Sepsis-Part 2


Treatment

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
  • 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)

Opinions

  • 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

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

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

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)
      • Risk Factors for Invasive Mold Infection
    • 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: the 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]

Bicarbonate Therapy (see Sodium Bicarbonate)

Clinical Efficacy

  • Prospective Trial of Sodium Bicarbonate in Critically Ill Patients with Lactic Acidosis (Ann Intern Med, 1990) [MEDLINE]
    • Sodium Bicarbonate Did Not Improve Hemodynamics in Critically Ill Patients with Metabolic Acidosis and Hyperlactatemia
    • Sodium Bicarbonate Did Not Increase the Cardiovascular Response to Infused Catecholamines in in Critically Ill Patients with Metabolic Acidosis and Hyperlactatemia
    • Sodium Bicarbonate Decreased Plasma Ionized Calcium and Increased the pCO2
  • Prospective, Randomized Trial of Sodium Bicarbonate in Lactic Acidosis (Crit Care Med, 1991) [MEDLINE]
    • Sodium Bicarbonate Administration Did Not Improve Hemodynamic Variables in Patients with Lactic Acidosis, But Did Not Worsen Tissue Oxygenation
  • French Multi-Center, Randomized BICAR-ICU Trial of Sodium Bicarbonate for ICU Patients with Severe Acidemia and Lactic Acidosis (Lancet, 2018) [MEDLINE]: n = 389 (from 26 French ICU’s)
    • Total Group
      • Sodium Bicarbonate Therapy for Severe Acidemia (pH ≤7.20, pCO2 ≤45 mm Hg, Serum Bicarbonate ≤20 mmol/L, SOFA ≥4. Arterial Lactate ≥2 mmol/L) Targeting a Serum pH >7.30 Did Not Significantly Decrease the 28-Day Mortality Rate (45%), as Compared to Control (54%)
      • Sodium Bicarbonate Did Not Decrease the Occurrence of at Least One Organ Failure at Day 7
    • Prespecified Acute Kidney Injury Network Group (with a Score of 2-3)
      • Sodium Bicarbonate Therapy Decreased the Mortality Rate (46%), as Compared to Control (63%)
      • Sodium Bicarbonate Decreased the Occurrence of at Least One Organ Failure at Day 7
    • Metabolic Alkalosis, Hypernatremia, and Hypocalcemia were Observed More Frequently in the Bicarbonate Group than in the Control Group

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

  • For Adults with Septic Shock and Hypoperfusion-Induced Lactic Acidemia, Sodium Bicarbonate Therapy to Improve Hemodynamics or to Decrease Vasopressor Requirement is Not Recommended (Weak Recommendation, Low Quality of Evidence)
  • For Adults with Septic Shock and Severe Metabolic Acidemia (pH ≤ 7.2) and Acute Kidney Injury (AKIN Score 2-3), Sodium Bicarbonate Therapy is Recommended (Weak Recommendation, Low Quality of Evidence)

Blood Pressure Target

Clinical Efficacy

  • French SEPSISPAM Trial Examining Blood Pressure Targets in Septic Shock (NEJM, 2014) [MEDLINE]
    • MAP Target 80-95 mm Hg Had No 28-day Mortality (and 90-Day Mortality) Benefit, as Compared to MAP Target 65-70 mm Hg
    • Incidence of Newly Diagnosed Atrial Fibrillation was Higher in the MAP Target 80-95 mm Hg Group
    • In Patients with Chronic Hypertension, Those in the MAP Target 80-95 mm Hg Group Required Less Hemodialysis than Those in the MAP Target 65-70 mm Hg Group: however, no difference in mortality rate was observed
  • Systematic Review of Blood Pressure Target in Sepsis (Shock, 2015) [MEDLINE]
    • MAP Target of 80-85 mm Hg vs 65-70 mm Hg Had No Effect on 28-Day Mortality Rate
    • MAP Target of 80-85 mm Hg Increased the Risk of Atrial Fibrillation and a Lower Risk of Hemodialysis in Hypertensive Patients
    • Crossover Trials Suggested MAP Target of 80-85 mm Hg (Achieved by Increasing Vasopressor Doses) Increased Heart Rate and Cardiac Index Without an Effect on Serum Lactate
  • Critical Review of the Currently Recommended Blood Pressure Target of 65 mm Hg in Sepsis (Crit Care Med, 2015) [MEDLINE]
    • While MAP Target of >65 mm Hg is Appropriate in Most Patients, MAP Target of 75-85 mm Hg Decreases the Risk of Acute Kidney Injury in Patients with a History of Hypertension
  • Trial of Higher vs Lower Blood Pressure Targets for Vasopressor Therapy in Shock (Intensive Care Med, 2016) [MEDLINE]
    • In the Subgroup of Patients >75 y/o, Mortality was Decreased with MAP Target of 60–65 mmg Hg (13%) vs 75–80 mm Hg (60%)

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

  • For Adults with Septic Shock (on Vasopressors), Initial Mean Arterial Pressure (MAP Target of ≥65 mm Hg is Recommended Over a Higher MAP Target (Strong Recommendation, Moderate Quality of Evidence)
    • However, Consideration of a Higher MAP Target (75-85 mm Hg) Might Be Appropriate in Patients with a History of Hypertension as This Intervention Might Decrease the Risk of Acute Kidney Injury Requiring Hemodialysis (NEJM, 2013) [MEDLINE]

Intravenous Fluid Resuscitation Strategy

Rationale

  • In the Setting of Sepsis, Increased Serum Lactate is a Marker of Impaired Microcirculatory Flow with Tissue Hypoxia (see Lactic Acidosis)
    • However, There are Scant Data that Tissue Hypoxia Occurs in Patients with Sepsis
    • In Addition, Increasing Oxygen Delivery in Patients with Sepsis Does Not Increase Oxygen Consumption
    • Increased Serum Lactate Levels are Associated with Worse Outcome (Crit Care Med, 2015) [MEDLINE]

Clinical Efficacy of Early Goal-Directed Therapy

  • Rivers Early Goal-Directed Therapy Trial (NEJM, 2001) [MEDLINE]
    • Triggers
      • SIRS Criteria + Systolic BP ≤90 mm Hg or Serum Lactate ≥4 mmol/L
    • Protocol
      • Continuous ScvO2 Monitoring and Early Goal-Directed Therapy for ≥6 hrs
      • Maintain CVP ≥8–12 mm Hg
      • Maintain MAP ≥65 mm Hg
      • Maintain Urine Output ≥0.5 mL/kg/hr
      • Maintain ScvO2 ≥70%
        • SaO2 ≥93%
        • Hematocrit ≥30%
        • Cardiac Index
        • VO2
    • Early Goal-Directed Therapy (Used for First 6 hrs of Emergency Department Care) Decreased 28-Day Mortality in Severe Sepsis and Septic Shock
    • Features of Early Goal-Directed Therapy Group From 7-72 hrs, as Compared to Standard Therapy
      • Higher pH
      • Lower Base Deficit
      • Lower Lactate Concentration
      • Significantly Higher Mean Central Venous Oxygen Saturation (ScvO2)
  • EMShockNet Trial (JAMA, 2010) [MEDLINE]
    • In Patients with Severe Sepsis/Septic Shock Treated to Normalize Central Venous Pressure/Mean Arterial Pressure, Additional Management to Normalize Lactate Clearance vs Management to Normalize Central Venous Oxygen Saturation Did Not Improve In-Hospital Mortality
  • US Protocolized Care for Early Septic Shock (PROCESS) Trial (NEJM, 2014) [MEDLINE]: tertiary care, multi-center trial (n = 1,341) from 2008-2013 -> 439 were randomly assigned to protocol-based early goal-directed therapy (transfusion threshold hematocrit >10 g/dL when the ScvO2 was <70% after the initial resuscitation), 446 to protocol-based standard therapy (transfusion threshold hemoglobin >7.5 g/dL when the ScvO2 was <70% after the initial resuscitation), and 456 to usual care
    • Average Volume of Intravenous Fluid Given in the PROCESS Trial Pre-Randomization was 30 mL/kg (Intensive Care Med, 2017) [MEDLINE]
    • With Diagnosis of Sepsis in the ED, Protocol-Based Resuscitation Did Not Improve In-Hospital Mortality Rate, 60 Day Mortality Rate or 1 Year Mortality Rate
    • Early Goal-Directed Protocol-Directed Therapy Significantly Increased IV Fluid Resuscitation During the First 6 hrs (2.8L), as Compared to Usual Care (2.3L)
    • Early Goal-Directed Protocol-Directed Therapy Significantly Increased ICU Admission Rates (91.3% of Cases), as Compared to Usual Care (86.2% of Cases)
  • Australasian Resuscitation in Sepsis Evaluation (ARISE) Trial (NEJM, 2014) [MEDLINE]: multi-center RCT in Australia/New Zealand (n = 1600)
    • Average Volume of Intravenous Fluid Given in the ARISE Trial Pre-Randomization was 30 mL/kg (Intensive Care Med, 2017) [MEDLINE]
    • With Diagnosis of Septic Shock in the ED, Early Goal-Directed Therapy Had No Impact on 90-day Mortality (18.6% mortality), as Compared to Usual Care (18.8% Mortality)
    • No Significant Differences in Survival Time, In-Hospital Mortality, Duration of Organ Support, or Length of Hospital Stay Between the Groups
  • Analysis of the Performance of Surviving Sepsis Guidelines from 2005-2012 in 218 Community/Academic/Tertiary Hospitals (Crit Care Med, 2015) [MEDLINE]
    • Increased Compliance with Surviving Sepsis Performance Bundles was Associated with 25% Relative Risk Reduction in the Mortality Rate
  • Protocolized Management in Sepsis (ProMISe) trial in the United Kingdom (NEJM, 2015) [MEDLINE]: randomized trial with integrated cost-effectiveness analysis in 56 hospitals in England (n = 1260)
    • Average Volume of Intravenous Fluid Given in the PROMISE Trial Pre-Randomization was 2L (Intensive Care Med, 2017) [MEDLINE]
    • With Early Diagnosis of Septic Shock, Early Goal-Directed Therapy Did Not Improve 90-Day All-Cause Mortality, as Compared to Usual Care
    • Early Goal-Directed Therapy Group Manifested Significantly Worse Organ-Failure Scores, More Days Receiving Advanced Cardiovascular Support, and Longer ICU Stays
    • Early Goal-Directed Therapy Increased Treatment Intensity (With Increased Use of Intravenous Fluids, Vasoactive Drugs, and Red Blood Cell Transfusions)
    • Early Goal-Directed Therapy Increased Costs (the Probability That it Was Cost-Effective Was <20%)
  • Systematic Review and Meta-Analysis of Early Goal-Directed Therapy in Septic Shock (by the the ARISE, ProCESS and ProMISe Investigators) ( Intensive Care Med, 2015) [MEDLINE]
    • Early Goal-Directed Therapy was Not Superior to Usual Care for Emergency Department Patients with Septic Shock, But is Associated with Increased Utilisation of ICU Resources
  • Meta-Analysis and Systematic Review of Early Goal-Directed Therapy (J Crit Care, 2016) [MEDLINE]
    • Early Goal-Directed Therapy Did Not Decrease the Mortality Rate
    • Benefit of Early Goal-Directed Therapy was Confined to Patients with a >35% Control Group Mortality Rate
    • Lactate-Guided Therapy Improved Outcome, as Compared to Usual Care or a ScvO2 Normalization Strategy
  • Patient-Level Meta-Analysis of Early Goal-Directed Therapy in Septic Shock (NEJM, 2017) [MEDLINE]
    • Early Goal-Directed Therapy Did Not Improve Outcome in Septic Shock Over Usual Care and was Associated with Higher Hospitalization Costs Across a Broad Range of Patient and Hospital Characteristics
  • Meta-Analysis and Trial Sequential Analysis of Early Goal-Directed Therapy in Septic Shock (J Intensive Care Med, 2018) [MEDLINE]
    • Adults with Severe Sepsis and Septic Shock Who Received Early Goal-Directed Therapy Had a Lower Mortality Rate than Those Who Received Usual Care
      • The Benefit May Mainly Be Attributed to Treatments Administered within the First 6 hrs

Clinical Efficacy of Early Goal-Directed Therapy in Resource-Limited Settings

  • Zambian Randomized Trial of Early Resuscitation Protocol in Sepsis in Developing Countries (JAMA, 2017) [MEDLINE]
    • Among Adults with Sepsis and Hypotension, Most of Whom were Positive for HIV, in a Resource-Limited Setting, a Protocol for Early Resuscitation with Administration of Intravenous Fluids and Vasopressors Increased In-Hospital Mortality, as Compared to Usual Care

Clinical Efficacy of Centers for Medicare and Medicaid Services (CMS)-Mandated Hemodynamic Interventions (SEP-1) in Sepsis

  • 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
  • Systematic Review of the Evidence Base Supporting the Centers for Medicare and Medicaid Services (CMS)-Mandated Hemodynamic Interventions (SEP-1) in Sepsis (Ann Intern Med, 2018) [MEDLINE]: 20 studies
    • No Moderate or High-Quality Evidence Indicated that SEP-1 or its Hemodynamic Interventions Decreased the Mortality Rate in Sepsis
      • Only One Single-Center Observational Study Reported Decreased In-Hospital Mortality with SEP-1
      • Sixteen Studies (2 Randomized and 14 Observational) Reported Decreased Mortality with Serial Lactate Measurements or 30 mL/kg Intravenous Fluid Infusions
      • None of the 17 Studies were Free of Confounders or at Low Risk of Bias
      • In 3 Randomized Trials, Fluid Responsiveness Testing Did Not Decrease the Mortality Rate

Clinical Efficacy-Clinical Utility of Central Venous Pressure (CVP) to Assess Volume Status and Volume Responsiveness (see Hemodynamics)

  • Systematic Review of the Clinical Utility of CVP (Chest, 2008) [MEDLINE]: systematic review of 24 studies (studied either the relationship between CVP and blood volume or reported the associated between CVP/DeltaCVP and the change in stroke volume/cardiac index following a fluid challenge)
    • Very Poor Relationship Between CVP and Blood Volume, As Well as the Inability of CVP/DeltaCVP to Predict the Hemodynamic Response to an Intravenous Fluid Challenge: despite widely-used clinical guidelines recommending the use of CVP, the CVP should not be used to make clinical decisions regarding fluid management
  • Systematic Review Examining CVP in Predicting Fluid Responsiveness in Critically Ill Patients (Intensive Care Med, 2016) [MEDLINE]: n = 1148 (51 studies)
    • CVP was Subgrouped into Low (<8 mmHg), Intermediate (8-12 mmHg), High (>12 mmHg) Baseline CVP
    • Although Authors Identified Some Positive and Negative Predictive Values for Fluid Responsiveness for Specific Low and High Values of CVP, None of the Predictive Values were >66% for Any CVP from 0-20 mm Hg
    • CVP in the Normal Range (Especially in the 8-12 mm Hg Range) Does Not Predict Fluid Responsiveness

Clinical Efficacy of Lactate-Guided Therapy

  • Trial of Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy (JAMA, 2010) [MEDLINE]
    • In Septic Shock Treated to Normalize Central Venous Pressure and Mean Arterial Pressure, Additional Management to Normalize Lactate Clearance, as Compared with Management to Normalize ScvO2 Did Not Significantly Decrease In-Hospital Mortality
  • LACTATE Study Examining Lactate-Guided Therapy in Critically Ill Patients (Am J Respir Crit Care Med, 2010) [MEDLINE]: multi-center
    • Early, Aggressive Resuscitation is Associated with Improved Outcome in Sepsis
    • In Patients with Hyperlactatemia on ICU Admission, Lactate-Guided Therapy Decreased the Hospital Mortality Rate When Adjusting for Predefined Risk Factors
  • Analysis of Serum Lactate in Sepsis-Associated Hypoperfusion from the Surviving Sepsis Campaign Database (Crit Care Med, 2015) [MEDLINE]
    • Increased Lactate Levels were Associated with Increased In-Hospital Mortality in Sepsis
    • However, Only Patients Who Presented with Serum Lactate >4 mmol/L (with and without Hypotension) were at Significantly Higher Risk for In-Hospital Mortality, as Compared to Serum Lactate at Lower Levels (2-3 and 3-4 mmol/L)
  • Meta-Analysis and Systematic Review of Early Goal-Directed Therapy (J Crit Care, 2016) [MEDLINE]
    • Early Goal-Directed Therapy Did Not Decrease the Mortality Rate
    • Benefit of Early Goal-Directed Therapy was Confined to Patients with a >35% Control Group Mortality Rate
    • Lactate-Guided Therapy Improved Outcome, as Compared to Usual Care or a ScvO2 Normalization Strategy

Clinical Efficacy-Urine Output Monitoring

  • Retrospective Cohort Study of Impact of Intensive Urine Output Monitoring in Critically Ill Patients on Development of Acute Kidney Injury (Chest, 2017) [MEDLINE]: 15,724 adults admitted to ICUs from 2000-2008
    • Intensive Urine Output Monitoring: hourly urine output recordings and no gaps of >3 hrs for the initial 48 hrs after ICU admission
    • Intensive Urine Output Monitoring was Associated with Improved Detection of Acute Kidney Injury and Decreased 30-Day Mortality in Patients Experiencing Acute Kidney Injury
    • Intensive Urine Output Monitoring was Associated with Less Cumulative Fluid Volume and Less Fluid Overload for All Patients During the First 72 hrs of ICU Stay

