part of the SEP-1 Bundle (Chest, 2018) [MEDLINE]
  • Serum Lactate was Measured within the Mandated Window 32% of the Time on the Ward (n = 505), as Compared with 55% (n = 818) in the ICU and 79% (n = 2,144) in the ED
  • Patients with Delayed Serum Lactate Measurement Demonstrated the Highest In-Hospital Mortality at 29%, with Increased Time to Antibiotic Administration (Median Time, 3.9 vs 2.0 h)
  • Patients with Initial Serum Lactate >2.0 mmol/L Demonstrated an Increase in the Odds of Death with Hourly Delay in Lactate Measurement (OR, 1.02; 95% CI, 1.0003-1.05; P = .04)
• Study of SEP-1 Impact on Mortality Rate in Community-Onset vs Hospital-Onset Sepsis (JAMA Intern Med, 2020) [MEDLINE]: n = 6,404
  • Community-Onset Sepsis (64.1% of Cases)
    • Serum Lactate Testing within 3 hrs of Time 0 was Associated with Decreased Mortality Rate (Absolute Difference -7.61%; 95% CI: -14.70% to -0.54%)
    • Blood Cultures (Absolute Difference -1.10 days; 95% CI: -1.85 to -0.34 Days) and Broad-Spectrum Antibiotics (Absolute Difference -0.62 days; 95% CI: -1.02 to -0.22 Days) were Associated with Fewer Vasopressor days
    • Complete SEP-1 Compliance was Associated with Increased Vasopressor Days (Absolute Difference 0.31 days; 95% CI: 0.11-0.51 days) But was Not Significantly Associated with Decreased Mortality Rate (Absolute Difference -0.07%; 95% CI: -3.02% to 2.88%)
  • In Hospital-Onset Sepsis
    • Broad-Spectrum Antibiotics was the Only Bundle Component Associated with Decreased Mortality Rate (Mortality Difference -5.20%; 95% CI: -9.84% to -0.56%)
    • Complete SEP-1 Compliance was Not Associated with Decreased Mortality Rate (Absolute Difference -0.42%; 95% CI: -6.77% to 5.93%)
• Longitudinal, Cross-Sectional, Cohort Study of the SEP-1 Metric in Adult Patients with Sepsis in a Single Health System (Ann Intern Med, 2021) [MEDLINE]: n= 54,225 encounters between Jan, 2013-Dec, 2017 for adults with sepsis who were hospitalized through the emergency department
  • SEP-1 was Associated with Variable Changes in Process Measures
    • Two Years After SEP-1 Implementation, the Greatest Effect was an Increase in Lactate Measurement within 3 hrs of Sepsis Onset (Absolute Increase of 23.7 Percentage Points; 95% CI: 20.7_26.7 Percentage Points; p<0.001)
  • SEP-1 Resulted in a Small Increase in Antibiotic Administration (Absolute Increase of 4.7 Percentage Points; CI, 1.9-7.6 Percentage Points; p=0.001)
  • SEP-1 Resulted in a Small Increase in Fluid Administration (30 mL/kg) within 3 hrs of Sepsis Onset (Absolute Increase of 3.4 Percentage Points; CI, 1.5-5.2 Percentage Points; p<0.001)
  • SEP-1 Resulted in No Change in Vasopressor Administration
  • SEP-1 Resulted in a Small Increase in ICU Admission Rate (Absolute Increase of 2.0 Percentage Points [CI: 0-4.0 Percentage Points; p=0.055])
  • SEP-1 Resulted in No Change in the Mortality Rate (Absolute Change of 0.1 Percentage Points; CI: -0.9 to 1.1 Percentage Points]; p=0.87) or Discharge to Home
• Retrospective Cohort Study of SEP-1 Core Measure on Patients with Suspected Sepsis in US Hospitals (JAMA Netw Open, 2021) [MEDLINE]: n = 117,510
  • SEP-1 Implementation was Associated with an Immediate Increase in Lactate Testing Rates, No Change in Already-Increasing Rates of Broad-Spectrum Antibiotic Use, and No Change in Short-Term Mortality Rates for Patients with Suspected Sepsis
• Study of Impact of SEP-1 Core Measure on Antibiotic Use in Hospitals (Clin Infect Dis, 2021) [MEDLINE]
  • SEP-1 Implementation was Associated with Immediate and Long-Term Increases in Broad-Spectrum Hospital-Onset/Multidrug-Resistant (MDR) Organism Antibiotics
• Propensity Score Matched Cohort Study (from 2015 to 2017) of the Effects of SEP-1 Compliance on Mortality in Medicare Patients (Chest, 2022) [MEDLINE]
  • In Standard Match, SEP-1 Compliance was Associated with Decreased 30-Day Mortality Rate (21.81% vs 27.48%, Respectively), Yielding an Absolute Risk Reduction of 5.67% (95% CI: 5.33-6.00; P < 0.001)
  • In Stringent Match, SEP-1 Compliance was associated with Decreased 30-Day Mortality Rate (22.22% vs 26.28%, Respectively), Yielding an Absolute Risk Reduction of 4.06% (95% CI: 3.70-4.41; P < 0.001)
  • At the Subject Level, the Hierarchical General Linear Model Found that SEP-1 Compliance was Associated with Decreased 30-Day Risk-Adjusted Mortality Rate (Adjusted Conditional Odds Ratio 0.829; 95% CI: 0.812-0.846; P < 0.001)
  • Each SEP-1 Bundle Element that Achieved Statistical Significance was Associated with Mortality Rate (Except Vasopressor Use)
  • SEP-1 Compliance was Associated with Shorter Median Length of Stay (5 vs 6 Days; Interquartile Range, 3-9 vs 4-10, Respectively; P < 0.001)
• Retrospective Longitudinal Cohort Study of SEP-1 Core Measure Implementation on Antibacterial Utilization (Clin Infect Dis, 2022) [MEDLINE]: n = 701,055 eligible patient admissions (and 4.2 million patient-days)
  • Overall Antibacterial Utilization Increased 2% Each Month During SEP-1 Preparation (Relative Rate 1.02 Per Month (95% CI: 1.00-1.04]; P = 0.02)
  • Cumulatively, the Mean Monthly Days of Therapy Per 1,000 Patient-Days Increased 24.4% (95% CI: 18.0%-38.8%) Over the Entire Study Period (Oct 2014-Oct 2016)
  • Rate of Sepsis Diagnosis/1,000 Patients Increased 2% Each Month During SEP-1 Preparation (Relative Rate 1.02 Per Month [95% CI: 1.00-1.04]; P = 0.04)
  • All-Cause Mortality Rate Per 1,000 Patients Decreased During the Study Period
    • Relative Rate for SEP-1 Preparation 0.95; 95% CI: 0.92-0.98; P = 0.001
    • Relative Rate for SEP-1 Implementation 0.98; CI: 0.97-1.00; P = 0.01
  • Cumulatively, the Monthly Mean All-Cause Mortality Rate/1,000 Patients Decreased 38.5% (95% CI: 25.9%-48.0%) Over the Study Period

