Sepsis

Definitions

Definitions Based on Systemic inflammatory Response Syndrome (SIRS) Criteria

  • Systemic Inflammatory Response Syndrome (SIRS) Criteria: any of the following
    • Fever (Temperature >100.9° F) or Hypothermia (Temperature <96.8° F)
    • Leukocytosis (White Blood Cell >12k) or Leukopenia (WBC <4k) or Bandemia (Bands >10%)
    • Tachycardia (Heart Rate >90 bpm)
    • Tachypnea (Respiratory Rate >20 breaths/min)
  • Sepsis: including both of the following
    • Suspected or Possible Source of Infection
    • ≥2 Systemic Inflammatory Response Syndrome (SIRS) Criteria
  • Severe Sepsis: including both of the following
    • Sepsis
    • Organ Dysfunction Criteria (Hypotension, Hypoxemia/Respiratory Failure, Oliguria/Acute Kidney Injury, Hepatic Dysfunction, Thrombocytopenia, Coagulopathy, Lactic Acidosis)
  • Septic Shock: including both of the following
    • 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

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: life-threatening organ dysfunction caused by dysregulated host response to infection
    • Organ Dysfunction: an infection-related acute change in sequential organ failure assessment (SOFA) score ≥2 pts
    • Sepsis Mortality Rate: approximate 10% mortality rate
  • Septic Shock: sepsis with persistent vasopressor-dependent hypotension (to maintain MAP ≥65 mm Hg) and serum lactate level >2 mmol/L despite adequate intravenous volume resuscitation
    • Septic Shock Mortality Rate: >40% mortality rate

Epidemiology

Incidence

  • Incidence of Septic Shock is Increasing
    • Retrospective Study of Central Venous Catheter Use in Septic Shock Using Data from the Nationwide Inpatient Sample (NIS), 1998-2009 (Crit Care Med, 2013) [MEDLINE]: n = 203,481 admitted through the ED with septic shock
      • From 1998 to 2009, US Adult Population-Adjusted Rates of Septic Shock Increased from 12.6 Cases Per 100k to 78 Cases Per 100k
    • Systematic Review of the Global Incidence and Mortality of Sepsis (Am J Respir Crit Care Med, 2016) [MEDLINE]: studies from 1979 to 2015
      • In Articles Restricted to the Last 10 Years
        • Sepsis Incidence Rate: 437 Cases Per 100k
        • Severe Sepsis Incidence Rate: 270 Cases Per 100k
      • In Articles Restricted to the Last 10 Years
        • Sepsis In-Hospital Mortality Rate: 17%
        • Severe Sepsis In-Hospital Mortality Rate: 26%
    • Study of the Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data (2009-2014) (JAMA, 2017) [MEDLINE]
      • In Clinical Data from 409 Hospitals, Sepsis was Present in 6% of Adult Admissions, While in Claims-Based Data, Neither the Incidence of Sepsis Nor the Combined Outcome or Death or Discharge to Hospice Changed Significantly from 2009-2014
      • Findings Suggest that Electronic Health Record-Based Clinical Data Provide More Objective Estimates than Claims-Based Data for Sepsis Surveillance
    • Study of Septic Shock Incidence and Mortality Rate in United States Academic Medical Centers Using Clinical Data (Chest, 2017) [MEDLINE]: of 6.5 million adult hospitalizations, 99,312 (1.5%) were flagged by clinical criteria, 82,350 (1.3%) by ICD-9 codes, and 44,651 (0.7%) by both
      • Sensitivity for Clinical Criteria was Higher than Claims (74.8% vs 48.3%), Whereas Positive Predictive Value was Comparable (83% vs 89%)
      • Septic Shock Incidence (Based on Clinical Criteria) Increased from 12.8 to 18.6 Cases Per 1,000 Hospitalizations (Average, 4.9% Increase Per Year; 95% CI, 4.0%-5.9%), While the Mortality Rate Decreased from 54.9% to 50.7% (Average, 0.6% Decline Per Year; 95% CI, 0.4%-0.8%)
      • In Contrast, Septic Shock Incidence (Based on ICD-9 Codes) Increased from 6.7 to 19.3 Per 1,000 Hospitalizations (19.8% Increase Per Year; 95% CI, 16.6%-20.9%), While the Mortality Rate Decreased from 48.3% to 39.3% (1.2% Decline Per Year; 95% CI, 0.9%-1.6%)
      • Clinical Surveillance Definition (Based on Concurrent Vasopressors, Blood Cultures, and Antibiotics Accurately Identified Septic Shock Hospitalizations
      • Incidence of Patients Receiving Treatment for Septic Shock Has Increased and Mortality Rates Have Decreased (But Less Dramatically than Estimated on the Basis of ICD-9 Billing Codes)