Clinical Efficacy-Fluid Balance/Targeted Fluid Minimization

  • Trial of Two Fluid Management Strategies in Acute Lung Injury (NEJM, 2006) [MEDLINE]
    • Although There was No Significant Difference in the Primary Outcome of 60-Day Mortality, the Conservative Fluid Management Strategy Improved Lung Function and Shortened the Duration of Mechanical Ventilation and intensive Care without Increasing Nonpulmonary Organ Failures
    • These Results Support the Use of a Conservative Fluid Management Strategy in Patients with Acute Lung Injury
  • Systematic Review of Fluid Overload and Re-Resuscitation in Sepsis (Anaesthesiol Intensive Ther, 2014) [MEDLINE]
    • Positive Cumulative Fluid Balance is Associated with Intra-Abdominal Hypertension and Worse Outcome
    • Interventions to Limit the Development of Positive Fluid Balance are Associated with Improved Outcome
    • Late Conservative Fluid Management and De-Resuscitation Should Be Considered
  • Study of the Association Between Fluid Balance and Survival in Critical Illness (J Intern Med, 2015) [MEDLINE]
    • Positive Fluid Balance at the Time of ICU Discharge is Associated with Increased 90-Day Mortality, Especially in Patients with Underlying Heart/Kidney Disease
  • Pilot Study of Targeted Fluid Minimization After Initial Resuscitation (Chest, 2015) [MEDLINE]: pilot study (n= 82) conducted at Barnes-Jewish Hospital
    • Targeted Fluid Minimization Strategy Resulted in Non-Significant Decreases in Positive Fluid Balance at Days 3/5, as Compared to Usual Care
    • Targeted Fluid Minimization Strategy Did Not Impact Mortality Rate, Ventilator Days, Need for Renal Replacement Therapy, or Vasopressor Days
  • Prospective Study of Fluid Balance in Sepsis (Crit Care, 2015) [MEDLINE]: n = 173 (single-center trial)
    • Persistent Daily Positive Fluid Balance Over Time was Strongly Associated with Higher Mortality Rate in Sepsis
  • Retrospective Review of Fluid Management in Septic Shock (Ann Am Thorac Soc, 2015) [MEDLINE]
    • Volume Overload Was Independently Associated with Impaired Mobility and Discharge to a Healthcare Facility in Survivors of Septic Shock
  • Retrospective Study of Fluid Balance and Risk for Acute Kidney Injury and Mortality in Severe Sepsis/Septic Shock (J Crit Care, 2015) [MEDLINE]
    • Late Positive Fluid Balance is an Independent Risk Factor for Mortality in Severe Sepsis
    • Positive Fluid Balance Has No Impact on the Risk for Acute Kidney Injury
  • Retrospective Analysis of the Impact Early Goal-Directed Therapy on Fluid Overload in Severe Sepsis and Septic Shock (Shock. 2015) [MEDLINE]
    • When Adjusted for Baseline Severity of Illness, Fluid Overload was Associated with Increased Use of Fluid-Related Medical Interventions (Thoracentesis and Diuretics) and Hospital Mortality (Odds Ratio, 1.92; Confidence Interval, 1.16-3.22)
  • Single-Center Retrospective Study of Fluid Balance in Severe Sepsis/Septic Shock (Am J Emerg Med, 2016) [MEDLINE]
    • Positive Fluid Balance Increased Both the ICU and In-Hospital Mortality Rate
  • Systematic Review and Meta-Analysis of Conservative Fluid Management or Deresuscitation in Sepsis or ARDS Following the Resuscitation Phase of Critical Illness (Intensive Care Med, 2017) [MEDLINE]
    • Conservative or Deresuscitative Fluid Strategy Resulted in an Increased Number of Ventilator-Free Days and a Decreased ICU Length of Stay, as Compared to Liberal Strategy or Standard Care
    • The Effect on Mortality Remains Uncertain
  • International (European) Open-Label, Randomized Conservative vs Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trial of Intravenous Fluid Restriction in Intensive Care Unit Adult Patients with Septic Shock (NEJM, 2022) [MEDLINE]: n = 1,554
    • Patients Received a Median of 3 Liters of Intravenous Fluid Before They were Randomized and They were Enrolled within 3 Hours After ICU Admission
    • Intravenous Fluid Given After Randomization
      • Restrictive-fluid Group Received a Median of 1,798 mL of Intravenous Fluid (Interquartile Range: 500-4,366 mL)
      • Standard-Fluid Group Received a Median of 3,811 mL (Interquartile Range: 1,861-6,762 mL)
    • Restrictive Fluid Group Had 90-Day Death Rate was 42.3%, While the Standard Fluid Group was 42.1% (Adjusted Absolute Difference, 0.1 Percentage Points; 95% CI: -4.7 to 4.9; P = 0.96)
    • At 90 Days After Randomization, Number of Days Alive without Life Support and Days Alive and Out of the Hospital were Similar in Both Groups
    • Serious Adverse Events were Similar in Both Groups
    • Critique: patients received median of 3 liters of fluid prior to randomization, which could have influenced the results

Clinical Efficacy-Passive Leg Raise (PLR)

  • Systematic Review and Meta-Analysis of Passive Leg Raise in Predicting Fluid Responsiveness (Intensive Care Med, 2016) [MEDLINE]: n = 991 (21 studies)
    • Cardiac Output was Measured by Echocardiogram (6 Studies), Calibrated Pulse Contour Analysis (6 Studies), Bioreactance (4 Studies), Esophageal Doppler (3 Studies), Transpulmonary Thermodilution or Pulmonary Artery Catheter (1 Study(, and Suprasternal Doppler (1 Study)
      • Pooled Correlation Between the Passive Leg Raise-Induced and the Fluid-Induced Changes in CO was 0.76 (0.73-0.80)*
      • For the Passive Leg Raise-Induced Changes in CO, Pooled Sensitivity was 85% (0.81-0.88) and Pooled Specificity was 91% (0.88-0.93)
        • The Best Threshold was a Passive Leg Raise-Induced Increase in Cardiac Output ≥10 ± 2 %
      • For the Passive Leg Raise-Induced Changes in Pulse Pressure, Pooled Sensitivity was 56% and Pooled Specificity was 83%
    • Passive Leg Raise-Induced Changes in Cardiac Output Very Reliably Predicted the Response of CO to Fluid Challenge in Adults with Acute Circulatory Failure
    • When Passive Leg Raise Effects are Assessed by Changes in Pulse Pressure, the Specificity of the Passive Leg Raise Test Remained Acceptable, But its Sensitivity was Poor
  • Prospective, Multicenter, Randomized Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) Trial of the Effect of Passive Leg Raise on Stroke Volume in US and UK (Chest, 2020) [MEDLINE]
    • Fluid Balance at 72 hrs or ICU Discharge was Significantly Lower (-1.37 L Favoring Intervention Arm, 0.65 ± 2.85 L Intervention Arm vs. 2.02 ± 3.44 L Usual Care Arm, p = 0.021)
    • Fewer Patients Required Renal Replacement Therapy (5.1% vs 17.5%, p = 0.04) or Mechanical Ventilation (17.7% vs 34.1%, p=0.04) in the Intervention Arm, a Compared to Usual Care
  • Systematic Review and Meta-Analysis of Dynamic Assessments of Fluid Responsiveness in Goal-Directed Therapy in Septic Shock (Crit Care Med. 2017 Sep;45(9):1538-1545. doi: 10.1097/CCM.0000000000002554 [MEDLINE]: n = 1,652 (13 trials)
    • Assessments Included Stroke Volume Variation (9 Trials), Pulse Pressure Variation (1 Trial), and Stroke Volume Change with Passive Leg Raise/Fluid Challenge (3 Trials)
    • In 12 Trials Reporting Mortality Rate, the Risk Ratio for Death Associated with Dynamic Assessment of Fluid Responsiveness was 0.59 (95% CI: 0.42-0.83; I = 0%; n = 1,586)
    • The Absolute Risk Reduction in Mortality Associated with Dynamic Assessment of Fluid Responsiveness was -2.9% (95% CI, -5.6% to -0.2%)
    • Dynamic Assessment of Fluid Responsiveness was Associated with Decreased ICU Length of Stay (Weighted Mean Difference -1.16 Days [95% CI: -1.97 to -0.36]; I = 74%; n = 394, 6 Trials) and Decreased Duration of Mechanical Ventilation (Weighted Mean Difference -2.98 hr [95% CI: -5.08 to -0.89]; I = 34%; n = 334, 5 Trials)

Clinical Efficacy-Pulse Pressure Variation

  • Study of Pulse Pressure Variation (Respiratory Changes in Arterial Pressure) in Mechanically-Ventilated Patients with Sepsis (Am J Respir Crit Care Med. 2000) [MEDLINE]
    • DeltaPp (Respiratory Change in Pulse Pressure) = Pp(max) – Pp(min), Divided by the Mean of the Two Values and Expressed as a Percentage
    • DeltaPs (Respiratory Change in Systolic Pressure) was Calculated Similarly
    • In Mechanically-Ventilated Patients with Sepsis, DeltaPp Predicted Fluid Responsiveness Better than DeltaPs
  • Systematic Review and Meta-Analysis of Pulse Pressure Variation in Predicting Fluid Responsiveness in the ICU (Crit Care, 2014) [MEDLINE]” n = 22 studies (n = 807 patients)
    • Pulse Pressure Variation Predicts Fluid Responsiveness Accurately in Mechanically-Ventilated Patients with Relatively Large Tidal Volumes (VT ≥8 mL/kg) (without Spontaneous Breathing or Arrhythmia)
      • Using Pulse Pressure Variation Cutoff of >12%
        • Sensitivity = 88%
        • Specificity = 89%
      • In General, Pulse Pressure Variation >13% Implied Fluid Responsiveness, While Pulse Pressure Variation <10% Indicated Fluid Unresponsiveness
      • Pulse Pressure Variation May Be of Limited Value in Patient on Tidal Volumes <8 mL/kg, Due to the Fact that Cyclic Changes in Intrathoracic Pressures Were Not Significant Enough to Induce Preload Variations (Although When Using Higher Levels of PEEP, this May Enhance the Cyclic Changes in Pleural Pressure): for this reason, tidal volume can be temporarily adjusted to allow measurement of the pulse pressure variation
  • Systematic Review and Meta-Analysis of Dynamic Assessments of Fluid Responsiveness in Goal-Directed Therapy in Septic Shock (Crit Care Med. 2017 Sep;45(9):1538-1545. doi: 10.1097/CCM.0000000000002554 [MEDLINE]: n = 1,652 (13 trials)
    • Assessments Included Stroke Volume Variation (9 Trials), Pulse Pressure Variation (1 Trial), and Stroke Volume Change with Passive Leg Raise/Fluid Challenge (3 Trials)
    • In 12 Trials Reporting Mortality Rate, the Risk Ratio for Death Associated with Dynamic Assessment of Fluid Responsiveness was 0.59 (95% CI: 0.42-0.83; I = 0%; n = 1,586)
    • The Absolute Risk Reduction in Mortality Associated with Dynamic Assessment of Fluid Responsiveness was -2.9% (95% CI, -5.6% to -0.2%)
    • Dynamic Assessment of Fluid Responsiveness was Associated with Decreased ICU Length of Stay (Weighted Mean Difference -1.16 Days [95% CI: -1.97 to -0.36]; I = 74%; n = 394, 6 Trials) and Decreased Duration of Mechanical Ventilation (Weighted Mean Difference -2.98 hr [95% CI: -5.08 to -0.89]; I = 34%; n = 334, 5 Trials)

Clinical Efficacy-Rate of Fluid Resuscitation

  • Brazilian Randomized BaSICS Trial Studying the Rate of Fluid Resuscitation in Sepsis in the Intensive Care Unit (JAMA, 2021) [MEDLINE]: n = 10, 520 (in 75 ICU’s)
    • Slow Rate of Intravenous Fluid Resuscitation Did Not Impact the 90-Day Mortality Rate, as Compared to Fast Rate of Fluid Resuscitation (26.6% vs 27.0%)
    • There was No Significant Interaction Between the Fluid Type and the Fluid Infusion Rate

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

  • Assessment of Cardiac Function is Recommended if Clinical Examination Does Not Indicate a Clear Diagnosis (Best Practice Statement)

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

  • Sepsis/Septic Shock are Medical Emergencies and Treatment/Resuscitation Should Begin Immediately (Best Practice Statement)
  • For Patients with Sepsis-Induced Hypoperfusion or Septic Shock, ≥30 mL/kg of Intravenous Crystalloid Fluid Should Be Given within the First 3 hrs of Resuscitation (Weak Recommendation, Low Quality of Evidence)
  • For Adults with Sepsis/Septic Shock, Use of Dynamic Hemodynamic Variables are Recommended to Guide Intravenous Fluid Resuscitation Over Physical Examination or Static Parameters (CVP, ScvO2 Obtained from Central Venous Catheter, SvO2 Obtained from Swan-Ganz Catheter, etc) Alone (Weak Recommendation, Very Low Quality of Evidence)
    • Dynamic Hemodynamic Variables
      • Passive Leg Raise/Fluid Challenge Against Stroke Volume
      • Variation in Systolic Blood Pressure in Response to Changes in Intrathoracic Pressure Associated with Mechanical Ventilation
      • Variation in Pulse Pressure in Response to Changes in Intrathoracic Pressure Associated with Mechanical Ventilation
      • Variation in Stroke Volume in Response to Changes in Intrathoracic Pressure Associated with Mechanical Ventilation
      • Echocardiogram (see Echocardiogram)
    • Static Hemodynamic Variables with Target
      • CVP 8-12 mm Hg
      • ScvO2 ≥70% (Obtained from Central Venous Catheter)
      • SvO2 ≥65% (Obtained from Swan-Ganz Catheter)
  • For Adults with Sepsis/Septic Shock, Guiding Resuscitation to Decrease the Serum Lactate in Patients with Elevated Serum Lactate Level is Recommended Over Not Using the Serum Lactate (Weak Recommendation, Low Quality of Evidence)
    • During Acute Intravenous Fluid Resuscitation, Serum Lactate Level Should Be Interpreted Considering the Clinical Context and Other Etiologies of Elevated Serum Lactate
  • For Adults with Septic Shock, Use of Capillary Refill Time to Guide Resuscitation as an Adjunct to Other Measures of Perfusion is Recommended (Weak Recommendation, Low Quality of Evidence)
  • Insufficient Evidence to Make a Recommendation on the Use of Restrictive vs Liberal Fluid Strategies in the First 24 hrs of Resuscitation in Patients with Sepsis/Septic Shock Who Still Have Signs of Hypoperfusion and Volume Depletion After the Initial Resuscitation (No Recommendation)
    • Intravenous Fluid Resuscitation Should Be Given Only in Patients Have Signs of Hypoperfusion

Choice of Resuscitation Fluid

Clinical Efficacy

  • SAFE Trial: Comparing Crystalloid (Normal Saline) vs Colloid (4% Albumin) in Heterogenous Population of ICU Patients (NEJM, 2004) [MEDLINE]
    • No Difference in 28-Day Mortality or Need for Hemodialysis
    • Traumatic Brain Injury (TIB) Subgroup: Colloid Use Increased the Mortality Rate (see Traumatic Brain Injury)
    • Colloid Use in Septic Shock Subgroup Demonstrated a Trend Toward Lower Mortality Rate
  • German VISEP Trial of Pentastarch and Intensive Insulin Therapy in Severe Sepsis (NEJM, 2008) [MEDLINE]
    • Intensive Insulin Therapy Placed Critically Ill Patients with Sepsis at Increased Risk for Serious Adverse Events Related to Hypoglycemia
    • Hydroxyethyl Starch was Harmful, and its Toxicity Increased with Accumulating Doses
  • ATS/ERS/ESICM/SCCM/SRLF Statement: Prevention and Management of Acute Renal Failure in the ICU Patient (Am J Respir Crit care Med, 2010) [MEDLINE]
    • Hyper-Oncotic Fluids (Hydroxyethyl Starch, Dextrans, 20-25% Albumin) are Not Recommended, Due to Their Risk of Renal Dysfunction
    • Hypo-Oncotic Colloids (5% Albumin) are as Effective as Crystalloids
  • Systematic Review/Meta-Analysis of Albumin in Sepsis (Crit Care Med, 2011) [MEDLINE]
    • Albumin-Containing Solutions Were Associated with Lower Mortality Than Other Fluid Resuscitation Regimens in Sepsis
  • Australian/New Zealand Crystalloid vs Hydroxyethyl Starch Trial (CHEST): Comparing Hydroxyethyl Starch vs Normal Saline Resuscitation in ICU Patients (NEJM, 2012) [MEDLINE]
    • No Difference in 90-Day Mortality Between 6% Hydroxyethyl Starch vs Normal Saline
    • However, Hydroxyethyl Starch Group Had Higher Need for Hemodialysis
  • Danish 6S Trial of Hydroxyethyl Starch vs Ringer’s Acetate in Severe Sepsis (NEJM, 2012) [MEDLINE]
    • Hydroxyethyl Starch Increased the 90-Day Mortality Rate and were More Likely to Require Renal Replacement Therapy
  • Study of Chloride-Restrictive Intravenous Fluid Resuscitation Strategy in Critically Ill Patients (JAMA, 2012) [MEDLINE]: study is based on the observation that hyperchloremia may induce renal vasoconstriction
    • Chloride-Restrictive IV Fluid Resuscitation Strategy Decreased Incidence of Acute Kidney Injury and Use of Hemodialysis
    • Chloride-Restrictive IV Fluid Resuscitation Strategy Demonstrated No Difference in Hospital Mortality, Hospital or ICU Length of Stay, or Need for Hemodialysis After Hospital Discharge
  • CRISTAL Trial Examining Crystalloid vs Colloid Intravenous Fluid Resuscitation in Critically Ill Patients with Hypovolemic Shock (JAMA, 2013) [MEDLINE]
    • 28-Day Mortality: no difference between use of crystalloid vs colloid in septic shock
    • 90-Day Mortality: improved with use of colloids (although authors note that these findings need to be confirmed in future trials)
  • Fluids in Sepsis and Septic Shock Group Study (Ann Intern Med, 2014) [MEDLINE]: systematic review and network meta-analysis (14 studies, n = 18,916 patients)
    • Network Meta-Analysis at the 4-Node Level: higher mortality with starches than with crystalloids (high confidence)
    • Network Meta-Analysis at the 4-Node Level: lower mortality with albumin than with crystalloids (moderate confidence) or starches (moderate confidence)
    • Network Meta-Analysis at the 6-Node Level: lower mortality with albumin than with saline (moderate confidence) and low-molecular-weight starch (low confidence) and with balanced crystalloids than with saline (low confidence) and low and high-molecular-weight starches (moderate confidence)
    • Conclusions: resuscitation with balanced crystalloids (lactated ringers, etc) or albumin was associated with decreased mortality, as compared to other fluids
  • Italian ALBIOS Study of Albumin Fluid Resuscitation in Severe Sepsis (NEJM, 2014) [MEDLINE]
    • Albumin in Addition to Crystalloids Did Not Improve the 28-Day and 90-Day Survival, as Compared to Crystalloid Alone
    • Subgroup Analysis Suggested that Albumin Decreased the 90-Day Mortality Rate in Subgroup of Patients with Septic Shock
  • Meta-Analysis of Impact of Albumin and Crystalloid on Mortality in Adult Patients with Severe Sepsis and Septic Shock (Crit Care, 2014) [MEDLINE]
    • A Trend Toward Decreased 90-Day Mortality was Observed in Severe Sepsis Patients Resuscitated with Albumin, as Compared Crystalloid and Saline
    • Moreover, the 90-Day Mortality of Patients with Septic Shock Decreased Significantly
  • Meta-Analysis of Impact of Albumin vs Other Fluids on Mortality in Sepsis (PLoS One, 2014) [MEDLINE]
    • No Significant Advantage of Albumin Over Any Other Fluids in Sepsis of Any Severity
  • Study of Effect of Hyperchloremia of Hospital Mortality in Critically Ill Sepsis Patients (Crit Care Med, 2015) [MEDLINE]
    • In Critically Ill Sepsis Patients, Hyperchloremia (Serum Cl ≥110 mEq/L) on ICU Admission, as Well as Higher Serum Chloride and within Subject Worsening of Hyperchloremia at 72 hrs of the ICU Stay were Associated with Increased All-Cause Hospital Mortality
      • The Associations were Independent of Base Deficit, Cumulative Fluid Balance, Acute Kidney Injury, and Other Critical Illness Parameters
  • French HYPERS2S Trial of Hyperoxia and Hypertonic Saline in Septic Shock (Lancet Respir Med, 2017) [MEDLINE]
    • Trial Stopped Prematurely for Safety Reasons
    • Setting FiO2 to 100% to Induce Arterial Hyperoxia Might Increase the Mortality Rate in Septic Shock
    • Hypertonic (3%) Saline Resuscitation Did Not Decrease the Mortality Rate in Septic Shock
  • Retrospective Review of Resuscitative Fluids in Sepsis in the Emergency Department (Am J Emerg Med, 2018) [MEDLINE]
    • Use of Balanced Resuscitative Fluids (Lactated Ringer’s or Isolyte) was Associated with Decreased Mortality Rate, as Compared to Normal Saline
  • Cluster-Randomized, Multiple-Crossover SMART-MED and SMART-SURG Trial of Balanced Crystalloids vs Normal Saline in Critically Ill Adults (NEJM, 2018) [MEDLINE]: n = 7,942 (5 ICU’s)
    • Balanced Crystalloids (Lactated Ringers or Plasma-Lyte) for Intravenous Fluid Resuscitation Decreased the Composite Outcome of All-Cause Mortality Rate, Need for New Renal Replacement Therapy, and Persistent Renal Dysfunction, as Compared to Normal Saline
  • Brazilian Randomized BaSICS Trial of Fluid Resuscitation in Sepsis in the Intensive Care Unit (JAMA, 2021) [MEDLINE]: n = 10,520 (in 75 ICU’s)
    • Among Critically Ill Patients Requiring Intravenous Fluid Challenge, the Use of a Balanced Solution (as Compared with Normal Saline) Did Not Significantly Decrease the 90-Day Mortality Rate