Opinions/Position Papers

• Paul Marik Editorial Regarding Use of Lactate in SEP-1 Bundle (Crit Care Med, 2018) [MEDLINE]
  • In His Opinion, Apart from the Timely Administration of Antibiotics, None of the Other SEP-1 Bundle Elements are Supported by Any Scientific Data, Nor Have They Been Demonstrated to Improve Patient Outcome
• Joint IDSA/ACEP/PIDS/SHEA/SHM/SIDP Position Paper on Improving Sepsis Outcomes in the Era of Pay-for-Performance and Electronic Quality Measures (Clin Infect Dis, 2023) [MEDLINE]
  • Recommends Removing SEP-1 Rather than Using it in a Payment Model and Shifting Instead to New Sepsis Metrics Which Focus on Patient Outcomes
  • CMS is Developing a Community-Onset Sepsis 30-Day Mortality Electronic Clinical Quality Measure (eCQM)
    • The eCQM Preliminarily Identifies Sepsis Using Systemic Inflammatory Response Syndrome (SIRS) Criteria, Antibiotic Administrations or Diagnosis Codes for Infection or Sepsis, and Clinical Indicators of Acute Organ Dysfunction
    • They Support the eCQM, But Recommend Removing SIRS Criteria and Diagnosis Codes to Streamline Implementation, Decrease Variability Between Hospitals, Maintain Vigilance for Patients with Sepsis but without SIRS, and Avoid Promoting Antibiotic Use in Uninfected Patients with SIRS

Vascular Access

Central Venous Catheter (CVC) (see Central Venous Catheter)

• Rationale
  • Adequate Intravenous Access is Critical to Allow Intravenous Fluid Resuscitation, Antibiotic Administration, and Vasopressor Administration
  • Placement of a Central Venous Catheter is the Most Common Means of Securing Such Intravenous Access
• Clinical Efficacy
  • Retrospective Study of Central Venous Catheter Use in Septic Shock (Crit Care Med, 2013) [MEDLINE]: n = 203,481 (admitted through the emergency department with septic shock)
    • Placement of a Central Venous Catheter Early in Septic Shock has Increased 3-Fold Since 1998
    • The Mortality Associated with Early Central Venous Catheter Insertion Decreased After Publication of Evidence-Based Instructions for Central Venous Catheter Use

Intraosseous (IO) Vascular Access

• Rationale
  • IO Vascular Access Allows for Fluid Resuscitation, Antibiotic Administration, and Vasopressor Administration When Rapid Intravenous Access is Not Possible

Arterial Line Placement (see Arterial Line)

• Rationale
  • Arterial Line Allows for Accurate Hemodynamic Monitoring of Arterial Blood Pressure
    • Noninvasive Cuff Measurement of Blood Pressure (Especially Automated Cuff Measurement) is Less Accurate in Shock States (JAMA, 1967) [MEDLINE]
• Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
  • For Adults with Septic Shock, Invasive Arterial Blood Pressure Monitoring is Recommended Over Noninvasive Arterial Blood Pressure Monitoring, as Soon as Practical and if Resources are Available (Weak Recommendation, Very Low Quality of Evidence)

Swan-Ganz Catheterization (see Swan-Ganz Catheter)

• Findings
  • High Cardiac Output + Low Systemic Vascular Resistance (SVR) State
  • Decreased Extraction Ratio (Increased SvO2)
• Clinical Efficacy
  • French PA Catheter Study of Swan-Ganz Catheter in Shock and ARDS (JAMA, 2003) [MEDLINE]
    • Early Swan-Ganz Catheter Use Did Not Impact the Mortality in Shock and ARDS
  • Meta-Analysis of Swan-Ganz Catheter Trials in the ICU (JAMA, 2005) [MEDLINE]
    • Swan-Ganz Catheter Did Not Impact the Mortality or Number of Hospital Days
  • PAC-Man Study of Swan-Ganz Catheter Use in the ICU (Lancet, 2005) [MEDLINE]
    • Swan-Ganz Catheter Did Not Impact the Mortality Rate
  • Study of Swan-Ganz Catheter vs Central Venous Catheter in Acute Lung Injury (NEJM, 2006) [MEDLINE]
    • Swan-Ganz Catheter Did Not Improve Mortality Rate vs Using a Central Venous Catheter, But Was Associated with an Increased Risk of Complications
  • Systematic Review and Meta-Analysis of Swan-Ganz Catheter in the Outcome of Moderate to High-Risk Surgical Patients (Anesth Analg, 2011) [MEDLINE]
    • Preemptive Strategy of Swan-Ganz Catheter Hemodynamic Monitoring and Coupled Therapy Decreased Surgical Mortality and Morbidity
• Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
  • Swan-Ganz Catheter is Not Routinely Recommended in the Management of Sepsis-Associated ARDS (Strong Recommendation, High Quality of Evidence)