Seasonality

  • Incidence of Sepsis and Severe Sepsis are Highest in Winter Months (Predominantly Associated with an Increased Risk of Respiratory Infections) (Crit Care Med, 2007) [MEDLINE]: retrospective study
    • Seasonal Incidence Rate of Sepsis Increased from 41.7 Cases Per 100k in the Fall to 48.6 Cases Per 100k in the Winter
    • Seasonal Incidence Rate of Severe Sepsis Increased from 13.0 Cases Per 100k in the Fall to 15.3 Cases Per 100k in the Winter
    • Seasonal Changes in the Incidence of Sepsis Varied According to Geographic Region: greatest seasonal change in sepsis rates occurred in the Northeast (+30%)
    • Sepsis Case-Fatality Rates Were 13% Greater in the Winter, as Compared to the Summer, Despite Similar Severity of Illness

Disease Severity

  • Sepsis Severity is Increasing
    • Rate of Severe Sepsis Hospitalization Doubled from 1993 to 2003 (Crit Care Med, 2007) [MEDLINE] (Crit Care Med, 2013) [MEDLINE]
      • Mortality from Severe Sepsis Also Increased Significantly During This Period
      • However, Case Fatality Rates Decreased During This Period
    • Study of Septic Shock Incidence and Mortality Rate in United States Academic Medical Centers Using Clinical Data (Chest, 2017) [MEDLINE]: of 6.5 million adult hospitalizations, 99,312 (1.5%) were flagged by clinical criteria, 82,350 (1.3%) by ICD-9 codes, and 44,651 (0.7%) by both
      • Incidence of Patients Receiving Treatment for Septic Shock Has Increased and Mortality Rates Have Decreased (But Less Dramatically than Estimated on the Basis of ICD-9 Billing Codes)