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

  • Hyperchloremia Should Be Avoided (Regardless of Which Fluid is Used)
    • Due to Concern that Hyperchloremia May Induce Renal Vasoconstriction

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, Crystalloids are Recommended as the First-Line Intravenous Fluid for Resuscitation (Strong Recommendation, Moderate Quality Evidence)
  • For Adults with Sepsis/Septic Shock, Balanced Crystalloids are Recommended for Resuscitation Instead of Normal Saline (Weak Recommendation, Low Quality Evidence)
  • For Adults with Sepsis/Septic Shock, Albumin is Recommended in Patients Who Have Received Large Volumes of Crystalloids (Weak Recommendation, Moderate Quality Evidence)
  • For Adults with Sepsis/Septic Shock, Hydroxyethyl Starches are Not Recommended for Resuscitation (Strong Recommendation, High Quality Evidence)
    • Due to Concerns Related to an Increased Mortality Rate and Increased Risk for Hemodialysis
  • For Adults with Sepsis/Septic Shock, Gelatin is Not Recommended for Resuscitation (Weak Recommendation, Moderate Quality Evidence)

Choice of Vasopressor (or Inotrope)

Agents (see Critical Care Pharmacology)

  • Angiotensin II (Giapreza) (see Angiotensin II)
    • Pharmacology
      • Synthetic Human Angiotensin II
    • Clinical
      • FDA Approved for the Treatment of Sepsis in 2018
  • Dobutamine (Dobutrex) (see Dobutamine)
    • Pharmacology
      • Positive Enantiomer Functions as β1-Adrenergic Receptor Agonist (see β1-Adrenergic Receptor Agonists)
        • Chronotropic Effect (Increases Heart Rate)
        • Inotropic Effect (Increases Myocardial Contractility)
        • Decreases Central Venous Pressure (CVP)
        • Decreases Pulmonary Capillary Wedge Pressure (PCWP)
      • Vascular β2-Adrenergic Receptor Agonist and α1-Adrenergic Receptor Agonist (see β2-Adrenergic Receptor Agonists) and α1-Adrenergic Receptor Agonists)
        • Some Peripheral Vasodilation May Occur
        • Minimal Effect on Pulmonary Vascular Resistance (PVR)
  • Dopamine (see Dopamine)
    • Pharmacology
      • Dose 0.5-2.0 μg/kg/min: Dopamine Receptor Agonist -> Renal Vasodilation
      • Dose 2-10 μg/kg/min
        • α1-Adrenergic Receptor Agonist -> Vasoconstriction with Increase in Mean Arterial Pressure
        • β1-Adrenergic Receptor Agonist -> Positive Chronotropy and Inotropy -> Increase in Stroke Volume, Resulting in an Increase in Cardiac Output
      • Dose 10-30 μg/kg/min: α1-Adrenergic Receptor Agonist -> Marked Vasoconstriction with Increase in Mean Arterial Pressure
      • Other: β2-Adrenergic Receptor Agonist -> Bronchodilation
  • Epinephrine (see Epinephrine)
    • Pharmacology
      • α1-Adrenergic Receptor Agonist -> Vasoconstriction with Increase in Mean Arterial Pressure
      • β1-Adrenergic Receptor Agonist -> Positive Chronotropy + Inotropy -> Increase in Stroke Volume, Resulting in an Increase in Cardiac Output
      • β2-Adrenergic Receptor Agonist -> Bronchodilation
      • β3-Adrenergic Receptor Agonist -> Lipolysis
  • Hydroxocobalamin (Cyanokit) (see Hydroxocobalamin)
    • Pharmacology
      • Hydroxocobalamin is Vitamin B12
        • Inhibition of Nitric Oxide and Inducible Endothelial Nitric Oxide Synthase, Inhibiting Nitric Oxide Induced-Vasodilation
        • Inhibition of Hydrogen Sulfide (an Endothelial-Bound Endogenous Vasodilator), Enhancing its Elimination
  • Levosimendan (Simdax) (see Levosimendan)
    • Pharmacology
      • Binding to Cardiac Troponin C in a Calcium-Dependent Manner, Increasing Calcium Sensitivity of Cardiac Myocytes and Increased Myocardial Contractility
      • Opens Adenosine Triphosphate (ATP)-Sensitive Potassium Channels in Vascular Smooth Muscle, Causing Smooth Muscle Relaxation and a Vasodilator Effect (and Decreased Preload and Afterload)
  • Methylene Blue (see Methylene Blue)
    • Pharmacology
      • Methylene Blue Selectively Inhibits the Action of Nitric Oxide on Guanylate Cyclase, Decreasing Endotoxin-Mediated Vasodilation, and Resulting in Increased Systemic Blood Pressure
    • Administration
      • Single Intravenous Bolus Dose of 1-2 mg/kg Over 20-60 min
        • Improvement in Shock (i.e. Increased Systemic Vascular Resistance, Decreased Vasopressor Dosage, etc) May Be Observed within 1-2 hrs After Dose
        • May Subsequently Continue Dosing with Infusion of 0.5-1 mg/kg/hr
      • Indicated for Septic Shock and Hypotension Refractory to Multiple Vasopressors without Evidence of Acute Respiratory Distress Syndrome (ARDS)
      • Duration of Action: 2-3 hrs
  • Milrinone (Primacor) (see Milrinone)
    • Pharmacology
      • Phosphodiesterase Type 3 Inhibitor (Which Inhibits cAMP Degradation) (see Phosphodiesterase Type 3 Inhibitors)
        • Increases Myocardial Contractility
        • Vasodilation (Afterload Reduction)
        • Decreases Pulmonary Vascular Resistance (PVR)
  • Norepinephrine (Levophed) (see Norepinephrine)
    • Pharmacology
      • α1-Adrenergic Receptor Agonist -> Vasoconstriction with Increase in Mean Arterial Pressure
      • β1-Adrenergic Receptor Agonist -> Positive Chronotropy + Inotropy -> Increase in Stroke Volume, Resulting in an Increase in Cardiac Output
        • However, Norepinephrine Induces a Lesser Increase in Stroke Volume Than Dopamine
        • Norepinephrine Induces Less Tachycardia and is Less Arrhythmogenic Than Dopamine
      • β2-Adrenergic Receptor Agonist -> Bronchodilation
  • Phenylephrine (Neosynephrine) (see Phenylephrine)
    • Pharmacology
      • α1-Adrenergic Receptor Agonist -> Vasoconstriction with Increase in Mean Arterial Pressure
  • Vasopressin (see Vasopressin)
    • Physiology
      • Vasopressin is normally synthesized in the hypothalamus and released by the pituitary in response to water deprivation
    • Pharmacology
      • Vasopressin V1 Receptor Agonist (Vascular Smooth Muscle) -> Vasoconstriction with Increase in Mean Arterial Pressure
        • Less Vasoconstriction Occurs in the Mesenteric/Cerebral/Coronary Circulations Than in Skin/Muscle
        • Vasoconstrictor Effect Occurs at Higher Doses Than the Anti-Diuretic Effect
        • Increased Vascular Sensitivity to Other Pressors
        • Mild Pulmonary Artery Vasodilation (Pulmonary Artery Vasoconstriction at Very High Doses)
        • Increased Renal Blood Flow (Low Dose)/Decreased Renal Blood Flow (Dose-Dependent at Pressor Doses)
        • Increased Serum Cortisol
      • Vasopressin V2 Receptor Agonist (Renal Collecting Duct) -> Water Reabsorption (Anti-Diuretic Hormone Effect)
    • Administration
      • Non-Titrating 0.04 U/min Intravenous (IV) Infusion
      • At This Low Dose, Vasopressin Causes Systemic Vasoconstriction, with Increased Mean Arterial Pressure (and Decreased Cardiac Output): however, splanchnic blood flow is usually increased or unchanged
      • This Low Dose Can May Also Modestly Increase Pulmonary Pressures

Clinical Efficacy-Vasopressors

  • Vasopressin and Septic Shock Trial (VASST) of Vasopressin Add-On Therapy (to Norepinephrine) in Septic Shock (NEJM, 2008) [MEDLINE]
    • Low-Dose Vasopressin (0.01-0-03 U/min) Add-On Therapy to Norepinephrine Did Not Decrease Mortality, as Compared to Norepinephrine Alone in Septic Shock
    • Lower Mortality Rates were Observed in the Stratum of Patients Randomized to Receive Vasopressin with Norepinephrine-Equivalent Doses <15 μg/min at the Time of Randomization (90-Day Mortality 35.8% vs 46.1%; Absolute Risk Reduction, –10.4% [95% CI, –20.3% to –0.4%]), as Compared with Those Who Received Norepinephrine Alone (Stratum Interaction p = 0.10)
  • Sepsis Occurrence in Acutely Ill Patients (SOAP) II Trial Comparing Dopamine with Norepinephrine in Shock of Various Etiologies (NEJM, 2010) [MEDLINE]
    • No Mortality Difference Between Dopamine and Norepinephrine in Shock
    • However, Dopamine Was Associated with More Arrhythmic Adverse Events
    • Use of Additional Vasopressin and Epinephrine for Unresponsive Shock was Similar in Both Groups
    • In Subgroup with Cardiogenic Shock, Dopamine Increased 28-Day Mortality, as Compared to Norepinephrine: this increase in mortality was not observed in septic and hypovolemic shock
  • Small Randomized Trial Comparing Phenylephrine with Norepinephrine in Septic Shock Unresponsive to Dopamine Therapy (Indian J Crit Care Med, 2010) [MEDLINE]: n = 54
    • Phenylephrine was Comparable to Norepinephrine in Reversing the Hemodynamic and Metabolic Abnormalities in Septic Shock
      • Phenylephrine Had the Additional Benefit of Decreasing the Heart Rate and Improving the SVI
  • Meta-Analysis Comparing Dopamine with Norepinenephrine in Septic Shock (Crit Care Med, 2012) [MEDLINE]
    • In Septic Shock, Dopamine Increased Arrhythmias and Mortality Rate, as Compared to Norepinephrine
  • Comparison of the Cardiopulmonary Effects Vasopressin and Norepinephrine in Septic Shock (Chest, 2012) [MEDLINE]: data from VASST trial patients
    • Vasopressin Decreased the Norepinephrine Requirement
    • Vasopressin Decreased the Heart Rate, But Did Not Decrease Cardiac Output
      • However, There was an Increased Use of Inotropic Drugs (Mostly Dobutamine) in the Vasopressin Group (Especially in the Most Severe Subset of Patients)
    • No Difference Between Vasopressin and Norepinephrine with Regard to Pulmonary Artery Pressures, Oxygenation, and Cardiac Filling Pressures
  • Prospective Substudy (of a Randomized Trial) of Myocardial Ischemia in Septic Shock (Crit Care, 2013) [MEDLINE]
    • Troponin Elevation is Common in Adults with Septic Shock
    • No Differences in Troponin Elevation, CK Elevation, or EKG Changes in Patients Treated with Vasopressin vs Epinephrine
  • Bayesian Network Meta-Analysis of Vasopressors Effect on Mortality Rate in Septic Shock (J Crit Care, 2014) [MEDLINE]
    • Norepinephrine (with/without Vasopressin) is the Preferred First Choice Pressor in Septic Shock in Terms of Mortality Benefit
    • No Evidence Exists that Epinephrine vs Dopamine as the Second-Line Agent Decreases the Mortality Rate
    • No Evidence that the Addition of an Inotropic Agent (Such as Dobutamine) Decreases the Mortality Rate
  • Pilot Study Examining the Effect of Corticosteroids on Vasopressor Requirement in Septic Shock (Crit Care Med, 2014) [MEDLINE]
    • Hydrocortisone Decreased Vasopressin Duration and Dose Requirements in Septic Shock: although hydrocortisone did not alter the plasma vasopressin level
  • Systematic Review and Meta-Analysis Examining Various Vasopressors in Septic Shock (Ther Clin Risk Mgmt, 2015) [MEDLINE]
    • Norepinephrine May Be Superior to Dopamine in Terms of Mortality Rate
    • There is Insufficient Evidence to Suggest Superiority of Any Other Pressor Over Another
  • Systematic Review and Meta-Analysis Examining Various Vasopressors in Septic Shock (PLoS One, 2015) [MEDLINE]
    • Norepinephrine is Superior to Dopamine in Terms of Hemodynamic Profile and Adverse Events: authors recommend norepinephrine as the first choice vasopressor
  • Meta-Analysis Examining the Effect of Inotropes/Vasopressors on the Mortality Rate in Critically Ill Patients (Br J Anaesth, 2015) [MEDLINE]: included n = 28,280 patients from 177 trials
    • Inotropes/Vasopressors Did Not Improve Mortality in Critically Ill Patients
    • Inotropes/Vasopressors Did Improve Mortality in the Subsets of Patients with Sepsis, Vasoplegic Syndrome, and Cardiac Surgery
  • Systematic Review and Meta-Analysis of Vasopressors in Septic Shock (PloS One, 2015) [MEDLINE]: n = 32 trials
    • Evidence Suggests a Survival Benefit, Better Hemodynamic Profile, and Decreased Adverse Events for Norepinephrine Over Dopamine
  • VANISH Trial (JAMA, 2016) [MEDLINE]: randomized trial (n = 409) of patients in septic shock (enrolled within 6 hrs) conducted in the UK
    • Early Use of Vasopressin Did Not Decrease the Incidence of Acute Kidney Injury, as Compared to Norepinephrine: although vasopressin group had less use of renal replacement therapy (25.4% vs 35.3%)
    • No Difference in Mortality Between the Early Use of Vasopressin Compared with Norepinephrine
  • Network Meta-Analysis of Vasopressors in Septic Shock ( J Intensive Care Soc, 2016) [MEDLINE]
    • Vasopressin was Superior to Dopamine for in Terms of 28-Day Mortality in Septic Shock
    • Existing Pairwise Information Supports the Use of Norepinephrine Over Dopamine
  • Cochrane Database Systematic Review of Vasopressors for Septic Shock (Cochrane Database Syst Rev, 2016)
    • No Evidence of Substantial Differences in Total Mortality Between Several Vasopressors
      • Dopamine Increases the Risk of Arrhythmia (as Compared to Norepinephrine) and Might Increase Mortality Rate
      • Otherwise, Evidence of Any Other Differences Between Any of the 6 Vasopressors Examined is Insufficient
      • Authors Identified Low Risk of Bias and High-Quality Evidence for the Comparison of Norepinephrine vs Dopamine and Moderate to Very Low-Quality Evidence for All Other Comparisons (Mainly Because Single Comparisons Occasionally were Based on Only a Few Participants)
      • Increasing Evidence Indicates that the Treatment Goals Most Often Employed are of Limited Clinical Value
      • Authors’ Findings Suggest that Major Changes in Clinical Practice are Not Required, But that Selection of Vasopressors Could Be Better Individualized and Could Be Based on Clinical Variables Reflecting Hypoperfusion
  • Systematic Review and Meta-Analysis of Efficacy of Vasopressin with Catecholamines vs Catecholamines Alone in Septic Shock (JAMA, 2018) [MEDLINE]
    • The Addition of Vasopressin to Catecholamine Vasopressors (as Compared with Catecholamines Alone) was Associated with a Lower Risk of Atrial Fibrillation
  • Single Center Phase II Randomized Thailand CENSER Trial of Early Norepinephrine Use in Septic Shock (Am J Respir Crit Care Med, 2019) [MEDLINE]: n= 310
    • Primary Endpoint: shock control rate (defined as achievement of mean arterial blood pressure >65 mm Hg, with urine flow >0.5 mL/kg/hr for 2 consecutive hrs, or decreased serum lactate >10% from baseline) by 6 hrs after diagnosis
      • Median Time from Emergency Department Arrival to Norepinephrine Administration was Significantly Shorter in the Early Norepinephrine Group (93 v 192 min; p<0.001)
    • Early Norepinephrine Use was Associated with Increased Shock Control by 6 hrs
    • Early Norepinephrine Use was Associated with Decreased Incidence of Pulmonary Edema (22/155 [14.4%] vs. 43/155 [27.7%]; P=0.004) and New Onset Arrhythmia (17/155 [11%] vs. 31/155 [20%]; P=0.03)
    • Early Norepinephrine Did Not Impact the 28-Day Mortality Rate
  • Cleveland Clinic Health System Retrospective, Observational Study of Timing of Initiation of Add-On Vasopressin in Septic Shock (Crit Care Med, 2022) [MEDLINE]: n = 1,610
    • At Vasopressin Initiation, Median Serum Lactate was 3.9 mmol/L (Interquartile Range: 2.3–7.2 mmol/L), Median Norepinephrine-Equivalent Dose was 25 μg/min (Interquartile Range: 18–40 μg/min), and Median 5.3 hrs (Interquartile Range: 2.1–12.2 hrs) Had Elapsed Since Shock Onset
    • Odds of In-Hospital Mortality Increased 20.7% for Every 10 μg/min Increase in Norepinephrine-Equivalent Dose Up to 60 μg/min at the Time of Vasopressin Initiation (Adjusted Odds Ratio 1.21 (95% CI: 1.09–1.34), But There was No Association When the Norepinephrine-Equivalent Dose Exceeded 60 μg/min (Adjusted Odds Ratio: 0.96 (95% CI: 0.84–1.10)
    • There was a Significant Interaction Between the Timing of Vasopressin Initiation and Lactate Concentration (p = 0.02) for the Association with In-Hospital Mortality
    • A Linear Association Between Increasing In-Hospital Mortality was Detected for Increasing Lactate Concentration at the Time of Vasopressin Initiation, But No Association was Detected for Time Elapsed from Shock Onset
    • Conclusions
      • There was a Lower Mortality Rate When Vasopressin was Initiated at a Lower (vs a Higher) Norepinephrine Dose
      • There was a Lower Mortality Rate When Vasopressin was Initiated at a Lower (vs a Higher) Serum Lactate Level
      • Further Prospective Studies Should Explore This Association