Source Identification and Control

Specific Interventions for Sources of Sepsis

• Cardiovascular
  • Valve Replacement for Endocarditis (see Endocarditis): may require valve replacement
  • Removal of Infected Device
    • Arterial Line (see Arterial Line)
    • Automatic Implantable Cardioverter-Defibrillator (AICD) (see Automatic Implantable Cardioverter-Defibrillator)
    • Cardiac Pacemaker (see Cardiac Pacemaker)
    • Cardiac Valve Replacement
    • Central Venous Catheter (CVC) (see Central Venous Catheter)
    • Foley Catheter (see Foley Catheter)
    • Orthopedic (Joint/Spine, etc) Hardware
    • Vascular Graft
• Dermatologic
  • Drainage of Skin Abscess (see Skin Abscess)
• Gastrointestinal
  • Endoscopic Retrograde Cholangiopancreatography (ERCP) Drainage of Biliary Tree (see Endoscopic Retrograde Cholangiopancreatography)
    • Acute Cholangitis (see Acute Cholangitis)
  • Interventional Radiology Cholecystostomy or Surgical Cholecystectomy (see Cholecystostomy and Cholecystectomy)
    • Cholecystitis
      • Acalculous Cholecystitis (see Acalculous Cholecystitis)
      • Acute Cholecystitis (see Acute Cholecystitis)
  • Interventional Radiology or Surgical Drainage of Abscess
    • Abdominal Abscess (see Abdominal Abscess)
    • Pyogenic Liver Abscess (see Pyogenic Liver Abscess)
  • Surgical Exploration/Abscess Drainage/Bowel Resection
    • Gastrointestinal Ischemia/Infarction/Perforation
      • Esophageal Ischemia/Infarction (see Acute Esophageal Necrosis)
      • Esophageal Perforation (see Esophageal Perforation)
      • Gastric Ischemia/Infarction (see Gastric Ischemia)
      • Gastric Perforation (see Gastric Perforation)
      • Small Intestinal Ischemia/Infarction (see Acute Mesenteric Ischemia)
      • Small Bowel/Intestinal Perforation (see Small Bowel Perforation)
      • Colonic Ischemia (Ischemic Colitis)/Infarction (see Colonic Ischemia)
      • Colonic Perforation (see Colonic Perforation)
• Neurologic
  • Removal of Infected Device
    • Neurostimulator (see Neurostimulator)
    • Ventriculoperitoneal (VP) Shunt (see Ventriculoperitoneal Shunt)
• Otolaryngologic
  • Surgical Drainage of Deep Neck Infection (see Deep Neck Infection)
• Pulmonary
  • Chest Tube or Surgical Drainage of Complicated Parapneumonic Effusion/Empyema (see Pleural Effusion-Parapneumonic,)
  • Lung Resection in Pulmonary Gangrene (see Necrotizing Pneumonia and Pulmonary Gangrene)
• Renal
  • Foley Catheter, Nephrostomy, Ureteral Stent, or Surgical Drainage of Infected Urinary Space
    • Pyelonephritis with Abscess/Obstruction (see Urinary Tract Infection
• Rheumatologic/Orthopedic
  • Joint Washout in Septic Arthritis (see Septic Arthritis)
  • Surgical Debridement of Infected Space/Tissue
    • Necrotizing Fasciitis (see Necrotizing Soft Tissue Infection)

Clinical Efficacy

• Surgical Infection Society and Infectious Diseases Society of America Guidelines for the Diagnosis and Management of Complicated Intra-Abdominal Infection in Adults and Children (Surg Infect, 2010) [MEDLINE]
  • Without Adequate Source Control, More Severe Clinical Presentations Will Not Improve Despite Aggressive Resuscitation and Antimicrobials: for this reason, prolonged efforts aimed to medically stabilize the patient beyond 6-12 hrs prior to source control are unlikely to be successful

Recommendations (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]

• When Peri-Pancreatic Necrosis is Identified as a Potential Source, Definitive Intervention is Best Delayed Until Adequate Demarcation of Viable and Non-Viable Tissues Has Occurred (Grade 2B Recommendation)

Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

• For Adults with Sepsis/Septic Shock, Rapid Identification/Exclusion of a Specific Anatomical Diagnosis of Infection Which Requires Emergent Source Control (and Implementing Any Required Source Control Intervention) is Recommended as Soon as Medically and Logistically Practical (Best Practice Statement)
  • Required Source Control Interventions Should Generally Be Implemented Within 6-12 hrs
• For Adults with Sepsis/Septic Shock, Prompt Removal of Intravascular Access Devices Which are a Possible Source of Sepsis/Septic Shock is Recommended After Other Vascular Access Has Been Established (Best Practice Statement)

Antimicrobial Therapy

Rationale

• Prompt Antimicrobial Therapy Has Long Been Believed to Impact Sepsis Outcome
  • Each Hour of Delay in the Administration of Antimicrobials is Associated with a Defined Increase in the Mortality Rate
  • Delay in Antimicrobial Administration is Also Associated with an Increased Risk of Acute Lung Injury, Acute Kidney Injury, and Other Organ Injury
• Failure to Administer Appropriate Empiric Antimicrobial Therapy is Associated an Increased Probability of Progression from Gram-Negative Bacteremia to Septic Shock and Increased Morbidity/Mortality Rates
• Approximately 33% of Patients with Sepsis Do Not Have a Causative Pathogen Identified
  • Some of These Cases May Be Attributed to the Fact that Cultures Were Not Obtained Initially or Were Obtained Only After Antimicrobials Were Administered
• Routine Antifungal Therapy is Not Routinely Required in Non-Neutropenic Patients

Clinical Efficacy-Early Antimicrobial Treatment

• Edusepsis Trial Examining Impact of Early Antibiotics in Sepsis (Am J Resp Crit Care Med, 2009) [MEDLINE]
  • Early Antibiotics (Treatment Within 1 hr) Decreased In-Hospital Mortality Rate, As Compared to No Treatment Within 6 hrs
• Trial Examining Impact of Time to Antibiotics in Severe Sepsis/Septic Shock in Patients Receiving Goal-Directed Therapy in the ED (Crit Care Med, 2010) [MEDLINE]
  • Time From Triage to Appropriate Antibiotics of <1 hr Improved the In-Hospital Mortality Rate
  • Time From Qualification for Early Goal-Directed Therapy to Appropriate Antibiotics of <1 hr Improved the In-Hospital Mortality Rate
• Examination of Performance and Efficacy of Each of the SEP-1 Bundle Elements in Sepsis and Septic Shock in New York (N Engl J Med, 2017) [MEDLINE]: n = 49,331 (at 149 hospitals)
  • Only 82.5% of Patients Had the 3 hr Sepsis Bundle (Blood Cultures Drawn, Broad-Spectrum Antibiotics, and Serum Lactate Measurement) Completed within 3 hrs
  • Time to Completion of Bundle Elements
    • Median Time for 3 hr Sepsis Bundle (Blood Cultures Drawn, Broad-Spectrum Antibiotics, and Serum Lactate Measurement) Completion was 1.3 hrs (Interquartile Range, 0.65 to 2.35)
    • Median Time to the Administration of Antibiotics was 0.95 hrs (Interquartile Range, 0.35 to 1.95)
    • Median Time to Completion of the Intravenous Fluid Bolus was 2.56 hours (Interquartile Range, 1.33 to 4.20)
  • More Rapid Completion of the 3 hr Sepsis Bundle Early Rapid Antibiotic Administration (But Not the Rapid Completion of an Initial Bolus of Intravenous Fluids) were Associated with Decreased Risk-Adjusted In-Hospital Mortality Rate