Risk Factors

  • African-American Race
    • Sepsis Incidence is Highest in African-American Males (NEJM, 2003) [MEDLINE]
  • Age ≥65 y/o
    • Up to 65% of Patients Who Develop Severe Sepsis in the US are ≥65 y/o (Clin Infect Dis, 2005) [MEDLINE]
    • 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
  • Bacteremia (see Bacteremia)
    • Bacteremia is Frequently Associated with Sepsis, with 95% of Bacteremic Patients Meeting SIRS Criteria (QJM, 1996) [MEDLINE]
  • Cancer
    • Cancer Increases the Risk of Hospitalization with Severe Sepsis (Relative Risk 3.96) (Crit Care, 2004) [MEDLINE]
      • 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)
    • Patients with a History of Cancer are at Increased Risk for Acquiring and Dying from Sepsis, as Compared to the General Population (Chest, 2006) [MEDLINE]: however, incidence and fatality rates are decreasing over time
  • Community-Acquired Pneumonia (CAP) (see Community-Acquired Pneumonia)
    • Severe Sepsis Occurs in 48% of Patients with CAP (Chest, 2006) [MEDLINE]
    • Septic Shock Occurs in 5% of Patients with CAP (Chest, 2006) [MEDLINE]
  • Diabetes Mellitus (DM) (see Diabetes Mellitus)
    • Diabetes Mellitus Impairs Immune System Function and Increases the Risk of Infection (and Sepsis) (Diabetes Care, 2003) [MEDLINE]
    • Diabetes Mellitus is Not Associated with Changes in Sepsis Presentation or 90-Day Mortality Rate (Crit Care, 2016) [MEDLINE]
  • Ethanol Abuse (see Ethanol)
    • Ethanol Dependence Increases the Risk of Sepsis, Septic Shock, and Organ Failure (Crit Care Med, 2007) [MEDLINE]
    • Ethanol Dependence Increases Hospital Mortality in ICU Patients (Crit Care Med, 2007) [MEDLINE]
  • Genetic Factors
    • Various Genetic Defects (Antibody Synthesis Defects, T-Cell Deficiency, Phagocyte Deficiency, Natural Killer Cell Deficiency, Complement Deficiency, or Impaired Innate Immunity Pathogen Pattern Recognition Receptors) Have Been Demonstrated to Increase the Risk of Sepsis (N Engl J Med, 2011) [MEDLINE]
      • Defects in Toll-Like Receptors (TLR’s): defects/deficiencies have been identified in TLR3, TLR5, MyD88, IRAK-4, UNC93B
      • Defects in C-Type Lectin Receptors (CLR’s): defects/deficiencies have been identified in Dectin-1, CARD-9, Mannose-Binding Lectin
      • Defects in Nucleotide-Binding Oligomerization Domain (NOD) Leucine-Rich-Repeat Containing Receptors (NLR’s): defects/deficiencies have been identified in NOD2, NLRP3
      • Complement Deficiency
      • T-Cell Defects
      • Phagocyte Defects
  • Immunosuppression
    • Immunosuppressing Conditions
    • Corticosteroids (see Corticosteroids)
      • United States Population-Based Retrospective Cohort Study of the Risks of Short-Term Corticosteroid Use in Adults (BMJ, 2017) [MEDLINE]
        • One in Five American Adults in a Commercially-Insured Plan were Given at Least One Outpatient Short-Term Corticosteroid Course During the Three Year Study (2012-2014): mostly for upper respiratory tract infections, spinal conditions, and allergies
        • Within 30 Days of Initiation, Short-Term Use of Corticosteroids Increased the Risk of Sepsis (Incidence Rate Ratio 5.30, 95% CI: 3.80-7.41), Venous Thromboembolism (Incidence Rate Ratio 3.33, 95% CI: 2.78 to 3.99), and Fractures (Incidence Rate Ratio 1.87, 95% CI: 1.69 to 2.07): increased risk persisted at prednisone equivalent doses of <20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture)
    • Other Immunosuppressant Medications
  • Intensive Care Unit (ICU) Admission
    • Intensive Care Unit Admission is a Risk Factor for Infection with Drug-Resistant Organisms, Which May Lead to Sepsis (JAMA, 1995) [MEDLINE]
  • Obesity (see Obesity)
    • Obesity is Believed to Impair Immune System Function, Increasing the Risk of Infections Which May Lead to Sepsis (Especially Aspiration Pneumonia During Hospitalization, Community-Acquired Pneumonia, Biliary Tract Disease, Skin Infections) (Lancet Infect Dis, 2006) [MEDLINE]
  • Prior Hospitalization
    • Hospitalization Alters the Microbiome (Especially in Patients Treated with Antibiotics), Increasing the Risk of Sepsis (Am J Respir Crit Care Med, 2015) [MEDLINE]: prior hospitalization results in a 3x-fold increased risk of sepsis in the subsequent 90 days (with patients hospitalized for infection-related conditions, especially Clostridium Difficile infection, being at the greatest risk)

Etiology

Cardiovascular Sources

Dermatologic Sources

  • Cellulitis (see Cellulitis)
  • Erysipelas (see Erysipelas)
  • Gangrene
  • Necrotizing Soft Tissue Infection (Necrotizing Fasciitis) (see Necrotizing Soft Tissue Infection)
    • Necrotizing Cellulitis
      • Meleney’s Synergistic Gangrene
      • Clostridial Anaerobic Necrotizing Cellulitis
      • Non-Clostridial Anaerobic Necrotizing Cellulitis
    • Necrotizing Fasciitis: deep-seated infection of subcutaneous tissue (involving fascia and fat), which may spare the skin
      • Type I (Mixed Aerobic and Anaerobic Infection)
      • Type II (Monomicrobial Infection)
    • Necrotizing Myositis (Spontaneous Gangrenous Myositis)
  • Skin Abscess (see Skin Abscess)
  • Surgical Wound

Gastrointestinal Sources

Hematologic Sources

Infectious (Non-Localized) Sources

  • Bacteremia of Unknown Source
  • Disseminated Lomentospora Prolificans Infection (Formerly Scedosporium Prolificans) (see Lomentospora Prolificans)