Clinical Efficacy-Weaning of Vasopressors

  • Retrospective Cohort Study Examining the Order of Vasopressor Weaning in Septic Shock (J Crit Care, 2010) [MEDLINE]
    • Tapering of Vasopressin Before Norepinephrine Resulted in a Greater Incidence of Clinically Significant Hypotension than Did the Reverse Order
  • Small Single-Center DOVSS Trial Examining the Order of Vasopressor Withdrawal in Septic Shock (Crit Care, 2018) [MEDLINE]: n = 78
    • In Patients on Concomitant Norepinephrine and Vasopressin, Tapering Norepinephrine Rather than Vasopressin May Be Associated with a Higher Incidence of Hypotension in Patients Recovering from Septic Shock
  • Study Examining the Order of Vasopressor Weaning in Septic Shock (J Intensive Care Med, 2017) [MEDLINE]
    • Adult Patients Receiving Norepinephrine and Vasopressin in the Resolving Phase of Septic Shock May Be Less Likely to Develop Clinically Significant Hypotension if Vasopressin is the Final Vasopressor Discontinued

Clinical Efficacy-Angiotensin II (see Angiotensin II)

  • Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Trial ( NEJM, 2017) [MEDLINE]; n = 344
    • Angiotensin II Effectively Increased Blood Pressure in Patients with Vasodilatory Shock Who Did Not Respond to High Doses of Conventional Vasopressors
  • Post-Hoc Analysis of the Effect of Angiotensin II on Renal Outcomes in Vasodilatory Shock in the ATHOS-3 Trial (Crit Care Med, 2018) [MEDLINE]
    • In Patients with Acute Kidney Injury Requiring Renal Replacement Therapy at Study Initiation, 28-Day Survival in the Angiotensin II Group, as Compared to the Placebo Group
    • In Patients with Acute Kidney Injury Requiring Renal Replacement Therapy at Study Initiation, Mean Arterial Pressure was Higher and Rate of Liberation from Renal Replacement Therapy was Greater in the Angiotensin II Group, as Compared to the Placebo Group

Clinical Efficacy-Methylene Blue (see Methylene Blue)

  • Randomized Trial of Methylene Blue in Sepsis (Crit Care Med, 2001) [MEDLINE]
    • Continuously-Infused Methylene Blue Counteracted Myocardial Depression, Maintained Oxygen Transport, and Decreased Concurrent Vasopressor Support
  • Systematic Review of the Efficacy of Methylene Blue in Sepsis (J Intensive Care Med, 2006) [MEDLINE]
    • Methylene Blue Increased Mean Arterial Pressure, Increased Systemic Vascular Resistance, and Decreased Vasopressor Requirement in Septic Shock
    • Bolus Dosing of Methylene Blue Increased Pulmonary Vascular Resistance, But Might Be Avoided with Continuous Infusion
    • No Other Ill Effects were Reported
    • Effects on Mortality were Not Evaluated in the Literature

Clinical Efficacy-Hydroxocobalamin (see Hydroxocobalamin)

  • Case Report of Hydroxocobalamin in Septic Shock (Cureus, 2021) [MEDLINE]
  • Single Center, Retrospective Case Series of Hydroxocobalamin in Refractory Septic Shock (Crit Care Explor, 2021) [MEDLINE]: n = 26
    • Hydroxocobalamin Increase in Mean Arterial Pressure at 1, 6, and 24 hrs (+16.3, +14.3, and +16.3 mm Hg, Respectively; p < 0.001)
    • Increase in Mean Arterial Pressure from Baseline Remained Statistically Significant When Controlling for Age/Sex/Comorbid Conditions
    • There was No Change in the Norepinephrine Equivalents Patients Required 1 hr Following Hydroxocobalamin, But a Statistically Significant Decrease in Norepinephrine Equivalent was Observed at 6 and 24 hrs (p < 0.001)

Clinical Efficacy-Inotropes

  • Trial of Dobutamine to Increase Cardiac Output and Oxygen Delivery in Critically Ill Patients (NEJM, 1994) [MEDLINE]: intervention increased the mortality rate
  • Trial of Achieving Supranormal Cardiac Output or Normal SvO2 in Critically Ill Patients (NEJM, 1995) [MEDLINE]: no mortality benefit
  • Study of Effects of Dobutamine on Physiologic Parameters in Septic Shock (Intensive Care Med, 2013) [MEDLINE]
    • Dobutamine Had No Effect on Sublingual Microcirculatory, Metabolic, Hepatosplanchnic, or Peripheral Perfusion Parameters Despite an Increase in Systemic Hemodynamic Variables in Septic Shock Patients with Persistent Hypoperfusion, But Without Low Cardiac Output

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

  • General Recommendations
    • Vasopressor Dosing Should Be Titrated to an Endpoint Reflecting Perfusion (and Decreased/Stopped in the Face of Worsening Hypotension or Arrhythmias)
  • Dopamine (Low Dose) is Not Recommended for Renal Protection (Strong Recommendation, High Quality of Evidence)
  • Phenylephrine Use Should Be Limited in Sepsis Until Further Data are Available
    • However, the 2012 Surviving Sepsis Guidelines Stated that Phenylephrine was Not Recommended, Except When Norepinephrine is Associated with Arrhythmias, Cardiac Output is High with Low Mean Arterial Pressure, or as Salvage Therapy When Combined Inotropes/Vasopressors Fail to Achieve Mean Arterial Pressure Targets (Grade 1C Recommendation) (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [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, Norepinephrine is Recommended as the First-Line Vasopressor (Strong Recommendation)
    • vs Dopamine (High Quality Evidence)
    • vs Vasopressin (Moderate Quality Evidence)
    • vs Epinephrine (Low Quality of Evidence)
    • vs Selepressin (Low Quality of Evidence)
    • vs Angiotensin II (Very Low Quality Evidence)
    • General Comments
      • If Norepinephrine is Not Available, Dopamine or Epinephrine May Be Used as an Alternative (with Caution Regarding the Potential for Development of Arrhythmias)
  • For Adults with Septic Shock on Norepinephrine with Inadequate Mean Arterial Pressure, Addition of Vasopressin (Up to 0.03-0.04 U/min) is Recommended Instead of Escalating the Norepinephrine Dose (Weak Recommendation, Moderate Quality of Evidence)
  • For Adults with Septic Shock and Inadequate Mean Arterial Pressure Despite Norepinephrine and Vasopressin, Addition of Epinephrine is Recommended (Weak Recommendation, Low Quality of Evidence)
  • For Adults with Septic Shock, Terlipressin is Not Recommended (Weak Recommendation, Low Quality of Evidence)
  • For Adults with Septic Shock and Cardiac Dysfunction with Persistent Hypoperfusion Despite Adequate Volume Status and Arterial Blood Pressure, Addition of Dobutamine to Norepinephrine or Using Epinephrine Alone is Recommended (Weak Recommendation, Low Quality of Evidence)
    • Dobutamine Should Not Be Used Target a Supranormal Cardiac Output
    • Monitoring Response in Indices of Perfusion to a Measured Dobutamine-Induced Increase in Cardiac Output is Recommended
  • For Adults with Septic Shock and Cardiac Dysfunction with Persistent Hypoperfusion Despite Adequate Volume Status and Arterial Blood Pressure, Levosimendan is Not Recommended (Weak Recommendation, Low Quality of Evidence)
  • 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)
  • For Adults with Septic Shock, Starting Vasopressors Peripherally is Recommended to Restore Mean Arterial Pressure, Rather than Delaying Vasopressor Initiation Until a Central Venous Line is Placed (Weak Recommendation, Very Low Quality of Evidence)
    • When Using Vasopressors Peripherally, They Should Be Administered Only for a Short Period of Time and in a Vein in or Proximal to the Antecubital Fossa

Midodrine (see Midodrine)

General Comments

  • Rationale: midodrine is a peripheral vasoconstrictor
  • Administration: 10 mg PO TID

Clinical Efficacy

  • Trial of Midodrine During Recovery Phase in Septic Shock (Chest, 2016) [MEDLINE]
    • Midodrine Decreased the Duration of Vasopressor Use During the Recovery Phase of Septic Shock and May Be Associated with Decreased ICU Length of Stay

Arrhythmia Management

Clinical Efficacy

  • Retrospective Cohort Study of Practice Patterns in the Management of Atrial Fibrillation During Sepsis (Chest, 2016) [MEDLINE]: n = 39,693
    • While Calcium Channel Blockers were the Frequently Used Intravenous Medications for Atrial Fibrillation During Sepsis, β-Blockers were Associated with Superior Clinical Outcomes (In-Hospital Mortality Rate) in the Subgroups Analyzed: results were similar among subgroups with new-onset vs pre-existing AF, heart failure, vasopressin-dependent shock, or hypertension
  • Multicenter Retrospective Cohort Study of the Treatment of Sepsis-Associated Atrial Fibrillation with Rapid Ventricular Response (with Heart Rate > 110 beats/min) (Chest, 2020) [MEDLINE]: n = 666
    • In the Study, 50.6% Initially Received Amiodarone, 33.8% Received a Calcium Channel Blocker, 10.1% Received a β-Blocker, and 5.6% Received Digoxin
    • Adjusted Hazard Ratio for Heart Rate of <110 beats/min by 1 hr
      • Amiodarone vs β-Blocker: 0.50 (95% CI; 0.34-0.74)
      • Digoxin vs β-Blocker: 0.37 (95% CI; 0.18-0.77)
      • Calcium Channel Blocker vs β-Blocker: 0.75 (95% CI; 0.51-1.11)
    • Adjusted Hazard Ratio for Heart Rate of <110 beats/min by 6 hrs
      • Amiodarone vs β-Blocker: : 0.67 (95% CI, 0.47-0.97)
      • Digoxin vs β-Blocker: 0.60 (95% CI, 0.36-1.004)
      • Calcium Channel Blocker vs β-Blocker: 1.03 (95% CI, 0.71-1.49)
    • Conclusions
      • β-Blocker Treatment Strategy Improved Heart Rate Control at 1 hr
      • With All of the Strategies, There was Generally Similar Heart Rate Control at 6 hrs

Corticosteroids (see Corticosteroids)

General Comments

  • Corticosteroids Have Unclear Benefit in Septic Shock

Clinical Efficacy

  • CORTICUS Trial of Hydrocortisone Therapy for Septic Shock (NEJM, 2008) [MEDLINE]” n = 499 patients
    • Hydrocortisone Did Not Decrease the Mortality Rate or Enhance the Reversal of Shock in Patients with Septic Shock (Either Overall or in Patients Who Did Not Have a Response to Corticotropin): however, hydrocortisone hastened the reversal of shock in the subset of patients in whom shock was reversed
  • Subanalysis of CORTICUS Septic Shock Trial Data Examining the Effects of Etomidate (Intensive Care Med, 2009) [MEDLINE]
    • Use of Bolus Dose Etomidate in the 72 h Before Study Inclusion was Associated with an Increased Incidence of Inadequate Response to Corticotropin, But was Also Likely Associated with an Increase in the Mortality Rate
  • Review of Corticosteroid Use in Septic Shock (Am J Respir Crit Care Med, 2012) [MEDLINE]
    • Low-Dose Corticosteroids Improve Blood Pressure and Result in Shorter Duration of Vasopressor Use in Septic Shock
      • However, the Mortality Benefit is Unclear
      • Fludocortisone is Not a Beneficial Component of This Regimen and Might Increase the Infection Risk
    • Early High-Dose Corticosteroids are Potentially Harmful in the Treatment of Septic Shock
  • Analysis of Low-Dose Corticosteroids in Adult Septic Shock (Intensive Care Med, 2012) [MEDLINE]
    • Corticosteroids Increased the Adjusted Hospital Mortality Rate
  • Pilot Study Examining the Effect of Corticosteroids on Vasopressor Requirement in Septic Shock (Crit Care Med, 2014) [MEDLINE]
    • Hydrocortisone Decreased Vasopressin Duration and Dose Requirements in Septic Shock: although hydrocortisone did not alter the plasma vasopressin level
  • Cochrane Database Systematic Review of Corticosteroid Treatment in Sepsis (Cochrane Database Syst Rev, 2015) [MEDLINE]
    • Low-Quality Evidence Indicates that Corticosteroids Decreased Mortality in Sepsis
    • Moderate Quality Evidence Suggests that a Long Course of lLow-Dose Corticosteroids Decreased 28-day Mortality without Inducing Major Complications and Led to an Increase in Metabolic Disorders (Hyperglycemia, Hypernatremia)
  • German HYPRESS Trial of Hydrocortisone in Severe Sepsis without Shock (JAMA, 2016) [MEDLINE]: intention to treat analysis (n = 353)
    • Hydrocortisone Did Not Decrease the Development of Shock within 14 Days or the 28-Day Mortality Rate
    • Hydrocortisone Group Had Higher Incidence of Hyperglycemia (90.9% vs 81.5%), Secondary Infection (21.5% vs 16.9% ), and Muscle Weakness (30.7% vs 23.8% ), But No Difference in Weaning Failure (8.6% vs 8.5%), as Compared to Placebo Group
  • Australian-New Zealand Randomized, Placebo-Controlled ADRENAL Trial of Adjunctive Corticosteroids in Mechanically Ventilated Patients with Septic Shock (NEJM, 2018)> [MEDLINE]: n = 3800
    • Hydrocortisone Regimen: 200 mg/day, continuous intravenous infusion over 24 hrs for a maximum of 7 days or until ICU discharge or death
    • Continuous Hydrocortisone Infusion Resulted in Faster Time to Shock Resolution (3 Days vs 4 Days), as Compared to Placebo
    • Continuous Hydrocortisone Infusion Resulted in Shorter Duration of Initial Mechanical Ventilation (6 Days vs 7 Days), as Compared to Placebo
      • However, There Were No Differences in (Alive) Ventilator-Free Days
    • Continuous Hydrocortisone Infusion Resulted in Less Blood Transfusions, as Compared to Placebo
    • Continuous Hydrocortisone Infusion Did Not Impact Rate of Recurrence of Septic Shock, Number of Days Alive and Out of the ICU, Number of Days Alive and Out of the Hospital, Recurrence of Mechanical Ventilation, Rate of Renal Replacement Therapy, and Incidence of Bacteremia/Fungemia
    • Continuous Hydrocortisone Infusion Did Not Decrease 28-Day or 90-Day Mortality, as Compared to Placebo
  • French APROCCHSS Trial of Hydrocortisone and Fludrocortisone for Adults with Septic Shock (NEJM, 2018) [MEDLINE]: n = 1241
    • Hydrocortisone and Fludrocortisone Decreased the 90-Day All-Cause Mortality Rate, as Compared to Placebo
    • Hydrocortisone and Fludrocortisone Increased the Number of Vasopressors-Free Days and Organ Failure-Free Days
    • There was No Difference in Ventilator-Free Days
    • Hyperglycemia was More Common in the Hydrocortisone and Fludrocortisone Group
  • Systematic Review and Meta-Analysis of Corticosteroids in Adult Patients with Septic Shock (Intensive Care Med, 2018) [MEDLINE]: n = 7297 (22 trials)
    • Low-Dose Corticosteroids Did Not Impact Short or Long-Term Mortality Rates
    • Low-Dose Corticosteroids Decreased the Duration of Shock, Duration of Mechanical Ventilation, and Decreased the ICU Length of Stay
    • Low-Dose Corticosteroids Increased Adverse Events
  • Systematic Review and Meta-Analysis of Corticosteroids in Sepsis (Crit Care Med, 2018) [MEDLINE]: n = 10,194 (42 trials)
    • Based on Low Certainty, Corticosteroids Possibly Resulted in a Small Decrease in the Short-Term (28-Day/30-Day) Mortality Rate (Relative Risk, 0.93; 95% CI, 0.84-1.03; 1.8% Absolute Risk Reduction; 95% CI, 4.1% Reduction to 0.8% Increase
    • Based on Moderate Certainty, Corticosteroids Possibly Possibly Resulted in a Small Decrease in the Long-Term (60-Day/1-Year) Mortality (60 d to 1 yr) (Relative Risk, 0.94; 95% CI, 0.89-1.00; 2.2% Absolute Risk Reduction; 95% CI, 4.1% Reduction to No Effect)
    • Based on Moderate Certainty, Corticosteroids Probably Resulted in a Small Decrease in ICU Length (Mean Difference, -0.73 d; 95% CI, -1.78 to 0.31) and Hospital Length of Stay (Mean Difference, -0.73 d; 95% CI, -2.06 to 0.60)
    • Based on High Certainty, Corticosteroids Resulted in Higher Rates of Shock Reversal at Day 7 (Relative Risk, 1.26; 95% CI, 1.12-1.42) and Lower Sequential Organ Failure Assessment Scores at Day 7 (Mean Difference, -1.39; 95% CI, -1.88 to -0.89)
    • Based on Moderate Certainty, Corticosteroids Likely Increased the Risk of Hypernatremia (Relative Risk, 1.64; 95% CI, 1.32-2.03) and Hyperglycemia (Relative Risk, 1.16; 95% CI, 1.08-1.24)
    • Based on Low Certainty, Corticosteroids, Possibly Increased the Risk of Neuromuscular Weakness (Relative Risk, 1.21; 95% CI, 1.01-1.52)
    • Subgroup Analysis Did Not Demonstrate a Credible Subgroup Effect on Any of the Outcomes of Interest
  • Single-Blinded Randomized Controlled HYVCTTSSS Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 80
    • In Patients with Sepsis/Septic Shock, the Combination of Hydrocortisone/Vitamin C/Thiamine Did Not Decrease the 28-Day Mortality Rate, as Compared to Placebo
    • Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with a Significant Improvement of 72 hr Change in Sequential Organ Failure Assessment (SOFA) Score (P = 0.02)
    • Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with Higher Incidence of Hypernatremia (P = 0.005)
    • In Prespecified Subgroup Analysis, Patients of the Combination of Hydrocortisone/Vitamin C/Thiamine Treatment Subgroup Diagnosed with Sepsis within 48 hrs Demonstrated Decreased 28-Day Mortality Rate, as Compared to Control (P = 0.02)
  • Randomized, Double-Blinded, Placebo-Controlled ORANGES Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 137
    • Combination of Hydrocortisone/Vitamin C/Thiamine Decreased the Time to Resolution of Shock (27 ± 22 vs 53 ± 38 hrs, P < 0.001)
    • No Statistically Significant Change in SOFA Score was Demonstrated Between Groups 3 (1 – 6) vs 2 (0 – 4), P = 0.17
    • No Significant Differences were Demonstrated Between Study Arms in Terms of ICU/Hospital Mortality, ICU/Hospital Length of Stay, Ventilator-Free Days, or Procalcitonin Clearance
  • VITAMINS Trial of Vitamin C (1.5 g q6hrs), Hydrocortisone (50 mg q6hrs), and Thiamine (200 mg q12 hrs) vs Control Group with Hydrocortisone Alone (50 mg q6hrs) in Septic Shock (JAMA, 2020) [MEDLINE]: n = 211
    • Patients Received Treatment Until Shock Resolution or Up to 10 Days
    • No Significant Difference in 90-Day Mortality Between the Groups (28.6% in Triple Therapy Treatment Group vs 24.5% in the Control Group)
    • No Difference in Time Alive and Vasopressor-Free Up to Day 7 Between the Groups (122.1 hrs with Interquartile Range 76.3-145.4 hrs in the Triple Therapy Treatment Group vs 124.6 hrs with Interquartile Range 82.1-147.0 hrs in the Control Group)
    • No Serious Adverse Events were Reported
  • Multicenter, Randomized, Double-Blind, Placebo-Controlled VICTAS Trial of Vitamin C, Thiamine, and Hydrocortisone in Sepsis (JAMA, 2021) [MEDLINE]: n = 501
    • Trial was Terminated Early for Administrative Reasons (Therefore, May Have Been Underpowered to Detect Differences)
    • In Critically Ill Patients with Sepsis, Treatment with Vitamin C, Thiamine, and Hydrocortisone Did Not Increase Ventilator-Free and Vasopressor-Free Days within 30 Days