Clinical Efficacy-Early Involvement of Infectious Disease Consultation

• Prospective Observational Study Examining the Accuracy of Empiric Antimicrobial Therapy in Bacteremia (J Clin Microbiol, 2012) [MEDLINE]
  • Early Involvement of Infectious Disease Consultation (75%) Significantly Improves Microbiologically Correct Empiric Antimicrobial Therapy, as Compared to Standard Care (53%): this may be particularly true with infections due to specific organisms (such as Staphylococcus Aureus)
• Trial of Molecular Rapid Diagnostic Testing for the Diagnosis of Bloodstream Infections with/without Antibiotic Stewardship (Clin Microbiol Rev. 2018 May 30;31(3). pii: e00095-17. doi: 10.1128/CMR.00095-17 [MEDLINE]
  • Patient Population: adult inpatients in US hospitals with suspected bloodstream infection
  • Molecular Rapid Diagnostic Tests with an Antimicrobial Stewardship Program Had an 80.0% Chance of Being Cost-Effective, While Molecular Rapid Diagnostic Tests without an Antimicrobial Stewardship Programs Had Only a 41.1% Chance of Being Cost-Effectibve
  • Findings Suggest that Molecular Rapid Diagnostic Tests are Cost-Effective for the Diagnosis of Patients with Suspected Bloodstream Infection and Can Decrease Healthcare Expenditures

Clinical Efficacy-Optimization of Antimicrobial Dosing/Pharmacokinetics

• Meta-Analysis Comparing Intermittent vs Continuous Infusion of β-Lactams in Severe Sepsis (Am J Respir Crit Care Med, 2016) [MEDLINE]
  • Continuous Infusion of β-Lactams was Associated with Decreased Hospital Mortality, as Compared to Intermittent Dosing

Clinical Efficacy-Combination Therapy Aimed at Increasing Pathogen Clearance

• Propensity-Matched Analysis of Combination Therapy (Crit Care Med, 2010) [MEDLINE]
  • Early Combination Therapy (Aimed at Increasing Pathogen Clearance) Improves the Mortality Rate in Septic Shock
• Meta-Analysis/Meta-Regression Study of Combination Therapy (Crit Care Med, 2010) [MEDLINE]
  • Combination Therapy Improves Mortality Rate and Clinical Response in High-Risk (Mortality Risk >25%), Life-Threatening Infections (Particularly Septic Shock): however, combination may be detrimental in low-risk patients without septic shock (<15% mortality risk)

Clinical Efficacy-Antifungal Therapy

• Trial of Empiric Systemic Antifungal Therapy in Critically Ill, Mechanically-Ventilated Non-Neutropenic, Non-Transplant Patients (Am J Respir Crit Care Med, 2015) [MEDLINE]
  • Empiric Systemic Antifungal Therapy Had No Benefit (in Terms of Hospital Mortality or Occurrence of Invasive Candidiasis) in Critically Ill, Mechanically-Ventilated, Non-Neutropenic, Non-Transplant Patients
• Cochrane Database Systematic Review of Preventative Antifungal Therapy in Non-Neutropenic Critically Ill Patients (Cochrane Database Syst Rev, 2016) [MEDLINE]
  • Use of Untargeted Antifungal Treatment is Not Associated with a Significant Decrease in All-Cause Mortality in Critically Ill, Non-Neutropenic Adults and Children, as Compared to No Antifungal Treatment or Placebo
  • Untargeted Antifungal Treatment May Be Associated with a Decrease in Invasive Fungal Infections, But the Quality of Evidence is Low, and both the Heterogeneity and Risk of Publication Bias is High
• EMPIRICUS Trial of Empiric Micafungin in Adult Patients with ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure (But without Invasive Fungal Infection) (JAMA, 2016) [MEDLINE]
  • In Non-Neutropenic Critically Ill Patients with ICU-Acquired Sepsis, Candida Species Colonization at Multiple Sites, and Multiple Organ fFailure, Empiric Micafungin Did Not Increase Fungal Infection-Free 28-Day Survival, as Compared to Placebo

Clinical Efficacy-Antimicrobial De-Escalation/Shortened Duration of Antibiotic Therapy