Neurologic Sources

Otolaryngologic Sources

Pulmonary Sources

Renal Sources

Reproductive Sources

Rheumatologic/Orthopedic Sources

  • Acute Limb Ischemia (see Acute Limb Ischemia)
  • Clostridial Myonecrosis (Gas Gangrene) (see Clostridial Myonecrosis)
  • Infected Orthopedic Device
  • Necrotizing Soft Tissue Infection (Necrotizing Fasciitis) (see Necrotizing Soft Tissue Infection)
    • Necrotizing Cellulitis
      • Meleney’s Synergistic Gangrene
      • Clostridial Anaerobic Necrotizing Cellulitis
      • Non-Clostridial Anaerobic Necrotizing Cellulitis
    • Necrotizing Fasciitis: deep-seated infection of subcutaneous tissue (involving fascia and fat), which may spare the skin
      • Type I (Mixed Aerobic and Anaerobic Infection)
      • Type II (Monomicrobial Infection)
    • Necrotizing Myositis (Spontaneous Gangrenous Myositis)
  • Osteomyelitis (see Osteomyelitis)
  • Septic Arthritis (Native or Prosthetic) (see Septic Arthritis)

Physiology

Triggering Events for Normal Host Response to Infection

Immune Recognition of Microbial Components (Mostly by Macrophages)

  • Microbial Components Bind to Three Types of Pattern-Recognition Receptors (PRR’s) on the Surface of Host Immune Cells
    • Toll-Like Receptors (TLR’s)
      • Example: Gram-Positive Bacteria Binds to TLR-2 on Host Immune Cells
      • Example: Lipopolysaccharide of Gram-Negative Bacteria Binds to TLR-4 and/or the Lipopolysaccharide-Binding Protein (CD14 Complex) on Host Immune Cells
    • Nucleotide-Oligomerization Domain (NOD) Leucine-Rich Repeat Proteins
    • Retinoic-Acid-Inducible Gene I (RIG-I)-Like Helicases
  • Alarmins or Danger-Associated Molecular Patterns (DAMP’s) (Released During the Inflammatory Response) Bind to Pattern-Recognition Receptors (PRR’s) on Host Immune Cells
    • DAMP’s are a Variety of Nuclear, Cytoplasmic, or Mitochondria Structures Which Can Be Released Extracellularly
      • High Mobility Group Box-1 (HMGB1) Protein
      • S100 Proteins
      • Heat Shock Proteins
      • Mitochondrial DNA
      • Adenosine Triphosphate (ATP)
  • Microbial Components Bind to Triggering Receptor Expressed on Myeloid Cell (TREM-1) and the Myeloid DAP12-Associating Lectin (MDL-1) Receptors on Host Immune Cells

Other Triggering Events

  • Microparticles from Circulating and Vascular Cells Result in Intravascular Inflammation
  • Release of Nuclear Chromatin (DNA, Histones) and Bactericidal Proteins Promote Inflammation, Endothelial Damage, and Thrombosis

Inflammatory Events

  • Nuclear Factor-Kb (NF-Kb) Mediated Signaling Cascade with Movement from Cytosol to Nucleus, Binding to Transcription Sites, and Activation of Multiple Host Inflammatory Response Genes
    • Tumor Necrosis Factor-α (TNFα)
    • Interleukin-1 (IL-1)
    • Intercellular Adhesion Molecule-1 (ICAM-1): a chemokine
    • Vascular Cell Adhesion Molecule-1 (VCAM-1): a chemokine
    • Nitric Oxide (NO)
  • Neutrophil Activation and Expression of Adhesion Molecules, Resulting in Aggregation and Margination to the Vascular Endothelium
    • Endothelial Expression of Adherence Molecules Functions to Attract Leukocytes
    • Neutrophils Migrate to Site of Injury (Via Rolling, Adhesion, Diapedesis, and Chemotaxis)
    • Neutrophils Release of Mediators Results in Protein-Rich Edema (Due to Increased Microvascular Permeability) and Warmth/Erythema (Due to Local Vasodilation and Hyperemia)