Recommendations (American College of Critical Care Medicine Consensus Statement on the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients, Crit Care Med, 2008) [MEDLINE]

  • General Comments: involved a multi-disciplinary, multi-specialty group from the membership of the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and international experts in endocrinology
  • Use of Adrenocorticotrophic Hormone (ACTH) Stimulation Test
    • Adrenocorticotrophic Hormone (ACTH) Stimulation Test Should Not Be Used to Identify Those Patients with Septic Shock/ARDS Who Should Receive Glucocorticoids
  • Agents
    • Hydrocortisone (50 mg q6hrs IV for ≥7 Days) is Recommended for Septic Shock
    • Dexamethasone is Not Recommended to Treat Critical Illness-Related Corticosteroid Insufficiency
    • Methylprednisolone (1 mg/kg/day for ≥14 Days) is Recommended in Patients with Severe Early Acute Respiratory Distress Syndrome
  • Administration
    • Glucocorticoids Should be Weaned and Not Stopped Abruptly
    • Reinstitution of Treatment Should Be Considered with Recurrence of Signs of Sepsis, Hypotension, or Worsening Oxygenation
  • Glucocorticoids in the Management of Patients with Community-Acquired Pneumonia, Liver Failure, Pancreatitis, Those Undergoing Cardiac Surgery, and Other Groups of Critically Ill Patients Requires Further Investigation

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

  • For Adults with Septic Shock and Ongoing Vasopressor Requirement, Intravenous Corticosteroids are Recommended (Weak Recommendation, Moderate Quality Evidence)
    • It is Suggested that Intravenous Corticosteroids Should Be Initiated at a Dose of Norepinephrine or Epinephrine ≥0.25 μg/kg/min at Least 4 hrs After Initiation
    • Recommended Hydrocortisone Dosing: 50 mg q6hrs IV (Weak Recommendation, Low Quality of Evidence)
    • The 2012 Surviving Sepsis Guidelines Recommended that if Hydrocortisone is Used, it Should Be Tapered When Vasopressors are No Longer Required (Grade 2D Recommendation) (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]
    • The 2012 Surviving Sepsis Guidelines Recommended that ACTH Stimulation Testing Should Not Be Used to Identify Adults with Septic Shock Who Should Receive Hydrocortisone (Grade 2B Recommendation) (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]

Vitamin C (see Vitamin C)

Rationale

  • Acute Illness, Endotoxemia, and Sepsis Decrease Serum and Intracellular Ascorbic Acid (Vitamin C) Levels, Likely Due to Metabolic Consumption of Vitamin C (Pharmacol Ther, 2018) [MEDLINE]
    • Low Plasma Vitamin C Levels Predict the Development of Multiorgan Failure in Sepsis
    • Low Plasma Vitamin C Levels are Associated with Severity of Organ Failure and Mortality in Sepsis
  • Enzymes Which Require Vitamin C as a Cofactor
    • Peptidylglycine α-Amidating Monooxygenase: produces vasopressin
    • Dopamine β-Hydroxylase: produces norepinephrine
    • Propyl/Lysyl Hydroxylase: produces collagen, elastin, hydroxylated hypoxia inducible factor-1α (HIF1-α)
    • γ-Butyrobetaine Hydroxylase: produces carnitine
    • Histone Demethylase: produces methylated histones
    • Nucleic Acid Demethylase: produces thymine
    • 4-Hydroxyphenylpyruvate Hydroxylase: produces homogenisate
  • Hydrocortisone and Ascorbic Acid Act Synergistically to Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction (Chest, 2017) [MEDLINE]
  • Vitamin C Reverses the Microcirculatory Injury and Organ Dysfunction in Experimental Models of Sepsis

Clinical Efficacy

  • Retrospective Before/After Clinical Study of Hydrocortisone, Vitamin C, and Thiamine in Sepsis (Chest, 2017) [MEDLINE]
    • Early Use of Intravenous Vitamin C, Hydrocortisone, and Thiamine Prevented the Progression of Organ Dysfunction (Including Acute Kidney Injury) and Decreased Mortality in Severe Sepsis and Septic Shock: additional studies are required to confirm these preliminary findings
  • Meta-Analysis of Vitamin C in Sepsis (Crit Care, 2018) [MEDLINE]
    • Despite Varying Degrees of Statistical Significance Between the 2 Studies Included, Vitamin C Appeared to Improved Mortality Rate and Decreased the Duration of Vasopressor Use in Sepsis
    • Further Randomized Trials are Recommended
  • Randomized CITRIS-ALI Trial of Vitamin C in Sepsis (JAMA, 2019) [MEDLINE]: n = 167
    • No Significant Differences Between the Vitamin C and Placebo Groups in Terms of the Mean Modified Sequential Organ Failure Assessment (SOFA) Score from Baseline to 96 hrs (from 9.8 to 6.8 in the Vitamin C Group [3 Points] and from 10.3 to 6.8 in the Placebo Group [3.5 Points]; Difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-Reactive Protein Levels (54.1 vs 46.1 μg/mL; Difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and Thrombomodulin Levels (14.5 vs 13.8 ng/mL; Difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hrs
  • Single-Blinded Randomized Controlled HYVCTTSSS Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 80
    • In Patients with Sepsis/Septic Shock, the Combination of Hydrocortisone/Vitamin C/Thiamine Did Not Decrease the 28-Day Mortality Rate, as Compared to Placebo
    • Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with a Significant Improvement of 72 hr Change in Sequential Organ Failure Assessment (SOFA) Score (P = 0.02)
    • Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with Higher Incidence of Hypernatremia (P = 0.005)
    • In Prespecified Subgroup Analysis, Patients of the Combination of Hydrocortisone/Vitamin C/Thiamine Treatment Subgroup Diagnosed with Sepsis within 48 hrs Demonstrated Decreased 28-Day Mortality Rate, as Compared to Control (P = 0.02)
  • Randomized, Double-Blinded, Placebo-Controlled ORANGES Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 137
    • Combination of Hydrocortisone/Vitamin C/Thiamine Decreased the Time to Resolution of Shock (27 ± 22 vs 53 ± 38 hrs, P < 0.001)
    • No Statistically Significant Change in SOFA Score was Demonstrated Between Groups 3 (1 – 6) vs 2 (0 – 4), P = 0.17
    • No Significant Differences were Demonstrated Between Study Arms in Terms of ICU/Hospital Mortality, ICU/Hospital Length of Stay, Ventilator-Free Days, or Procalcitonin Clearance
  • VITAMINS Trial of Vitamin C (1.5 g q6hrs), Hydrocortisone (50 mg q6hrs), and Thiamine (200 mg q12 hrs) vs Control Group with Hydrocortisone Alone (50 mg q6hrs) in Septic Shock (JAMA, 2020) [MEDLINE]: n = 211
    • Patients Received Treatment Until Shock Resolution or Up to 10 Days
    • No Significant Difference in 90-Day Mortality Between the Groups (28.6% in Triple Therapy Treatment Group vs 24.5% in the Control Group)
    • *No Difference in Time Alive and Vasopressor-Free Up to Day 7 Between the Groups (122.1 hrs with Interquartile Range 76.3-145.4 hrs in the Triple Therapy Treatment Group vs 124.6 hrs with Interquartile Range 82.1-147.0 hrs in the Control Group)
    • No Serious Adverse Events were Reported
  • Multicenter, Randomized, Double-Blind, Placebo-Controlled VICTAS Trial of Vitamin C, Thiamine, and Hydrocortisone in Sepsis (JAMA, 2021) [MEDLINE]: n = 501
    • Trial was Terminated Early for Administrative Reasons (Therefore, May Have Been Underpowered to Detect Differences)
    • In Critically Ill Patients with Sepsis, Treatment with Vitamin C, Thiamine, and Hydrocortisone Did Not Increase Ventilator-Free and Vasopressor-Free Days within 30 Days
  • Meta-Analysis of Intravenous Vitamin C in the Treatment of Sepsis/Septic Shock (Am J Emerg Med, 2021) [MEDLINE]: n = 1,400 (10 randomized controlled trials)
    • Intravenous Vitamin C Improved SOFA Score within 72 hrs [RR = 1.32, 95% CI (0.80,1.85), P < 0.0001]
    • There were No Differences in Short-Term Mortality Rate (28-30 Days) [RR = 0.83,95% CI (0.65,1.05), P = 0.11], Long-Term Mortality Rate (90 Days) [RR = 1.16, 95% CI (0.82,1.66), P = 0.40], Hospital Length of Stay [RR = 0.15, 95% CI (-0.73,1.03), P = 0.55], ICU Length of Stay [RR = 0.22, 95% CI (-0.13,0.57), P = 0.22], or Ventilator-Free Days [RR = 0.09, 95% CI (-0.24,0.42), P = 0.60]
    • Subgroup Analysis Demonstrated that Intravenous Vitamin C Alone Can Reduce the Short-Term Mortality Rate (28-30 Days) [RR = 0.61, 95% CI (0.47,0.79), P = 0.0002]
    • Results Need to Be Verified in Large, Randomized Trials
  • LOVIT Trial of Vitamin C in Adults with Sepsis in the Intensive Care Unit (NEJM, 2022) [MEDLINE]: n = 872
    • Intravenous Vitamin C Increased the Mortality Rate and Risk of Persistent Organ Dysfunction at Day 28, as Compared to Placebo

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, Vitamin C Therapy is Not Recommended (Weak Recommendation, Low Quality of Evidence)

Glycemic Control

Clinical Efficacy

  • Belgian Leuven Medical Trial Examining Intensive Insulin Therapy (NEJM, 2006) [MEDLINE]
    • Mean Blood Glucose was Lower in the Intensive Insulin Therapy Group, as Compared to the Conventional Group
    • Intensive Insulin Therapy Decreased ICU Length of Stay, Hospital Length of Stay, Duration of Mechanical Ventilation, and Acute Kidney Injury
    • Intensive Insulin Therapy Significantly Decreased Morbidity, But Not Mortality in the Medical ICU
    • Hypoglycemia was More Common in the Intensive Insulin Therapy Group
  • Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) Trial of Intensive Insulin Therapy and Pentastarch in Severe Sepsis (NEJM, 2008) [MEDLINE]
    • Mean Morning Blood Glucose was Lower in the Intensive Insulin Therapy Group
    • Hypoglycemia was More Frequent in the Intensive Insulin Therapy Group
    • Intensive Insulin Therapy Did Not Improve the 28-Day Mortality Rate, 90-Day Mortality Rate, Morbidity, or Risk of Organ Failure
  • Glucontrol Trial of Intensive Insulin Therapy in Critically Ill Medical/Surgical ICU Patients (Intensive Care Med, 2009) [MEDLINE]
    • Trial was Terminated Early Due to High Frequency of Unintended Protocol Violations
    • Intensive Insulin Therapy Increased the Rate of Hypoglycemia
    • Intensive Insulin Therapy Did Not Improve the Mortality Rate: there was a non-significant trend toward increased 28-day mortality rare and hospital mortality rate
  • Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation (NICE-SUGAR) Trial Examining Intensive Insulin Therapy in Critically Ill Medical/Surgical ICU Patients (NEJM, 2009) [MEDLINE]
    • Intensive insulin Therapy Group Had Lower Time-Weighted Blood Glucose
    • Intensive insulin Therapy Group Had an Increased 90-Day Mortality Rate
    • Intensive insulin Therapy Group Had a Higher Incidence of Hypoglycemia
    • In the Subgroup of Operative Patients, Intensive insulin Therapy Increased Mortality Rate
  • Meta-Analysis of Intensive Insulin Therapy in Medical/Surgical ICU Patients (CMAJ, 2009) [MEDLINE]
    • Intensive Insulin Therapy Had No Mortality Benefit: although patients in surgical ICU’s appeared to benefit more from intensive insulin therapy
    • Intensive Insulin Therapy Significantly Increased the Risk of Hypoglycemia
  • Corticosteroid Treatment and Intensive insulin Therapy for Septic Shock (COIITSS) (JAMA, 2010) [MEDLINE]
    • Intensive insulin Therapy Did Not Improve Mortality in Patients Treated with Hydrocortisone for Septic Shock
    • No Difference in ICU Length of Stay, Ventilator-Free Days, or Vasopressor-Free Days
  • Systematic Review Examining the Effect of Intensive Insulin Therapy on Outcome in Hospitalized Patients (Ann Intern Med. 2011) [MEDLINE]
    • Trials Differed with Regard to Target Glucose Levels, Achieved Glucose Levels, Intensive Insulin Therapy Protocols, and Medical Settings: however, there was no statistical heterogeneity across the trials
    • No Short-Term (28-Day Hospital or ICU), 90-Day, or 180-Day Mortality Benefit with Intensive Insulin Therapy (Glucose 80-180 mg/dL)

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, Initiating Insulin Therapy at a Glucose Level of ≥ 180mg/dL is Recommended (10 mmol/L) (Strong Recommendation, Moderate Quality of Evidence)
    • Following Initiation of Insulin Therapy, Typical Target Blood Glucose Range is 144−180 mg/dL
    • Blood Glucose Should Be Monitored Every 1-2 hrs Until Insulin Infusions Rates and Glucose Values are Stable, Then Every 4 hrs Thereafter
    • Blood Glucose Values Obtained with Point-of-Care Testing Should Be Interpreted with Caution as These Values May Not Reflect Arterial Blood or Plasma Glucose Values
      • While Both the US FDA and Centers for Medicare and Medicaid Services (CMS) Have Advocated Prohibiting Using Point-of-Care Glucose Testing in Critically Ill Patients, Experts Have Suggested that This Recommendation Be Postponed (Due to the Potential Harm Which Could Result from Utilizing Laboratory Blood Glucose Testing with Slower Processing Times)
    • Arterial Blood Glucose Values are Suggested Over Point-of-Care Glucose Values in Patients with Arterial Lines

Anemia Management (see Anemia)

Rationale

  • No Specific Hematocrit Has Been Documented to Improve Any Clinical Factor or Outcome in Sepsis

Adverse Effects of Packed Red Blood Cell (PRBC) Transfusion (see Packed Red Blood Cells)