• Trial of Short-Course Antibiotics for Uncomplicated Cellulitis (Arch Intern Med, 2004) [MEDLINE]
  • In Patients with Uncomplicated Cellulitis, 5 Days of Therapy with Levofloxacin Appeared to Be as Effective as 10 Days of Therapy
• Retrospective Study of Antibiotic De-Escalation in a Medical-Surgical Intensive Care Unit (Crit Care, 2010)
  • De-Escalation Might Be Safe and Feasible in a Large Proportion of Patients
• Trial of Short-Course Antibiotic Therapy for Acute Pyelonephritis and Septic Urinary Tract Infection (J Antimicrob Chemother, 2013) [MEDLINE]
  • Seven Days of Treatment for Acute Pyelonephritis WAS Equivalent to Longer Treatment in Terms of Clinical Failure and Microbiological Failure, Including in Bacteraemic Patients
  • In Patients with Urogenital Abnormalities, the Evidence, Although Weak, Suggests that Longer Treatment is Required
• Cochrane Database Systematic Review of Antibiotic De-Escalation in Severe Sepsis and Septic Shock (Cochrane Database Syst Rev, 2013) [MEDLINE]
  • There is No Adequate, Direct Evidence as to Whether De-Escalation of Antimicrobial Agents is Effective and Safe for Adults with Sepsis, Severe Sepsis, or Septic Shock
• Prospective Observational Study of Antimicrobial De-Escalation in Severe Sepsis/Septic Shock (Intensive Care Med, 2014) [MEDLINE]
  • Antimicrobial De-Escalation Improved the Mortality Rate in Severe Sepsis/Septic Shock
• Multicenter Non-Blinded Randomized Noninferiority Trial of Antimicrobial De-Escalation in Severe Sepsis (Intensive Care Med, 2014) [MEDLINE]
  • Antimicrobial De-Escalation Did Not Affect the Mortality Rate (But Increased ICU Length of Stay) in Severe Sepsis
• STOP-IT Trial of Short-Course Antimicrobial Therapy for Intra-Abdominal Infection (NEJM, 2015) [MEDLINE]
  • In Patients with Intraabdominal Infections Who Had Undergone an Adequate Source-Control Procedure, the Outcomes After Fixed-Duration Antibiotic Therapy (Approximately 4 Days) were Similar to Those After a Longer Course of Antibiotics (Approximately 8 Days) Which Extended Until After the Resolution of Physiological Abnormalities
• Trial of Short-Course Antibiotics for Septic Intra-Abdominal Infection (J Am Coll Surg, 2016) [MEDLINE]
  • There was No Difference in Outcomes Between Short and Long-Course Antimicrobial Therapy in Patients with Complicated Intra-Abdominal Infection Presenting with Sepsis
  • Findings Suggest that the Presence of Systemic Illness Does Not Mandate a Longer Antimicrobial Course if Source Control of Complicated Intra-Abdominal Infection is Oobtained
• Israeli Systematic Review and Meta-Analysis of Procalcitonin in De-Escalation of Antibiotics for Bloodstream Infections and Pneumonia (Clin Microbiol Infect, 2016) [MEDLINE]: included 16 observational studies (risk of bias related to confounding was high in the observational studies) and 3 RCT’s
  • Definition of De-escalation changing an initially covering antibiotic regimen to a narrower spectrum regimen based on antibiotic susceptibility testing results within 96 hrs
  • Primary Outcome was 30-Day All-Cause Mortality
  • Unadjusted Analysis
    • De-Escalation was Associated with Lower Mortality (OR 0.53, 95% CI 0.39-0.73): 19 studies, moderate heterogeneity
    • There was a Significant Association Between De-Escalation and Survival in Bacteremia/Severe Sepsis (OR 0.45, 95% CI 0.30-0.67) and Ventilator-Associated Pneumonia (OR 0.49, 95% CI 0.26-0.95), But Not with Other Pneumonia (OR 0.97, 95% CI 0.45-2.12)*
  • Adjusted Analysis
    • De-Escalation was Associated with No Significant Difference in Mortality (Adjusted OR 0.83, 95% CI 0.59-1.16): 11 studies, moderate heterogeneity
    • Randomized Controlled Trials Demonstrated a Non-Significant Increase in Mortality with De-Escalation (OR 1.73, 95% 0.97-3.06), 3 trials: no heterogeneity
  • Only 2 Studies Reported on the Emergence of Resistance with Inconsistent Findings
  • Observational Studies Suggested Lower Mortality with Antibiotic Susceptibility Testing-Based De-Escalation for Bacteremia, Severe Sepsis, and Ventilator-Associated Pneumonia that was Not Demonstrated in Randomized, Controlled Trials
• Retrospective Cohort Study of Early Antibiotic Discontinuation in Sepsis with Negative Cultures (Open Forum Infect Dis, 2023) [MEDLINE]: n = 20,714
  • Antibiotics were Discontinued in 3 or 4 Days in 9% of Patients with Culture-Negative Serious Infection
  • Early Antibiotic Discontinuation was Not Associated with Higher Mortality Odds Overall (Adjusted Odds Ratio 1.27; 95% CI: 0.98-1.65), in Patients Presenting with (1.39; 95% CI: 0.88-2.22) and without Sepsis (1.17; 95% CI: 0.81-1.69), and in Those with Pulmonary (1.23; .65-2.34) and Non-Pulmonary Culture-Negative Serious Infections (1.30; 95% CI: 0.99-1.72)
  • Early Antibiotic Discontinuation Appeared Detrimental with Propensity Score Weighting (Adjusted Odds Ratio 1.36; 95% CI: 1.03-1.80) and When Retaining Patients with Sepsis Mimics (1.38; 95% CI: 1.16-1.65), But it was Protective (0.48; 95% CI: 0.37-.64]) when Retaining Patients Who Received Antibiotics on Their Last Hospital Day
  • Early Antibiotic Discontinuation in Culture-Negative Serious Infection was Not Associated with Significant Harm in the Primary Analysis, Dut Different Conclusions Based on Alternative Analytic Decisions, as Well as Risk of Residual Confounding, Indicate that Randomized Controlled Trials are Required