Regulation of the Inflammatory Response

  • Proinflammatory Mediators
    • Tumor Necrosis Factor-α (TNFα) and Interleukin-1 (IL-1) Produce Multiple Effects: TNfα functions in an autocrine manner (enhancing its own release), while IL-1 functions in a paracrine maner (enhancing release of other mediators)
      • Acute Phase Protein Response
      • Interleukin-6 (IL-6)/Interleukin-8 (IL-8) Induction
      • Activation of Coagulation and Fibrinolysis
      • Neutrophil Degranulation and Enhanced Antigen Expression: TNFα
      • Stress Hormone Response
      • Gluconeogenesis: Tumor Necrosis Factor-α (TNFα)
      • Lipolysis: Tumor Necrosis Factor-α (TNFα)
      • Increased Endothelial Permeability: Tumor Necrosis Factor-α (TNFα)
      • Fever (see Fever)
      • Hypotension (see Hypotension)
      • Leukocytosis (see Leukocytosis)
    • Interleukin-2 (IL-2)
    • Interleukin-6 (IL-6)
    • Interleukin-8 (IL-8)
    • Interleukin-10 (IL-10)
    • Interferons
    • Platelet Activating Factor (PAF)
    • Eicosanoids (Leukotrienes, Prostaglandins)
  • Antiinflammatory Mediators: inhibit mononuclear cell and monocyte-dependent T helper cell cytokine release
    • Interleukin-6 (IL-6)
    • Interleukin-10 (IL-10)

Transformation to Sepsis

  • Sepsis Occurs When the Inflammatory Response Becomes Generalized, Spreading Beyond the Bounds of the Locally-Infected Site
    • Potential Mechanisms Which Account for the Spread of the Inflammatory Response Beyond the Local Site
      • Effect of Bacterial Wall Components
        • Endotoxin: endotoxin is detectable in the bloodstream in sepsis and endotoxin injection can mimic many of the feeatures of sepsis in animal/human models
        • Peptidoglycan
        • Muramyl Dipeptide
        • Lipoteichoic Acid
      • Effect of Bacterial Products
        • Staphylococcal Enterotoxin B
        • Toxic Shock Syndrome Toxin-1
        • Pseudomonas Exotoxin A
        • M Protein of Hemolytic Group A Streptococci
      • Release of Large Quantities of Proinflammatory Mediators (TNFα, IL-1) into the Bloodstream
      • Complement Activation: inhibition of the complement cascade in animal models of sepsis reduces inflammation and mortality
      • Genetic Factors (Such as Single Nucleotide Polymorphisms/SNP’s in Multiple Inflammatory Mediator/Receptor/Ligand/Other Genes) Which are Associated with Increased Susceptibility to Infection and Poor Outcome
        • Tumor Necrosis Factor-α (TNFα)
        • Lymphotoxin-α
        • Interleukin-10 (IL-10)
        • Interleukin-18 (IL-18)
        • Interleukin-1 (IL-1) Receptor Antagonist
        • Interleukin-6 (IL-6)
        • CD14
        • MD2
        • Toll-Like Receptor-2 (TLR-2)
        • Toll-Like Receptor-4 (TLR-4)
        • Lipopolysaccharide Binding Protein
        • Angiotensin I-Converting Enzyme (ACE)
  • Sepsis is a State of Dysregulated Intravascular Inflammation

Systemic Effects of Sepsis

  • Peripheral Vasodilation
  • Tissue Ischemia
    • Impaired Autoregulation of Oxygen Delivery to Tissues
    • Microcirculatory Imbalances in the Coagulation and Fibrinolytic Systems
    • Endothelial Abnormalities
    • Loss of Erythrocyte Deformation Ability within the Microcirculation
  • Mitochondrial Dysfunction, Resulting in Cytopathic Injury
  • Delayed Apoptosis of Activated Macrophages/Neutrophils, Resulting in an Enhanced Immune Response: due to proinflammatory cytokines
  • Immunosuppression Occurring After the Sepsis Inflammatory Response