Clinical Efficacy-Erythropoietin (see Erythropoietin)

  • Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Erythropoietin in Critical Illness (Crit Care Med 1999) [MEDLINE]
    • Erythropoietin Did Not Impact the Mortality Rate
    • Erythropoietin Increased the Hematocrit and Decreased the Number of Units of Packed Red Blood Cells Required
  • Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Erythropoietin in Critical Illness (JAMA 2002) [MEDLINE]
    • Weekly Erythropoietin Did Not Impact the Mortality Rate
    • Weekly Erythropoietin Increased the Hematocrit and Decreased the Number of Units of Red Blood Cells Required
  • Meta-Analysis of the Effect of Erythropoietin on Acute Kidney Injury in the Setting of Critical Illness (J Cardiovasc Pharmacol, 2015) [MEDLINE]
    • Prophylactic Erythropoietin Did Not Prevent Acute Kidney Injury, Decrease the Requirement for Hemodialysis, or Impact the Mortality Rate in Critical Illness or in the Setting of Perioperative Care

Clinical Efficacy-Packed Red Blood Cell (PRBC) Transfusion (see Packed Red Blood Cells)

  • Canadian Critical Care Trials Group Transfusion Requirements in Critical Care (TRICC) Trial (NEJM, 1999) [MEDLINE]: trial comparing transfusion cut-offs of Hb 7g/dL vs 10 g/dL (trial excluded: acute myocardial infarction and unstable angina)
    • No Overall Difference in 30-Day Mortality: however, less acutely ill (APACHE score of ≤20) and <55 y/o groups had lower mortality rates with the restrictive transfusion strategy
    • Restrictive Transfusion Strategy Utilizing a Threshold Hemoglobin of 7 g/dL Decreased the Hospital Mortality Rate
  • Rivers Early Goal-Directed Therapy Trial (NEJM, 2001) [MEDLINE]
    • Resuscitation Protocol Used in the Trial Maintained Hematocrit ≥30%
    • Early Goal-Directed Therapy (Used for First 6 hrs of ED Care) Decreased 28-Day Mortality in Severe Sepsis and Septic Shock
  • Transfusion Requirements in Septic Shock (TRISS) Trial (NEJM, 2014) [MEDLINE]: Danish multi-center RCT (n = 998) comparing hemoglobin of 7 g/dL vs 9 g/dL in septic shock (trial excluded: acute myocardial ischemia, acute burn injury, previous PRBC transfusion, and acute life-threatening bleeding) -> primary outcome: 90-day mortality
    • No Difference in Mortality (and Rates of Ischemic Events, Transfusion Reactions, and Use of Life Support) Between the 7 g/dL and 9 g/dL Hemoglobin Groups: however, the 7 g/dL hemoglobin group had lower PRBC utilization
  • Protocolized Care for Early Septic Shock (PROCESS) Trial (NEJM, 2014) [MEDLINE]: tertiary care, multi-center trial (n = 1,341) from 2008-2013 -> 439 were randomly assigned to protocol-based early goal-directed therapy (transfusion threshold hematocrit >10 g/dL when the ScvO2 was <70% after the initial resuscitation), 446 to protocol-based standard therapy (transfusion threshold hemoglobin >7.5 g/dL when the ScvO2 was <70% after the initial resuscitation), and 456 to usual care
    • With Diagnosis of Sepsis in the ED, Protocol-Based Resuscitation Did Not Improve In-Hospital Mortality to 60-days or 1-Year Mortality Rate: importantly, the PROCESS trial was designed more to directly assess protocolized resuscitation, rather than tranfusion thresholds, but the use of a threshold for packed red blood cell transfusion does not support a higher transfusion threshold of 10 g/dL
  • Australasian Resuscitation in Sepsis Evaluation (ARISE) Trial (NEJM, 2014) [MEDLINE]: multi-center RCT in Australia/New Zealand (n = 1600)
    • Resuscitation Protocol Used in the Trial Targeted a Hematocrit ≥30% (Similar to the 2001 Rivers Trial)
    • With Diagnosis of Septic Shock in the ED, Early Goal-Directed Therapy Had No Impact on 90-day Mortality (18.6% mortality), as Compared to Usual Care (18.8% Mortality)
    • No Significant Differences in Survival Time, In-Hospital Mortality, Duration of Organ Support, or Length of Hospital Stay Between the Groups

Recommendations in Hemodynamically Stable Adults and Children (American Association of Blood Banks, AABB) (Ann Intern Med, 2012)[MEDLINE]

  • Restrictive Transfusion Strategy (Hemoglobin 7-8 g/dL) is Recommended in Hospitalized, Stable Patients (Grade: Strong Recommendation, High-Quality Evidence)
  • Restrictive Transfusion Strategy (Hemoglobin 7-8 g/dL) is Recommended in Hospitalized Patients with Preexisting Cardiovascular Disease (Grade: Weak Recommendation, Moderate-Quality Evidence)
    • Consider Transfusion for Patients with Symptoms or a Hemoglobin ≤8 g/dL (Grade: Weak Recommendation, Moderate-Quality Evidence)
  • No Recommendation for or Against a Liberal or Restrictive Transfusion Threshold for Hospitalized, Hemodynamically Stable Patients with Acute Coronary Syndrome (Grade: Uncertain Recommendation, Very Low-Quality Evidence)
  • Transfusion Decisions Should Be Influenced by Symptoms as Well as Hemoglobin Concentration (Grade: Weak Recommendation. Low-Quality Evidence)

Recommendations in Critically Ill Adults (British Journal of Hematology Guidelines) (Br J Haematol, 2013) [MEDLINE]

  • Transfusion Triggers
    • A Transfusion Threshold of ≤7 g/dL, with a target Hemoglobin Range of 7-9 g/dL, Should Be the Default for All Critically Ill Patients, Unless Specific Comorbidities or Acute Illness-Related Factors Modify Clinical Decision-Making (Grade 1B)
    • Transfusion Triggers Should Not Exceed 9 g/dL in Most Critically Ill Patients (Grade 1B)
  • Alternatives to Red Blood Cell Transfusion
    • Erythropoietin Should Not Be Used to Treat Anemia in Critically Ill Patients Until Further Safety and Efficacy Data are Available (Grade 1B)
    • In the Absence of Clear Evidence of Iron Deficiency, Routine Iron Supplementation is Not Recommended During Critical Illness (Grade 2D)
  • Blood Sampling Techniques to Decrease Iatrogenic Blood Loss
    • The Introduction of Blood Conservation Sampling Devices Should Be Considered to Decrease Phlebotomy-Associated Blood Loss (Grade 1C)
    • Pediatric Blood Sampling Tubes Should Be Considered for Decreasing Iatrogenic Blood Loss (Grade 2C)
  • Transfusion-Associated Circulatory Overload (TACO and Transfusion-Related Acute Lung Injury (TRALI) (see Transfusion-Related Acute Lung Injury)
    • Pre-Transfusion Clinical Assessment Should Be Undertaken Including Assessment of Concomitant Medical Conditions Which Increase the Risk of TACO (Congestive Heart Failure, Kidney Disease, Hypoalbuminemia, Fluid Overload) (Grade 1D)
    • Attention to the Rate of Transfusion Together with Careful Fluid Balance and Appropriate Use of Diuretics Can Decrease the Risk of TACO (Grade 1D)
    • Patients Developing Acute Dyspnoea with Hypoxemia and Bilateral Pulmonary Infiltrates During or within 6 hrs of Transfusion Should Be Carefully Assessed for the Probability of TRALI and Patients Should Be Admitted to a Critical Care Area for Supportive Care (Grade 1D)
    • Any Adverse Events or Reactions Related to Transfusion Should Be Appropriately Investigated and Reported Via Systems for Local Risk Management, and Also to National Hemovigilance Schemes (Grade 1D)
  • Red Blood Cell Storage Duration
    • The Evidence Base is Insufficient to Support the Routine Administration of “Fresher Blood” to Critically Ill Patients (Grade 2B)
  • Critically Ill Patients with Sepsis
    • In the Early Resuscitation Phase in Patients with Severe Sepsis, if There is Clear Evidence of Inadequate Oxygen Delivery, Transfusion of Red Blood Cells to a Target Hemoglobin of 9-10 g/dL Should Be Considered (Grade 2C)
    • During the Later Stages of Severe Sepsis, a Conservative Approach to Transfusion Should Be Followed with a Target Hemoglobin of 7-9 g/ldL(Grade 1B)
  • Weaning from Mechanical Ventilation (see Invasive Mechanical Ventilation-Weaning)
    • Red Cell Transfusion Should Not Be Used as a Strategy to Assist Weaning from Mechanical Ventilation When the Hemoglobin is >7 g/dL (Grade 2D)
  • Ischemic Heart Disease (see Coronary Artery Disease)
    • Anaemic Critically Ill Patients with Stable Angina Should Have a Hemoglobin Maintained >7 g/dL, But Transfusion to a Hemoglobin >10 g/dL has Uncertain Benefit (Grade 2B)
    • In Patients Suffering from Acute Coronary Syndrome the Hemoglobin Should Be Maintained at >8–9 g/dL (Grade 2C)
  • Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident)
    • In Patients Presenting to the ICU with an Acute ischemic Stroke the Hemoglobin Should Be Maintained >9 g/dL (Grade 2D)
  • Traumatic Brain Injury (TBI) (see Traumatic Brain Injury)
    • In Patients with TBI, the Target Hemoglobin should be 7–9 g/dL (Grade 2D)
    • In Patients with TBI and Evidence of Cerebral ischemia. the Target Hemoglobin should be >9 g/dL (Grade 2D)
  • Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage)
    • In Patients with SAH, the Target Hemoglobin Should Be 8-10 g/dL (Grade 2D)

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

  • Erythropoietin is Not Recommended to Treat Anemia Associated with Sepsis (Strong Recommendation, Moderate Quality of Evidence)
    • Erythropoietin May Increase the Risk of a Hypercoagulable State

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 Use of Restrictive Red Blood Cell Transfusion Strategy is Recommended Over a Liberal Red Blood Cell Transfusion Strategy (Strong Recommendation, Moderate Quality of Evidence)
    • Restrictive Packed Red Blood Cell Transfusion Strategy Typically Includes a Hemoglobin Transfusion Trigger of 7.0 mg/dL
      • However, Red Blood Cell Transfusion Should Be Guided by the Hemoglobin Concentration, as Well the Patient’s Overall Clinical Status (Including Acute Myocardial Ischemia, Severe Hypoxemia, Acute Hemorrhage, etc)

Fresh Frozen Plasma (FFP) Transfusion (see Fresh Frozen Plasma)

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

  • Fresh Frozen Plasma is Not Recommended to Correct Coagulopathy in the Absence of Bleeding or Planned Invasive Procedures (Weak Recommendation, Very Low Quality of Evidence)

Platelet Transfusion (see Platelet Transfusion)

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

  • Platelet Transfusion Threshold of 10k/mm3 is Recommended in the Absence of Bleeding (Weak Recommendation, Very Low Quality of Evidence
  • Platelet Transfusion Threshold of 20k/mm3 is Recommended if the Patient Has Significant Risk of Bleeding (Weak Recommendation, Very Low Quality of Evidence
  • Platelet Transfusion Threshold of <50k/mm3 is Recommended in the Presence of Active Bleeding or Prior to Surgery/Invasive Procedures (Weak Recommendation, Very Low Quality of Evidence

Deep Venous Thrombosis (DVT) Prophylaxis (see Deep Venous Thrombosis)

Agents

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

  • When Pharmacologic Deep Venous Thrombosis Prophylaxis is Contraindicated, Mechanical Prophylaxis is Recommended (Weak Recommendation, Low Quality of Evidence)

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, Pharmacologic Deep Venous Thrombosis Prophylaxis is Recommended (Unless a Contraindication Exists) (Strong Recommendation, Moderate Quality of Evidence)
    • For Adults with Sepsis/Septic Shock, Low Molecular Weight Heparin is Recommended Over Unfractionated Heparin for Deep Venous Thrombosis Prophylaxis (Strong Recommendation, Moderate Quality of Evidence)
    • For Adults with Sepsis/Septic Shock, Mechanical Deep Venous Thrombosis Prophylaxis is Not Recommended in Addition to Pharmacological Prophylaxis (Strong Recommendation, Low Quality of Evidence)

Nutritional Support

Clinical Efficacy

  • Meta-Analysis and Systematic Review of Prokinetic Agents in Critically Ill Patients Receiving Enteral Nutrition (Crit Care, 2016) [MEDLINE]
    • Prokinetic Agents Decrease Feeding Intolerance in Critically Ill Patients, as Compared to Placebo or No Intervention
    • However, the Impact of Prokinetic Agents on Other Outcomes (Such as Pneumonia, Mortality, and ICU Length of Stay is Unclear

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

  • Early Initiation of Enteral Feeding (Rather than Fasting or Glucose-Containing Intravenous Fluids) is Recommended in Critically ill Patients with Sepsis/Septic Shock Who Can Be Fed Enterally (Weak Recommendation, Low Quality of Evidence)
    • At Least Early Trophic Enteral Feeding is Recommended in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Moderate Quality of Evidence): enteral feeding should then be advanced, as tolerated
  • Early Total Parenteral Nutrition (TPN) (Alone or in Combination with Enteral Nutrition) is Not Recommended in Patients with Sepsis/Septic Shock Who Can Be Fed Enterally (Strong Recommendation, Moderate Quality of Evidence)
    • TPN is Not Recommended (Alone or in Combination with Enteral Nutrition) Over the First 7 Days in Patients with Sepsis/Septic Shock in Whom Enteral Feeding is Not Feasible (Strong Recommendation, Moderate Quality of Evidence): alternatively, glucose-containing intravenous fluids with attempts to advance the enteral feeding are instead recommended
  • Mechanical Aspects of Enteral Nutrition
    • Placement of Post-Pyloric Feeding Tube is Recommended in Critically ill Patients with Sepsis/Septic Shock Who at High Risk for Aspiration (Weak Recommendation, Low Quality of Evidence)
    • Prokinetic Agents (Metoclopramide, Erythromycin, Domperidone) are Recommended in Critically ill Patients with Sepsis/Septic Shock and Feeding Intolerance (Weak Recommendation, Low Quality of Evidence): feeding intolerance is defined as vomiting, aspiration of gastric contents, or high gastric residual volumes
    • Routine Monitoring of Gastric Residual Volumes are Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence): this recommendation is in accord with that of the Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN) (J Parenter Enteral Nutr, 2016) [MEDLINE]
      • However, Gastric Residual Volumes are Suggested in Patients Who are at High Risk for Aspiration (Weak Recommendation, Very Low Quality of Evidence): this recommendation is in accord with that of the Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN) (J Parenter Enteral Nutr, 2016) [MEDLINE]
  • Supplements
    • Omega-3 Fatty Acids are Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Strong Recommendation, Low Quality of Evidence)
    • Intravenous Selenium is Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Strong Recommendation, Moderate Quality of Evidence)
    • Arginine is Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence)
    • Glutamine is Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Strng Recommendation, Moderate Quality of Evidence)
    • No Recommendation is Made Regarding the Use of Carnitine in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence)

Recommendations for Enteral Nutrition in the Setting of Hemodynamic Instability (Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN, 2016 Guidelines) [MEDLINE]

  • Tube Feedings Should Be Withheld Until the Patient is Fully Resuscitated and/or Stable (Quality of Evidence: Expert Consensus)

Recommendations for Enteral Nutrition in the Setting of Sepsis (Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN, 2016 Guidelines) [MEDLINE]

  • Use of Exclusive/Supplemental Parenteral Nutrition are Not Recommended in the Acute Phase of Sepsis, Regardless of Degree of Nutrition Risk (Quality of Evidence: Very Low)
  • Benefits of Use of Selenium, Zinc, and Antioxidants in Sepsis are Unclear (Quality of Evidence: Moderate)
  • Immune Modulating Formulations are Not Recommended in Sepsis (Quality of Evidence: Moderate)

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

  • For Adult Patients with Sepsis/Septic Shock Who Can Be Fed Enterally, Early Initiation of Enteral Nutrition (within 72 hrs) is Recommended (Weak Recommendation, Very Low Quality of Evidence)

Renal Support

Clinical Efficacy

  • Systematic Review of Continuous vs Intermittent Renal Hemodialysis in the Intensive Care Unit (Am J Kidney Dis, 2002) [MEDLINE]
    • In Comparison to Intermittent Renal Replacement Therapy, Continuous Renal Replacement Therapy Does Not Improve Survival or Renal Recovery in Unselected Critically Ill Patients with Acute Kidney Injury
  • Meta-Analysis of Intermittent vs Continuous Renal Replacement Therapy in Critically Ill Patients (Intensive Care Med, 2002) [MEDLINE]
    • Overall, There was No Difference in Mortality Between Intermittent and Continuous Renal Replacement Therapy in Critically Ill Patients
    • However, After Adjusting for Study Quality and Severity of Illness, Continuous Renal Replacement Therapy Had a Lower Mortality Rate (Relative Risk 0.72)
  • French IDEAL-ICU Trial of Timing of Renal Replacement Therapy in Patients with Acute Kidney Injury Associated with Septic Shock (NEJM, 2018) [MEDLINE]
    • Early Renal Replacement Therapy Strategy Did Not Decrease the 90-Day Mortality Rate, as Compared to Delayed Strategy

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

  • In Adults with Sepsis/Septic Shock and Acute Kidney Injury, Renal Replacement Therapy Should Not Be Used in the Absence of Indications for Hemodialysis (Weak Recommendation, Moderate Quality of Evidence)
  • In Adults with Sepsis/Septic Shock and Acute Kidney Injury, Either Continuous Renal Replacement Therapy (CRRT) or Intermittent Renal Replacement Therapy are Recommended (Weak Recommendation, Low Quality of Evidence)
    • Continuous Renal Replacement Therapy is Suggested to Facilitate Management of Fluid Balance in Hemodynamically Unstable Patients

Respiratory Support (see Acute Respiratory Distress Syndrome)