Clinical Efficacy-Procalcitonin

• Systematic Review of Use of Procalcitonin for Antibiotic Therapy Decisions (Arch Intern Med, 2011) [MEDLINE]
  • Procalcitonin Guidance of Antibiotic Therapy Decisions Did Not Have a Negative Impact on Mortality Rate Overall (or in Primary Care, ED, or ICU Settings Individually)
  • Procalcitonin Guidance of Antibiotic Therapy Resulted in Decreased Antibiotic Prescription and Duration of Therapy (Due Mainly to Lower Prescribing in Low-Acuity Primary Care and ED Patients and Shorter Duration of Therapy in Moderate/High-Acuity ED and ICU Patients
• Meta-Analysis Examining the Use of Procalcitonin in Acute Respiratory Infections (Clin Infect Dis, 2012) [MEDLINE]
  • Procalcitonin Use Decreased Antibiotic Exposure Across All Settings Without an Increase in the Rate of Treatment Failure or Mortality
• Systematic Review and Meta-Analysis of Procalcitonin-Guided Antibiotic Therapy in Critically Ill Adult Patients (Intensive Care Med, 2012) [MEDLINE]
  • Procalcitonin-Guided Antibiotic Therapy Could Decrease the Duration of Antimicrobial Administration without Having a Negative Impact on Survival
• Systematic Review and Meta-Analysis of Procalcitonin Use in Severe Sepsis/Septic Shock in the Intensive Care Unit (Crit Care, 2013) [MEDLINE]
  • Procalcitonin is Useful to Guide Antibiotic Therapy and Surgical Interventions in Severe Sepsis/Septic Shock in ICU, But Does Not Impact the Mortality Rate
  • Procalcitonin Decreases the Duration of Antibiotic Therapy, as Compared to Standard Care
• Systematic Review and Meta-Analysis of Procalcitonin as. Diagnostic Marker for Sepsis (Lancet Infect Dis, 2013) [MEDLINE]
  • Procalcitonin is a Helpful Biomarker for Sepsis in Critically Ill Patients
• Systematic Review and Meta-Analysis of Procalcitonin-Guided Antibiotic Therapy (J Hosp Med, 2013) [MEDLINE]
  • Procalcitonin-Guided Antibiotic Therapy Can Safely Decrease Antibiotic Usage in Adult ICU Patients and When Used to Initiate or Discontinue Antibiotics in Adult Patients with Respiratory Tract Infections
• Australian Randomized Trial of Procalcitonin Algorithm in Critically Ill Adults with Suspected Sepsis (Am J Respir Crit Care Med, 2014) [MEDLINE]
  • Procalcitonin Algorithm with 0.1 ng/mL Cut-Off Did Not Achieve a 25% Reduction in Duration of Antibiotic Treatment
• Secondary Analysis of Procalcitonin Testing in Congestive Heart Failure Patients Presenting with Acute Respiratory Symptoms (Using Data from ProHOSP Trial) (Int J Cardiol, 2014) [MEDLINE]
  • In CHF Patients Presenting to the Emergency Department with Respiratory Symptoms and Suspicion for Respiratory Infection, Procalcitonin Decreased Antibiotic Exposure and Improved Outcome
• Systematic Review and Cost-Effectiveness Analysis of Procalcitonin (Health Technol Assess, 2015) [MEDLINE]
  • Procalcitonin May Be Effective and Cost-Effective When Used to Guide the Discontinuation of Antibiotics in Adults with Suspected/Confirmed Sepsis in the ICU
  • Procalcitonin May Be Effective and Cost-Effective When Being Used to Guide the Initiation of Antibiotics in Adults Presenting to the ED with Respiratory Symptoms and Suspected Bacterial Infection
• Dutch Randomized Trial Using Procalcitonin to De-Escalate Antibiotics in Adult Critically Ill Patients (Lancet Infect Dis, 2016) [MEDLINE]: Dutch prospective, randomized trial (n = 15 hospitals in the Netherlands) using a decrease in procalcitonin of ≥80% from the peak value (or to ≤0.5 μg/L) to prompt antibiotic discontinuation
  • Procalcitonin Guidance Decreased Antibiotic Usage in Critically Ill Patients with a Presumed Bacterial Infection
  • Procalcitonin Guided Decrease in Antibiotic Usage was Associated with Decreased Mortality Rate
• Cochrane Database Systematic Review of Procalcitonin Evaluation in Adults with Sepsis, Severe Sepsis, and Septic Shock (Cochrane Database Syst Rev, 2017) [MEDLINE]
  • Evidence of Very Low-Moderate Quality (with Insufficient Sample Power Per Outcome) Does Not Clearly Support the Use of Procalcitonin-Guided Antimicrobial Therapy to Minimize Mortality, Mechanical Ventilation, Clinical Severity, Reinfection, or Duration of Antimicrobial Therapy in Patients with Septic Conditions
• Retrospective, Propensity Score-Matched Multivariable Analysis Study (Using Premier Healthcare Database) of Procalcitonin Use in Sepsis (Chest, 2017) [MEDLINE]
  • Use of Procalcitonin Testing on the First Day of ICU Admission was Associated with Significantly Lower Hospital and ICU Length of Stay, as Well as Decreased Total, ICU, and Pharmacy Cost of Care
  • No Clinical Outcomes were Evaluated in This Study
• There is No Specific Evidence that the Use of Procalcitonin Impacts the Risk of Clostridium Difficile Infection in an Individual Patient: however, since Clostridium Difficile infection is associated with cumulative antibiotic exposure, an effect is likely
• There is No Specific Evidence that the Use of Procalcitonin Impacts the Rates of Antimicrobial Resistance: however, since the emergence of antimicrobial resistance is related to the total antimicrobial consumption in a region, an effect is likely

Clinical Efficacy-Antimicrobial Therapy in the Setting of Burns (see Burns)

• Systematic Review and Meta-Analysis of Prophylactic Antibiotics in Burns (BMJ, 2010) [MEDLINE]
  • Prophylaxis with Systemic Antibiotics Has a Beneficial Effect in Burn Patients, But the Methodological Quality of the Data is Weak
  • Antibiotic Prophylaxis is Not Recommended in Severe Burns (Except Perioperatively)

Clinical Efficacy-Antimicrobial Therapy in the Setting of Necrotizing Pancreatitis (see Acute Pancreatitis)

• IAP/IPA Evidence-Based Guidelines for the Management of Acute Pancreatitis (Pancreatology, 2013) [MEDLINE]
  • Prophylactic Antimicrobials are Not Recommended for Severe Necrotizing Pancreatitis

Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

• Initial Antimicrobial Regimen
  • Empiric Broad-Spectrum Antimicrobials (with Bacterial and Potentially Fungal/Viral Coverage) are Recommended to Cover All Likely Pathogens in Patients with Sepsis/Septic Shock (Strong Recommendation, Moderate Quality Evidence)
    • Factors to Consider in the Selection of an Appropriate Antimicrobial Regimen
      • Anatomic Site of Infection (Related to Penetration, etc)
      • Fungal Risk Factors (See Below)
      • Patient Age
      • Patient Location at the Time of Infection (Institutionalized, Acute Care Hospital, etc)
      • Potential for Antimicrobial Drug Intolerance/Toxicity
      • Presence of Comorbid Conditions (Diabetes Mellitus, Liver Disease, Renal Failure)
      • Presence of Immune Defects (Neutropenia, Splenectomy, Poorly-Controlled HIV, Defects of Immunoglobulin/Complement/Leukocyte Function, etc)
      • Presence of Invasive Devices
      • Prevalent Pathogens and Their Resistance Patterns (Utilizing Local Antibiograms)
      • Prior Colonization with Microorganisms (Especially Multidrug-Resistant Organisms)
      • Recent Antibiotic Treatment Within the Last 3 Months
  • Combination Therapy is Not Recommended for the Routine Treatment of Neutropenic Sepsis/Bacteremia without Shock (Strong Recommendation, Moderate Quality Evidence)
• Use of Antimicrobials in the Setting of Severe Non-Infectious Inflammatory States
  • Empiric Antibiotics are Not Recommended in the Setting of Severe Non-Infectious Inflammatory States (Acute Pancreatitis, Burns) (Best Practice Statement)
• De-Escalation of Antimicrobial Regimen
  • Empiric Antimicrobial Coverage Should Be Narrowed Once the Pathogen is Identified, Sensitivities are Available, and Clinical Improvement is Noted (Best Practice Statement)

Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

• Assessment for Sepsis/Septic Shock vs Alternative Diagnoses
  • For Adults with Suspected Sepsis/Septic Shock (But Unconfirmed Infection), Continuous Reevaluation for Alternative Diagnoses and Discontinuation of Empiric Antimicrobials is Recommended if an Alternative Etiology of Illness is Demonstrated or is Strongly Suspected (Best Practice Statement)
  • For Adults with Possible Sepsis without Shock, Rapid Assessment of the Likelihood of Infectious vs Noninfectious Etiologies of Acute Illness is Recommended (Best Practice Statement)
• Timing of Initial Antimicrobial Administration
  • For Adults with Possible Septic Shock or a High Likelihood for Sepsis, Administering Antimicrobials Immediately (Ideally within 1 hr of Recognition) is Recommended (Strong Recommendation, Low Quality of Evidence)
    • Intraosseous Access Can Be Utilized to Administer Any Antimicrobial Agent (In Cases Where Intravenous Access May Be Problematic) (see Intraosseous Vascular Access)
    • Intramuscular Antibiotic Administration (of Impenem, Ertapenem, Cefepime, and Ceftriaxone) May Be Utilized in Some Scenarios Where Intravenous Access is Not Available
      • However, Intramuscular Absorption and Distribution Has Not Been Well-Studied in the Setting of Critical Illness
  • For Adults with Possible Sepsis without Shock, Rapid Assessment of the Likelihood of Infectious vs Non-Infectious Etiologies of Acute Illness is Recommended (Best Practice)
    • History and Physical Exam
    • Diagnostic Testing for Infectious and Non-Infectious Etiologies
  • For Adults with Possible Sepsis without Shock, a Time-Limited Course of Rapid Investigation is Recommended and if Concern for Infection Persists, the Antimicrobial Administration is Recommended within 3 hrs from the Time When Sepsis was First Recognized (Weak Recommendation, Low Quality of Evidence)
  • For Adults with a Low Likelihood of Infection and without Shock, Deferring Antimicrobials While Continuing to Closely Monitor the Patient is Recommended (Weak Recommendation, Very Low Quality of Evidence)
  • For Adults with Suspected Sepsis/Septic Shock, Use of Procalcitonin Plus Clinical Evaluation to Decide When to Start Antimicrobials is Not Recommended, as Compared to Clinical Evaluation Alone (Weak Recommendation, Very Low Quality of Evidence)
• Antimicrobial Regimen for Suspected Methicillin-Resistant Staphylococcus Aureus (MRSA)
  • For Adults with Sepsis/Septic Shock at High Risk of MRSA, Use of Empiric Anti-MRSA Coverage is Recommended (Best Practice Statement)
  • For Adults with Sepsis/Septic Shock at Low Risk of MRSA, Use of Empiric Anti-MRSA Coverage is Not Recommended (Weak Recommendation, Low Quality of Evidence)
• Combination (“Double”) Initial Antimicrobial Coverage Regimen
  • For Adults with Sepsis/Septic Shock and High Risk for Multidrug-Resistant Organisms (MDRO), Use of Two Antimicrobials with Gram-Negative Coverage (Two Agents from Different Antimicrobial Classes) for Empiric Treatment is Recommended Over One Antimicrobial Agent Against Gram-Negative Organisms (Weak Recommendation, Very Low Quality of Evidence)
    • Example: use of piperacillin/tazobactam + aminoglycoside or fluoroquinolone to facilitate Gram-negative pathogen clearance of Gram-negative (rather than broaden the spectrum of antimicrobial coverage)
    • Other Examples (Apart from Gram-Negative Coverage) Where Combination Antimicrobial Coverage May Be Useful
      • Use of Combination Clindamycin and β-Lactams for Streptococcal Toxic Shock Syndrome (Due to the Inhibition of Bacterial Toxin by Clindamycin)
      • Use of Macrolides and β-Lactams for Pneumococcal Pneumonia (Due to the Potential Immunomodulatory Effect of Macrolides)
  • For Adults with Sepsis/Septic Shock and Low Risk for Multidrug-Resistant Organisms (MDRO), Antimicrobials with Gram-Negative Coverage (Two Agents from Different Antimicrobial Classes) for Empiric Treatment is Not Recommended, as Compared to One Antimicrobial Agent Against Gram-Negative Organisms (Weak Recommendation, Very Low Quality of Evidence)
  • For Adults with Sepsis/Septic Shock, Use of Double Gram-Negative Coverage (Two Agents from Different Antimicrobial Classes) is Not Recommended Once the Causative Pathogen and the Susceptibilities are Known (Weak Recommendation, Very Low Quality of Evidence)
• Antimicrobial Coverage for Suspected Fungal Organisms
  • Assessment of Risk Factors for Fungal Infection
    • Risk Factors for Candida Infection/Sepsis (see Candida)
      • Gastrointestinal Tract Perforation/Anastomotic Leak (see Colonic Perforation and Small Intestinal Perforation)
      • Immunocompromised State (Neutropenia, Chemotherapy, Transplant, Diabetes Mellitus, Liver Disease, Renal Failure)
      • Injection Drug Use (see Injection Drug Abuse)
      • Invasive Vascular Devices (Central Venous Catheters, Hemodialysis Catheters) (see Central Venous Catheter)
      • Multisite Candida Colonization (see Candida)
      • Necrotizing Pancreatitis (see Acute Pancreatitis)
      • Positive Serum(1-3)-β-D-Glucan (see Serum(1-3)-β-D-Glucan)
      • Prolonged Broad-Spectrum Antibiotic Administration
      • Prolonged Hospital/Intensive Care Unit (ICU) Admission
      • Recent Fungal Infection
      • Recent Major Surgery (Especially Abdominal Emergency Surgery)
      • Severe Burns (see Burns)
      • Severity of Illness (High APACHE Score)
      • Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition)
    • Risk Factors for Endemic Yeast Infection (Cryptococcus, Histoplasma, Blastomyces, Coccidioidomycosis)
      • Antigen Markers Such as Cryptococcal, Histoplasma or Blastomyces Assays
      • Certain Biologic Response Modifiers
      • Diabetes Mellitus (see Diabetes Mellitus)
      • Hematopoietic Stem Cell Transplantation (see Hematopoietic Stem Cell Transplant)
      • High Dose Corticosteroids (see Corticosteroids)
      • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
      • Solid Organ Transplant
    • Risk Factors for Invasive Mold Infection
      • Certain Biologic Response Modifiers
      • Neutropenia (see Neutropenia)
      • Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant)
      • High Dose Corticosteroids (see Corticosteroids)
      • Solid Organ Transplant
      • Surrogate Markers Such as Serum or Bronchoalveolar Lavage Galactomannan Assay (see Serum Galactomannan)
  • For Adults with Sepsis/Septic Shock at High Risk of Fungal Infection, Use of Empiric Antifungal Therapy is Recommended Over No Antifungal Therapy (Weak Recommendation, Low Quality of Evidence)
  • For Adults with Sepsis/Septic Shock at Low Risk of Fungal Infection, Use of Empiric Antifungal Therapy is Not Recommended (Weak Recommendation, Low Quality of Evidence)
• Antimicrobial Coverage for Suspected Viral Organisms
  • No Recommendation for the Use of Antiviral Agents
• Use of Pharmacokinetic/Pharmacodynamic Properties to Dose Antimicrobials
  • For Adults with Sepsis/Septic shock, Optimization of Antimicrobial Dosing Strategies Based on Accepted Pharmacokinetic/Pharmacodynamic Principles and Specific Drug Properties is Recommended (Best Practice Statement)
    • Factors Which Require the Optimization of Antimicrobial Pharmacokinetics in Sepsis
      • High Prevalence of Unrecognized Immune Dysfunction
      • Increased Frequency of Hepatic/Renal Dysfunction
      • Increased Frequency of Resistant Microorganisms
      • Increased Volume of Distribution (Due to Aggressive Intravenous Fluid Resuscitation with Expansion of Extracellular Volume)
    • Clinical Success with Vancomycin in Nosocomial Pneumonia and Septic Shock is Related to Achieving Adequate Trough Levels (Relative to the Minimum Inhibitory Concentration for the Organism)
      • Initial Loading Dose of 25-30 mg/kg (Ideal Body Weight) and Subsequent Dosing to a Trough of 15-20 mg/L is Recommended to Achieve Pharmacodynamic Targets, Improve Tissue Penetration, and Optimize Clinical Outcome
    • Clinical Success with Fluoroquinolones (in Nosocomial Pneumonia and Other Serious Infections) and Aminoglycosides (in Gram-Negative Bacteremia, Nosocomial Pneumonia, and Other Serious Infections) is Related to Achieving Higher Peak Blood Levels (Relative to the Minimum Inhibitory Concentration for the Organism)
• Continuous vs Bolus β-Lactam Dosing
  • For Adults with Sepsis/Septic Shock, Use of Prolonged β-Lactam Infusion for Maintenance (After an Initial Bolus) is Recommended Over Conventional Bolus Infusion (Weak Recommendation, Moderate Quality Evidence)
    • Continuous Infusion of β-Lactams (vs Intermittent Dosing) is Probably Beneficial in Sepsis
    • Clinical Success with β-Lactams (Especially in Critically Ill Patients) is Related to Achieving Longer Duration of Plasma Concentration Above the Minimum Inhibitory Concentration for the Organism (T > MIC)
      • T > MIC >60% is Generally Considered Adequate for a Good Clinical Response in Mild-Moderate Illness, But T > MIC of 100% May Improve Outcome in Severe Infection/Sepsis
• Duration of Antimicrobial Therapy and De-Escalation
  • For Adults with Sepsis/Septic Shock, Daily Assessment for De-Escalation of Antimicrobials is Recommended Over Using a Fixed Duration of Antimicrobial Therapy without Daily Reassessment for De-Escalation (Weak Recommendation, Very Low Quality of Evidence)
  • For Adults with an Initial Diagnosis of Sepsis/Septic Shock and Adequate Source Control Where Optimal Duration of Antimicrobial Therapy is Unclear, Use of Procalcitonin and Clinical Evaluation to Decide When to Discontinue Antimicrobials is Recommended Over Clinical Evaluation Alone (Weak Recommendation, Low Quality of Evidence)
  • For Adults with an Initial Diagnosis of Sepsis/Septic Shock and Adequate Source Control, Use of Shorter Antimicrobial Therapy Duration is Recommended Over Longer Antimicrobial Therapy Duration (Weak Recommendation, Very Low Quality of Evidence)
    • Longer Antimicrobial Courses May Be Required for Patients with Slow Clinical Response, Undrainable Infectious Foci, Staphylococcus Aureus (Especially Methicillin-Resistant Staphylococcus Aureus) Bacteremia, Some Fungal Infections (Candidemia or Invasive Candidiasis), Some Viral Infections (Cytomegalovirus, Herpes Simplex Virus), Presence of Immunologic Deficiency (Neutropenia)
      • Example: uncomplicated Staphylococcus Aureus infections (no endocarditis, no implanted prostheses, negative blood cultures after 2-4 days, defervescence within 72 hrs of antibiotic initiation, absence of metastatic infectious foci) should be treated for at least 14 days, while complicated cases require at least 6 wks of treatment
      • Example: Neutropenic Sepsis Cases Should Be Treated for At Least the Duration of Their Neutropenia
    • Shorter Antimicrobial Courses May Be Considered in Patients with Rapid Clinical Resolution Following Effective Source Control of Intra-Abdominal/Urinary Sepsis or Anatomically Uncomplicated Pyelonephritis