Clinical Efficacy

  • Italian Oxygen-ICU Trial of Conventional Oxygen Strategy (pO2 Up to 150 mm Hg or SaO2 97-100%) vs Conservative Oxygen Strategy (pO70-100 or SaO2 94-98%) in a General ICU Population (Stay of ≥72 hrs) (JAMA, 2016) [MEDLINE]: trial had unplanned, early termination
    • Conservative Oxygen Strategy Decreased the Mortality Rate in a General ICU Population, as Compared to the Conventional Oxygen Strategy
  • Improving Oxygen Therapy in Acute-illness (IOTA) Systematic Review and Meta-Analysis of Conservative vs Liberal Oxygen Strategy in Critically Ill Patients (Lancet, 2018) [MEDLINE]: n = 25 trials (in patients with sepsis, critical illness, stroke, trauma, myocardial infarction, cardiac arrest, and emergency surgery)
    • In Acutely Ill Adults, Liberal Oxygen Therapy Strategy (Median SaO2 96%, Range 94-99%) Increases the 30-Day (and Longest Follow-Up) Mortality Rate, as Compared to a Conservative Oxygen Therapy Strategy (Relative Risk at 30 Days was 1.21, 95% CI 1.03-1.43)
      • Supplemental Oxygen Might Become Unfavorable with SaO2 >94-96%

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

  • β2-Agonist Bronchodilators (see β2-Adrenergic Receptor Agonists)
    • In the Absence of Bronchospasm, β2-Agonists are Not Recommended in Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, Moderate Quality of Evidence)
  • Fluid Management in Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)
    • Conservative Fluid Management Strategy is Recommended in Established Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) in the Absence of Tissue Hypoperfusion (Strong Recommendation, Moderate Quality of Evidence)
  • Head of the Bed Elevation
    • Elevation of the Head of the Bed to 30-45 Degrees is Recommended to Limit the Aspiration Risk and to Prevent the Development of Ventilator-Associated Pneumonia (VAP) During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation, Low Quality of Evidence)
  • Lung-Protective Mechanical Ventilation (see Invasive Mechanical Ventilation-General)
    • Respiratory Rate Should Be ≤35 Breaths/min: recognizing that some patients may experience hypercapnia (hypercapnia is generally well-tolerated in the absence of contraindications, such as increased intracranial pressure, sickle cell crisis, etc)
  • Invasive Mechanical Ventilation Mode
    • No Ventilator Mode is Recommended Over Another
    • However, High-Frequency Oscillation Ventilation is Not Recommended in Adult Patients with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, Moderate Quality of Evidence) (see High-Frequency Ventilation)
  • Sedation (see Sedation and Neuromuscular Junction Antagonists)
    • Continuous or Intermittent Sedation Should Be Minimized (with Specific Sedation Endpoints) in Sepsis-Associated Mechanically-Ventilated Respiratory Failure (Best Practice Statement)
  • Weaning (see Ventilator Weaning)
    • Spontaneous Breathing Trials (When Specific Criteria are Met) are Recommended in Sepsis-Associated Respiratory Failure (Strong Recommendation, High Quality of Evidence)
    • Weaning Protocol is Recommended for Appropriate Patients During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation)
  • Swan-Ganz Catheter (see Swan-Ganz Catheter)
    • Swan-Ganz Catheter is Not Routinely Recommended in the Management of Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, High Quality of Evidence)

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

  • Supplemental Oxygen (see Oxygen)
    • In Adults with Sepsis-Induced Hypoxemic Respiratory Failure, There is Insufficient Evidence to Make a Recommendation Regarding the Use of Conservative Oxygen Targets (No Recommendation)
    • In Adults with Sepsis-Induced Hypoxemic Respiratory failure, High-Flow Nasal Cannula (HFNC) Oxygen is Recommended Over Noninvasive Positive-Pressure Ventilation (Weak Recommendation, Low Quality of Evidence)
  • Noninvasive Positive-Pressure Ventilation (NIPPV) (see Noninvasive Positive-Pressure Ventilation)
    • In Adults with Sepsis-Induced Hypoxemic Respiratory Failure, There is Insufficient Evidence to Make a Recommendation Regarding the Use of Noninvasive Positive-Pressure Ventilation in Comparison to Invasive Mechanical Ventilation (No Recommendation)
  • Invasive Mechanical Ventilation (see Invasive Mechanical Ventilation-General)
    • Tidal Volume
      • For Adults with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Low Tidal Volume Ventilation (6 mL/kg) is Recommended Over a High Tidal Volume Ventilation (> 10 mL/kg) (Strong Recommendation, High Quality Evidence)
      • For Adults with Sepsis-Associated Respiratory Failure without Acute Respiratory Distress Syndrome (ARDS), Low Tidal Volume Ventilation (6 mL/kg) is Recommended Over a High Tidal Volume Ventilation (> 10 mL/kg) (Weak Recommendation, Low Quality Evidence)
    • Plateau Pressure
      • For Adults with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Maintenance of the Plateau Pressure <30 cm H2O is Recommended (Strong Recommendation, Moderate Quality Evidence)
    • Positive End-Expiratory Pressure (PEEP)
      • For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Higher PEEP is Recommended Over Use of Lower PEEP (Weak Recommendation, Moderate Quality Evidence)
        • The Optimal Method for Selecting PEEP is Unclear (Titrating PEEP Upward on a Tidal Volume of 6 mL/kg Until Plateau Pressure is 28 cm H20, Titrating PEEP to Optimize Thoracoabdominal Compliance with the Lowest Driving Pressure, Titrating PEEP Based on Decreasing the FIO2 to Maintain Oxygenation, etc)
    • Recruitment Maneuvers
      • For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Recruitment Maneuvers is Recommended (Weak Recommendation, Moderate Quality Evidence)
      • When Using Recruitment Maneuvers, Use of Incremental PEEP Titration/Strategy is Not Recommended (Strong Recommendation, Moderate Quality Evidence)
    • Prone Ventilation
      • For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) and pO2/FIO2 Ratio <150, Use of Prone Ventilation for >12 hrs Daily is Recommended (Strong Recommendation, Moderate Quality Evidence)
  • Pharmacologic Paralysis (see Neuromuscular Junction Antagonists)
    • For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Intermittent Neuromuscular Junction Antagonist Boluses is Recommended Over Neuromuscular Junction Antagonist Continuous Infusion (Weak Recommendation, Moderate Quality Evidence)
  • Venovenous Extracorporeal Membrane Oxygenation (VV-EMCO) (see Venovenous Extracorporeal Membrane Oxygenation)
    • For Adults with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) When Conventional Invasive Mechanical Ventilation Fails is Recommended for Use in Experienced Centers with Adequate Infrastructure (Weak Recommendation, Low Quality Evidence)

Stress Ulcer Prophylaxis (see Peptic Ulcer Disease)

Clinical Efficacy

  • Systematic Review and Meta-Analysis of Stress Ulcer Prophylaxis in Critically Ill Patients (Intensive Care Med, 2014) [MEDLINE]
    • Both the Quality and the Quantity of Evidence Supporting the Use of Stress Ulcer Prophylaxis in Adult ICU Patients is Low
    • Moderate Quality Evidence Indicated that Stress Ulcer Prophylaxis (with Either PPI or H2-Blockers) Significantly Decreased the Risk of Gastrointestinal Bleeding in Critically Ill Patients (Relative Risk 0.44)
    • Low Quality Evidence Suggested that Stress Ulcer Prophylaxis Non-Significantly Increased the Risk of Pneumonia (Relative Risk 1.23)

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 Risk Factors for Gastrointestinal Hemorrhage, Stress Ulcer Prophylaxis is Recommended (Weak Recommendation, Moderate Quality Evidence

Other Agents without Defined Efficacy in Sepsis

Antithrombin III (see Antithrombin III)

  • Rationale
    • Antithrombin is the Most Abundant Anticoagulant Circulating in the Plasma
      • An Observed Decrease in Antithrombin Activity Early in the Course of Sepsis and is Correlated with the Occurrence of Disseminated Intravascular Coagulation (DIC) and Poor Outcome
  • Clinical Efficacy
    • Systematic Review of Antithrombin III in Critical Illness (Cochrane Database Syst Rev, 2016) [MEDLINE]
      • Antithrombin III Had No Impact on the Mortality Rate in Sepsis, But Increased the Risk of Bleeding
  • Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
    • Antithrombin is Not Recommended in Sepsis/Septic Shock (Strong Recommendation, Moderate Quality of Evidence)

Blood Purification

  • Techniques
    • High-Volume Hemofiltration or Hemoadsorption (Hemoperfusion): sorbents remove either endotoxin or cytokines
    • Plasma Exchange or Plasma Filtration: plasma is separated from whole blood, removed, and replaced wth either normal saline, albumin, or fresh frozen plasma
    • Hybrid System: coupled plasma filtration adsorption (CPFA), which combines plasma filtration and adsorption (by a resin cartridge which removes cytokines)
  • 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, Polymyxin B Hemoperfusion is Not Recommended (Weak Recommendation, Low Quality of Evidence)
    • There is Insufficient Evidence to Make a Recommendation Regarding the Use of Other Blood Purification Techniques (No Recommendation)

Drotrecogin Alfa (Xigris) (see Drotrecogin Alfa

  • Clinical Efficacy
    • PROWESS-SHOCK Trial (NEJM, 2012) [MEDLINE]
      • Drotecogin Alfa (Activated Protein C) Had No Impact on 28-Day or 90-Day Mortality (or Difference in Bleeding Risk) in Septic Shock: Drotecogin Alfa was pulled from the worldwide market on 10/25/11

Eritoran (see Eritoran)

  • Clinical Efficacy
    • ACCESS Trial of Eritoran in Sepsis (JAMA, 2013) [MEDLINE]
      • Eritoran (a Synthetic Lipid A Antagonist Which Blocks Lipopolysaccharide from Binding at the Cell Surface MD2-TLR4 receptor) Had No Impact on 28-Day Mortality in Sepsis

Heparin (see Heparin)

  • Clinical Efficacy
    • Systematic Review and Meta-Analysis of Heparin in Sepsis (Crit Care Med, 2015) [MEDLINE]
      • Unclear if Heparin Decreases the Mortality Rate in Sepsis: further trials are required
  • Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
    • No Recommendation Regarding the Use of Heparin in Sepsis/Septic Shock

Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin)

  • Clinical Efficacy
    • SBITS Study of Intravenous Immunoglobulin G in Sepsis (Crit Care Med, 2007) [MEDLINE]
      • Intravenous Immunoglobulin Did Not Impact the Mortality Rate in Sepsis
    • Systematic Review of Intravenous Immunoglobulin in Sepsis (Cochrane Database Syst Rev 2013) [MEDLINE]
      • Polyclonal Intravenous Immunoglobulin Decreased Mortality in Adults with Sepsis, But This Benefit was Not Observed in Trials with a Low Risk of Bias
      • IgM-Enriched Intravenous Immunoglobulin Trials Were Small and Evidence is Inconclusive
      • Monoclonal Intravenous Immunoglobulin Remains Experimental
  • 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, Intravenous Immunoglobulin is Not Recommended (Weak Recommendation, Low Quality Evidence)

Thrombomodulin (see Thrombomodulin)

  • Rationale
    • Thrombomodulin Trials Have Been Performed Predominantly for Sepsis with Disseminated Intravascular Coagulation (DIC)
  • Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
    • No Recommendation Regarding the Use of Thrombomodulin in Sepsis/Septic Shock

Vilobelimab (see Vilobelimab)

  • Rationale
    • Monoclonal Anti-C5a Antibody

Prognosis

General

  • Australia/New Zealand Study of Severe Sepsis and Septic Shock Mortality Rates (JAMA 2014) [MEDLINE]
    • From 2000 to 2012, there was a Decrease in the Absolute Sepsis Mortality Rate from 35.0% (95% CI, 33.2%-36.8%; 949/2708) to 18.4% (95% CI, 17.8%-19.0%; 2300/12,512; P <0.001)
  • Systematic Review of the Global Incidence and Mortality of Sepsis (Am J Respir Crit Care Med, 2016) [MEDLINE]
    • In Articles Restricted to the Last 10 Years, Incidence Rate was 437/100k for Sepsis and 270/100k for Severe Sepsis
    • In Articles Restricted to the Last 10 Years, Hospital Mortality Rate was 17% for Sepsis and 26% for Severe Sepsis
  • Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3: Society of Critical Care Medicine and European Society of Intensive Care Medicine) (JAMA, 2016) [MEDLINE]
    • Sepsis Mortality Rate: 10%
    • Septic Shock Mortality Rate: >40%

Prognostic Value of Sepsis Scoring Systems

  • Study of SIRS Criteria in Defining Severe Sepsis (NEJM, 2015) [MEDLINE]
    • Sepsis Mortality Rate Increases Linearly with the Sepsis Disease Severity
  • Australian/New Zealand Retrospective Cohort Analysis Examining the Accuracy of Sepsis Scoring Criteria in Predicting In-Hospital Mortality of Patients with Suspected Infection Admitted to the Intensive Care Unit (JAMA, 2017) [MEDLINE]: n = 184,875
    • Most Common Diagnosis was Bacterial Pneumonia (Accounted for 17.7% of Cases)
    • Overall, 18.7% of Patients Died in the Hospital
    • Increase in SOFA Score of ≥2 Had Greater Prognostic Accuracy for In-Hospital Mortality than SIRS Criteria or qSOFA Score
  • Systematic Review and Meta-Analysis of Sepsis Scoring with Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality (Chest, 2018) [MEDLINE]: n = 229,480 patients (from 10 studies)
    • SIRS Criteria were Significantly Superior to the qSOFA for the Diagnosis of Sepsis
      • Meta-Analysis of Sensitivity for the Diagnosis of Sepsis Comparing the qSOFA Criteria and SIRS Criteria was in Favor of SIRS Criteria (risk ratio [RR], 1.32; 95% CI, 0.40-2.24; P < .0001; I2 = 100%)
    • qSOFA Criteria were Slightly Better than the SIRS Criteria in Predicting Hospital Mortality
      • Meta-Analysis of the Area Under the Receiver Operating Characteristic Curve of 6 Studies Comparing the qSOFA Criteria and SIRS Criteria Favored the qSOFA Criteria (RR, 0.03; 95% CI, 0.01-0.05; P = .002; I2 = 48%) as a Predictor of In-Hospital Mortality
  • Systematic Review/Meta-Analysis of the Prognostic Accuracy of qSOFA Scoring in Predicting Sepsis Mortality (Ann Intern Med, 2018) [MEDLINE]: n = 385, 333 (from 38 studies)
    • Overall, qSOFA Score Had Poor Sensitivity (60.8%) and Moderate Specificity (72.0%) for Predicting Short-Term (28-Day or 30-Day) Sepsis Mortality
      • Sensitivity of qSOFA in Predicting Sepsis Mortality was Higher in the ICU Population (87.2% [CI, 75.8%-93.7%]) than the non-ICU Population (51.2% [CI, 43.6%-58.7%])
      • Specificity of qSOFA in Predicting Sepsis Mortality was Higher in the Non-ICU Population (79.6% [CI, 73.3%-84.7%]) than the ICU Population (33.3% [CI, 23.8%-44.4%]
    • SIRS Criteria Had High Sensitivity (88.1%) and Low Specificity (25.8%) for Predicting Short-Term (28-Day or 30-Day) Sepsis Mortality