Fever Control (see Fever)

Rationale

• Control of Fever During Sepsis Has Various Potential Benefits and Adverse Effects
  • Net Effect of These is Unclear

Clinical Efficacy

• Randomized Controlled Trial of Fever Control Using External Cooling in Septic Shock (Am J Respir Crit Care Med, 2012) [MEDLINE]
  • Fever Control Using External Cooling was Safe and Decreased Vasopressor Requirements and Early Mortality in Septic Shock
• Retrospective Cohort Study of Fever in Mechanically-Ventilated Patients (Shock, 2019) [MEDLINE]: n = 1,264
  • Multivariable Cox Proportional Hazard Ratios Demonstrated that a Maximum Temperature ≥39.5°C was Associated with iIncreased Mortality Rate (aHR 1.59 [95% CI: 1.05-2.39])
  • In the Subgroup of Patients with Sepsis, a Maximum Temperature of 38.3-39.4°C was Associated with Survival (aHR 0.61 [95% CI: 0.39-0.99])
  • There was No Difference in 28-Day Mortality Rate Between Patients Who Did and Did Not Receive Antipyretic Medication in Either the Overall Cohort or the Septic Subgroup
• Meta-Analysis of Fever Control in the Setting of Critical Illness (Intensive Care Med, 2019) [MEDLINE]: n = 1,413
  • There was no Statistically Significant Heterogeneity in the Effect of More Active Compared with Less Active Fever Management on Survival in Any of the Pre-Specified Subgroups Which Were Chosen to Identify Patients with Limited Physiologic Reserves
  • Overall, More Active Fever Management Did Not Result in a Statistically Significant Difference in Survival Time, as Compared with Less Active Fever Management [Hazard Ratio 0.91; (95% CI: 0.75-1.10), P = 0.32]