Poor Prognostic Factors

  • Atrial Fibrillation (see Atrial Fibrillation)
    • Study of New-Onset Atrial Fibrillation in Severe Sepsis (JAMA, 2011) [MEDLINE]
      • Patients with New-Onset AF and Severe Sepsis are at 4x Increased Risk of In-Hospital CVA and a 7% Increased Risk of Death, as Compared with Patients with No AF and Patients with Preexisting AF
      • Possible Mechanisms for Increased Risk of CVA in New-Onset AF in Severe Sepsis: new-onset AF might just be a marker for the sickest patients with greatest inherent CVA risk, sepsis itself might result in an increased risk for CVA (by hemodynamic collapse, coagulopathy, or systemic inflammation), or new-onset AF might be a source of cardioembolic CVA
      • Patients with Severe Sepsis Had a 6x Increased Risk of In-Hospital CVA, as Compared with Hospitalized Patients without Severe Sepsis
      • Patients with Severe Sepsis and Preexisting AF Did Not Have an Increased Risk of CVA, as Compared with Patients without AF
    • Prospective Observational Study of Atrial Fibrillation as a Predictor of Mortality in Critically Ill Patients (Crit Care Med, 2016) [MEDLINE]
      • AF in Critical Illness (Whether New-Onset or Recurrent) is Independently Associated with Increased Hospital Mortality (31% vs 17%), Especially in Patients without Sepsis
      • New-Onset AF (But Not Recurrent AF) was Associated with Increased Diastolic Dysfunction and Vasopressor Use and a Greater Cumulative Positive Fluid Balance
    • Dutch Cohort Study of the Incidence, Predictors, and Outcomes of New-Onset Atrial Fibrillation in Critically Ill Patients with Sepsis (Am J Respir Crit Care Med, 2017) [MEDLINE]
      • Atrial Fibrillation is a Common Complication of Sepsis and is Independently Associated with Excess Mortality
  • Cancer
    • Study of Hospitalized Patients with Cancer and Severe Sepsis (Crit Care, 2004) [MEDLINE]
      • Cancer Increases the Risk of Hospitalization with Severe Sepsis (Relative Risk 3.96)
      • As Compared with the General Population, Cancer Patients are Much More Likely to Be Hospitalized (Relative Risk, 2.77; 95% CI, 2.77-2.78) and to Be Hospitalized with Severe Sepsis (Relative Risk, 3.96; 95% CI, 3.94-3.99)
      • The In-Hospital Mortality Rate for Cancer Patients with Severe Sepsis was 37.8%
      • Sepsis is Associated with 8.5% of All Cancer Deaths at a Cost of $3.4 Billion Per Year
    • Study of Epidemiology of Sepsis in Patients with Cancer (Chest, 2006) [MEDLINE]
      • Patients with a History of Cancer are at Increased Risk for Acquiring and Dying from Sepsis, as Compared to the General Population: although incidence and fatality rates are decreasing over time
      • There are Significant Racial and Gender Disparities in the Incidence and Outcome of Sepsis Among Cancer Patients
  • Coagulopathy (see Coagulopathy)
    • Cohort Study of Coagulation in Severe Sepsis (Intensive Care Med, 2015) [MEDLINE]
      • Progressive Coagulopathy (as Defined by Thromboelastography Variables) was Associated with an Increased Risk of Death and Increased Risk of Hemorrhage
  • Delayed Antibiotic Therapy
    • Delayed Antibiotic Therapy is Associated with Increased Sepsis Mortality (Am J Med, 1980) [MEDLINE] and (Crit Care Med, 2011) [MEDLINE]
  • Ethanol Abuse (see Ethanol)
    • Study of the Impact of Ethanol Abuse on Sepsis Mortality (Crit Care Med, 2007) [MEDLINE]
      • Ethanol Dependence Increased the Risk of Sepsis, Septic Shock, and Organ Failure
      • Ethanol Dependence Increased Hospital Mortality in ICU Patients
  • Failure of Serum Procalcitonin to Decrease (see Serum Procalcitonin)
    • Prospective, Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study of Procalcitonin in Sepsis (Crit Care Med, 2017) [MEDLINE]
      • Inability to Decrease Serum Procalcitonin by >80% was a Significant Independent Predictor of Mortality
  • Hyperchloremia (see Hyperchloremia
    • Study of Effect of Hyperchloremia of Hospital Mortality in Critically Ill Sepsis Patients (Crit Care Med, 2015) [MEDLINE]
      • In Critically Ill Sepsis Patients, Hyperchloremia (Serum Cl ≥110 mEq/L) on ICU Admission, as Well as Higher Serum Chloride and within Subject Worsening of Hyperchloremia at 72 hrs of the ICU Stay were Associated with Increased All-Cause Hospital Mortality
        • The Associations were Independent of Base Deficit, Cumulative Fluid Balance, Acute Kidney Injury, and Other Critical Illness Parameters
  • Hyperglycemia (see Hyperglycemia)
    • Study of Admission Hyperglycemia in Critically Ill Sepsis Patients (Crit Care Med, 2016) [MEDLINE]
      • Admission Hyperglycemia was Associated with Adverse Sepsis Outcome of Irrespective of the Presence or Absence of Preexisting Diabetes Mellitus
        • Mechanism Appears to Be Unrelated to Exaggerated Inflammation or Coagulation
  • Hypothermia/Lack of Fever (Temperature <35.5 Degrees C)(see Fever)
    • Study of Sepsis Definitions (Chest, 1992) [MEDLINE]
      • Failure to Develop a Fever (Defined as a Temperature <35.5ºC) was More Frequent in Sepsis Non-Survivors (17%) than Sepsis Survivors (5%)
  • Immunosuppression
    • Study of Sepsis Mortality Risk Factors in Immunosuppressed Patients (Scand J Infect Dis, 2009) [MEDLINE]
      • Immunosuppressed Patients Had a Higher 28-Day Sepsis Mortality Rate, as Compared to Immunocompetent Patients (Adjusted Relative Risk 1.62, 95% CI 1.38-1.91)
        • Septic Shock, Hypothermia, Cancer and Invasive Fungal Infections were Associated with Increased Mortality in Immunosuppressed Patients
        • Black Race and the Presence of Rigors were Independent Predictors of Survival in Immunosuppressed Patients
    • Study of Immunologic Status in Sepsis and Septic Shock (Chest, 2014) [MEDLINE]
      • Immunodeficiency is Common in Severe Sepsis and Septic Shock
        • Non-Neutropenic Hematologic Malignancy
        • Non-Neutropenic Solid Tumor
        • Neutropenia (of Any Etiology)
      • Immunodeficiency is Associated with Increased Short-Term Mortality After Multivariate Analysis (Subdistribution Hazard Ratio, 1.37; 95% CI, 1.12-1.67)
      • AIDS (Subdistribution Hazard Ratio 1.9), Non-Neutropenic Solid Tumors (Subdistribution Hazard Ratio 1.8), Non-Neutropenic Hematologic Malignancy (Subdistribution Hazard Ratio 1.4), and Neutropenia (Subdistribution Hazard Ratio 1.7) were Associated with an Increased Risk of Death
  • Inadequate Sepsis Resuscitation
    • Inadequate Sepsis Resuscitation is Associated with Increased Sepsis Mortality (NEJM, 2001) [MEDLINE]
    • Severe Hyperlactatemia (>10 mmol/L) is Associated with Extremely High ICU Mortality (78.2%) in Sepsis, Especially When There is No Marked Lactate Clearance within 12 hrs (Intensive Care Med, 2016) [MEDLINE]
  • Leukopenia (see Leukopenia)
    • Study of Gram-Negative Bacteremia (Am J Med, 1980) [MEDLINE]
      • Leukopenia <4k was More Common in Non-Survivors (15%) than Non-Survivors (7%) in Gram-Negative Sepsis
  • Liver Disease (see Cirrhosis)
    • Study of the Impact of Ethanol Abuse on Sepsis Mortality (Crit Care Med, 2007) [MEDLINE]
      • Sepsis and Liver Disease were Associated with an Increased Mortality Rate for Alcohol-Dependent Patients, as Compared to Those without Alcohol Dependence
  • Non-Urinary Tract Site of Infection
    • Urinary Tract Site of Infection is Associated with Lower Sepsis Mortality Rate (30%), as Compared to Unknown/Gastrointestinal/Pulmonary Sources (50-55%) (J Infect Dis, 1983) [MEDLINE]
    • Ischemic Bowel Source of Infection is Associated with the Highest (78%) Sepsis Mortality Rate (Am J Respir Crit Care Med, 2014) [MEDLINE]
    • Urinary Tract is Associated with the Lowest (26%) Sepsis Mortality Rate (Am J Respir Crit Care Med, 2014) [MEDLINE]
  • Obesity (see Obesity)
    • Systematic Review of the Effect of Obesity on Sepsis Mortality (J Crit Care, 2015) [MEDLINE]: n = 7 studies
      • The Effect of Obesity on Sepsis Mortality Rate is Unclear
  • Older Age
    • Factors in Older Patients Which Contribute to Increased Sepsis Mortality Rates
      • Association of Sepsis with Comorbid Illness
      • Impaired Immunologic Response
      • Malnutrition
      • Increased Exposure to Multidrug-Resistant Pathogens (in Nursing Homes, etc)
      • Increased Utilization of Medical Devices (Intravenous/Arterial Catheter, Pacemaker, Joint Replacement, etc)
    • Age Independently Increases Both the Risk of Sepsis and the Mortality Rate Associated with Sepsis (Crit Care Med, 2006) [MEDLINE]
      • Elderly Patients Account for 12% of the US Population, But 65% of Sepsis Cases (Relative Risk 13.1, as Compared to Younger Patients)
      • Elderly Patients are More Likely to Have Gram-Negative Infections, Particularly in Association with Pneumonia (Relative Risk 1.66, as Compared to Younger Patients)
      • Case-Fatality Rates Increase Linearly with Age
      • Age is an Independent Predictor of Mortality (Odds Ratio 2.26)
      • Elderly Sepsis Patients Died Earlier During Hospitalization*
      • Elderly Survivors of Sepsis were More Likely to Be Discharged to a Non-Acute Health Care Facility
    • Australia/New Zealand Study of Severe Sepsis and Septic Shock Mortality Rates (JAMA 2014) [MEDLINE]
      • In Patients <44 y/o without Comorbidities, the Sepsis Mortality Rate was Far Lower (<10%)
  • Prior Antibiotic Therapy (in Patients with Gram-Negative Sepsis): likely due to increased risk of multidrug-resistant pathogens
    • Recent Antibiotic Exposure is Associated with Increased Hospital Mortality in Gram-Negative Bacteremia with Severe Sepsis or Septic Shock (Crit Care Med, 2011) [MEDLINE]
  • Specific Pathogens
    • Patients with Hospital-Acquired or Healthcare-Associated Bloodstream Infection Had Higher Sepsis Morbidity and Mortality than Community-Acquired Bloodstream Infection (Crit Care Med, 2006) [MEDLINE]
    • Increased Sepsis Mortality is Associated with Bloodstream Infection Due to Specific (More Commonly Hospital-Acquired) Pathogens (Crit Care Med, 2006) [MEDLINE]
      • Methicillin-Resistant Staphylococcus Aureus (Odds Ratio 2.70, 95% CI 2.03-3.58)
      • Non-Candida Fungus (Odds Ratio 2.66, 95% CI 1.27-5.58)
      • Candida (Odds Ratio 2.32 95% CI 1.21-4.45)
      • Methicillin-Sensitive Staphylococcus Aureus (Odds Ratio 1.9, 95% CI 1.53-2.36)
      • Polymicrobial Infection (Odds Ratio 1.69, 95% CI 1.24-2.30)
      • Pseudomonas (Odds Ratio 1.6, 95% CI 1.04-2.47)
    • In Patients with Septic Shock Due to Candidemia, Poor Prognostic Factors Included Inadequate Source Control, Inadequate Antifungal Therapy, and 1-Point Increments in the APACHE II Score (Intensive Care Med, 2014) [MEDLINE]
  • Thrombocytopenia (see Thrombocytopenia)
    • Study of Prognostic Value of Early Thrombocytopenia in Sepsis (Crit Care Med, 2016) [MEDLINE]
      • Thrombocytopenia Severity was Associated with Increased 28-Day Mortality Rate (by Kaplan-Meier Method)
        • Thrombocytopenia Severity was Associated with Increased 28-Day Mortality Rate (Hazard Ratio, 1.65; 95% CI, 1.31-2.08 for Platelet Count <50k vs>150k; p<0.0001)
      • Thrombocytopenia <100k was Associated with Increased 28-Day Mortality (by Multivariate Cox Regression)

Factors Which Do Not Impact Sepsis Mortality Rate

  • Presence of Bacteremia at the Time of Sepsis Diagnosis (see Bacteremia) (Crit Care Med, 2011) [MEDLINE]
    • Prognosis is Probably More Closely Associated with the Severity of the Infection and Severity of Sepsis

Sequelae of Sepsis

Subsequent Increased Mortality Rate

  • Nationwide Population-Based Study in Sepsis Survivors (Am J Respir Crit Care Med, 2016) [MEDLINE]
    • Sepsis Survivors Had Increased All-Cause Mortality Rate (Hazard Ratio, 2.18; 95% Confidence Interval, 2.14-2.22) at One Year Post-Discharge
    • Sepsis Survivors Had Increased Risk of Major Cardiovascular Events (Hazard Ratio, 1.37; 95% Confidence Interval, 1.34-1.41) at One Year Post-Discharge
    • Risk Persisted Up to 5 Years Post-Discharge
  • French Cluster Analysis Study of Patient Disposition and Outcome After Critical Illness (Chest, 2022) [MEDLINE]: n = 77,132 ICU ICU survivors who spent ≥2 nights in a French ICU during 2018 and were treated with invasive mechanical ventilation or vasopressors or inotropes (trauma, burn, organ transplant, stroke, and neurosurgical patients were excluded)
    • 89% of All Patients were Able to Return to Home
      • In the Year After Discharge, These Patients Spent a Median of 330 (Interquartile Range [IQR]: 283-349) Days at Home
    • At 1 Year
      • 77% of Patients were Still at Home
      • 17% Had Died
      • 51% Had Been Re-Hospitalized
      • 10% Required Further ICU Admission
    • 48% of Patients Required Rehabilitation Facilities and 5.7% Required Hospital at Home
    • Three Clusters of Patients with Distinct Post-ICU Trajectories were Identified
      • Patients in Cluster 1 (68% of Total) Survived and Spent Most of the Year at Home (338 [323-354] Days)
      • Patients in Cluster 2 (18%) Had More Complex Trajectories, But Most Could Return Home (91%), Spending 242 (174-277) Days at Home
      • Patients in Cluster 3 (14%) Died with Only 37% Returning Home for 45 (15-90) Days

    Subsequent Increased Risk of Future Sepsis

    • Study of Subsequent Infections in Sepsis Survivors (J Intensive Care Med, 2014) [MEDLINE]
      • Sepsis Survivors Have an Increased Risk of Future Infections with an Associated Increased Mortality Rate

    Subsequent Increased Healthcare Use

    • Study of Healthcare Utilization in Sepsis Survivors (Am J Respir Crit Care Med, 2014) [MEDLINE]
      • Healthcare Use is Markedly Elevated in the First Year After Severe Sepsis
    • French Cluster Analysis Study of Patient Disposition and Outcome After Critical Illness (Chest, 2022) [MEDLINE]: n = 77,132 ICU ICU survivors who spent ≥2 nights in a French ICU during 2018 and were treated with invasive mechanical ventilation or vasopressors or inotropes (trauma, burn, organ transplant, stroke, and neurosurgical patients were excluded)
      • 89% of All Patients were Able to Return to Home
        • In the Year After Discharge, These Patients Spent a Median of 330 (Interquartile Range [IQR]: 283-349) Days at Home
      • At 1 Year
        • 77% of Patients were Still at Home
        • 17% Had Died
        • 51% Had Been Re-Hospitalized
        • 10% Required Further ICU Admission
      • 48% of Patients Required Rehabilitation Facilities and 5.7% Required Hospital at Home
      • Three Clusters of Patients with Distinct Post-ICU Trajectories were Identified
        • Patients in Cluster 1 (68% of Total) Survived and Spent Most of the Year at Home (338 [323-354] Days)
        • Patients in Cluster 2 (18%) Had More Complex Trajectories, But Most Could Return Home (91%), Spending 242 (174-277) Days at Home
        • Patients in Cluster 3 (14%) Died with Only 37% Returning Home for 45 (15-90) Days

      Neuropsychologic Dysfunction

      • BRAIN-ICU Study (NEJM, 2013) [MEDLINE]
        • Study: patients with respiratory failure or shock in the medical or surgical intensive care unit (n = 821)
        • During Hospital Stay: delirium developed in 74% of cases
        • At 3 Months
          • Approximately 40% of Patients Had Impaired Global Cognition Scores Which Were 1.5 Standard Deviations Below the Population Mean (Similar to Scores for Patients with Moderate Traumatic Brain Injury)
          • Approximately 26% of Patients Had Scores 2 Standard Deviations Below the Population Mean (Similar to Scores for Patients with Mild Alzheimer’s Disease)
        • At 12 Months
          • Approximately 34% of Patients Had Similar Persistent Cognitive Dysfunction Occurred as in Those with Moderate Traumatic Brain Injury
          • Approximately 24% of Patients Had Similar Persistent Cognitive Dysfunction Occurred as in Those with Mild Alzheimer’s Disease
        • Impact of Delirium: longer duration of delirium was significantly associated with worse global cognition at 3 and 12 months and worse executive function at 3 and 12 months
        • Impact of Sedative Use: use of sedatives or analgesics was not associated with cognitive impairment at 3 and 12 months
      • SMOOTH Trial in Germany Employing a Primary Care Management Strategy in Sepsis Survivors (JAMA, 2016) [MEDLINE]
        • Primary Care Management Strategy in Sepsis Survivors Did Not Improve Mental Health-Related Quality of Life at 6 mo

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

      • For Adult Survivors of Sepsis/Septic Shock and Their Families, Referral to Peer Support Groups is Recommended (Weak Recommendation, Very Low Quality of Evidence)
      • For Adults with Sepsis/Septic Shock and Their Families, Written/Verbal Sepsis Education (Diagnosis, Treatment, and Post-Intensive Care Unit/Post-Sepsis Syndrome) Prior to Hospital Discharge and in the Follow-Up Setting is Recommended (Weak, very low quality of evidence)
      • For Adults with Sepsis/Septic Shock and Their Families, Clinical Team Should Provide the Opportunity to Participate in Shared Decision Making in Post-Intensive Care Unit and Hospital Discharge Planning to Ensure Discharge Plans are Acceptable and Feasible (Best Practice)
      • For Adults with Sepsis/Septic Shock and Their Families, Use of a Critical Care Transition Program on Transfer to the Floor is Recommended (Weak, very low quality of evidence)
      • For Adults with Sepsis/Septic Shock, Reconciling Medications at Both Intensive Care Unit and Hospital Discharge is Recommended (Best Practice)
      • For Adults with Sepsis/Septic Shock and Their Families, Including Information About the Intensive Care Unit Stay, Sepsis and Related Diagnoses, Treatments, and Common Impairments After Sepsis in the Written and Verbal Hospital Discharge Summary is Recommended (Best Practice)
      • For Adults with Sepsis/Septic Shock Who Have Developed New Impairments, Hospital Discharge Plans Should Include Follow-Up with Clinicians Able to Support and Manage New and Long-Term Sequelae (Best Practice)
      • For Adults with Sepsis/Septic Shock and Their Families, There is Insufficient Evidence to Make a Recommendation Regarding Early Post-Hospital Discharge Follow-Up, as Compared with Routine Post-Hospital Discharge Follow-Up (No Recommendation)
      • For Adults with Sepsis/Septic Shock, There is Insufficient Evidence to Make a Recommendation Regarding Early Cognitive Therapy (No Recommendation)
      • For Adult Survivors of Sepsis/Septic Shock, Assessment and Follow-Up for Physical, Cognitive, and Emotional Problems After Hospital Discharge is Recommended (Best Practice)
      • For Adult Survivors of Sepsis/Septic Shock, Referral to a Post-Critical Illness Follow-Up Program is Recommended, if Available (Weak Recommendation, Very Low Quality of Evidence)
      • For Adult Survivors of Sepsis/Septic Shock Receiving Mechanical Ventilation for >48 hrs or an Intensive Care Unit Stay of >72 hrs, Referral to a Post-Hospital Rehabilitation Program is Recommended (Weak Recommendation, Very Low Quality of Evidence)

      References

      Treatment

      General

      Triage

      SEP-1

      Setting Goals of Care

      Source Control

      Antimicrobial Therapy

      Fever Control

      Bicarbonate Therapy

      Blood Pressure Target

      Fluid Resuscitation Strategy (Including Early Goal-Directed Therapy)

      Lactate-Guided Therapy

      Choice of Resuscitation Fluid

      Choice of Vasopressor

      Inotropic Therapy

      Midodrine (see Midodrine)

      Arrhythmia Management

      Corticosteroids (see Corticosteroids)

      Vitamin C (see Vitamin C)

      Glycemic Control

      Anemia Management (see Anemia)

      Nutritional Support

      Renal Support

      Respiratory Support

      Stress Ulcer Prophylaxis

      Antithrombin III (see Antithrombin III)

      Heparin (see Heparin)

      Drotrecogin Alfa (Xigris) (see Drotrecogin Alfa)

      Eritoran (see Eritoran)

      Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin)

      Vilobelimab (see Vilobelimab)

      Prognosis/Sequelae