Organ-Specific Effects of Sepsis

  • Cardiovascular
    • Hypotension (see Hypotension)
      • Due to Endothelial Cell Release of Prostacyclin and Nitric Oxide-Induced Vasodilation
      • Due to Increased Endothelial Permeability and Decreased Arterial Vascular Tone with to Increased Capillary Pressure, Resulting in Redistribution of Intravascular Fluid
      • Due to Impaired Compensatory Secretion of the Antidiuretic Hormone, Vasopressin
      • Due to Myocardial Depression (Decreased Systolic and Diastolic Function)
      • Due to Regional Microvascular Dysfunction Resulting in Impaired Redistribution of Blood Flow from the Splanchnic Organs to the Core Organs (Brain, Heart)
    • Impaired Tissue Oxygen Extraction
      • Due to Capillary Dysfunction
      • Due to Decreased Red Blood Cell Deformability
    • Coagulation Abnormalities
      • Due to Endothelial Dysfunction
  • Pulmonary
    • Interstitial/Alveolar Pulmonary Edema with Ventilation/Perfusion Mismatch
      • Due to Endothelial Injury with Increased Vascular Permeability
  • Gastrointestinal
    • Impaired Barrier Function, Resulting in Bacterial/Endotoxin Translocation into the Systemic Circulation
  • Hepatic
    • Hepatic Dysfunction, Resulting in Impaired Clearance of Endotoxin and Other Bacterial Products
  • Renal
    • Acute Kidney Injury (AKI) (see Acute Kidney Injury)
      • Due to Hypoperfusion or Hypoxia-Induced Acute Tubular Necrosis
      • Due to Renal Vasoconstriction
      • Due to Neutrophil Activation by Endotoxin and Bacterial Cell Wall fMet-Leu-Phe (fMLP) Chemotactic Peptide
  • Neurologic
    • Encephalopathy
      • Due to Altered Central Nervous System Perfusion
      • Due to Dysfunction of the Blood Brain Barrier: allows leukocyte infiltration, mediator exposure, and active transport of cytokines across the blood-brain barrier
      • Due to Altered Metabolism and Cell Signalling
      • Due to Mitochondrial Dysfunction

Development of Lactic Acidosis (see Lactic Acidosis)

  • Increased β2-Adrenergic Activation (as Part of the Stress Response in Sepsis) Increases Glycogenolysis with Increased Production of Glucose (Stress Hyperglycemia), Resulting in Pyruvate (and Ultimately Lactate) Production
    • Glucose is Metabolized to Pyruvate at a Rate Which Exceeds its Metabolic Conversion in the Krebs Cycle, Resulting in Pyruvate Being Shunted Toward Lactate Production
    • Serum Lactate is an Indicator of the Degree of Activation of the Stress Response and a Marker of Disease Severity
    • This Phenomenon is Likely Compounded by Thiamine Deficiency and Cytokine-Mediated Downregulation of the Pyruvate Dehydrogenase Complex
      • Thiamine Pyrophosphate is a Critical Coenzyme for the Pyruvate Dehydrogenase Complex, the Rate-Limiting Step in the Krebs Cycle
      • Thiamine Deficiency is Common in Sepsis Patients, with Prevalence Ranging Between 20-70% (Intensive Care Med, 1988) [MEDLINE] (J Crit Care, 2010) [MEDLINE] (Crit Care Med, 2016) [MEDLINE]
      • Randomized Trial of Thiamine Treatment in Sepsis (Crit Care Med, 2016) [MEDLINE]
        • Thiamine Administration Did Not Improve Serum Lactate Level or Other Outcomes in the Overall Group of Patients with Septic Shock and Elevated Lactate
        • In Those with Baseline Thiamine Deficiency, Patients in the Thiamine Group had Significantly Lower Serum Lactate Levels at 24 hrs and a Possible Decrease in Mortality Rate

Alteration of Cortisol Synthesis/Metabolism in the Setting of Critical Illness

  • Hypercortisolemia Occurs in Critical Illness and is Proportionate to the Severity of Illness (see Hypercortisolemia)
    • Study of Cortisol Response to Critical Illness (J Clin Endocrinol Metab, 2006) [MEDLINE]
      • Critical Illness Increased Both Total and Calculated Free Cortisol Levels
      • Administration of Hydrocortisone at the Usual “Replacement” Dose Resulted in Severalfold Higher Total and Free Cortisol Levels
      • Authors Concluded that Stress Dose Steroids Which are Given in the Setting of Critical Illness with Presumed Adrenal Failure (at Hydrocortisone 200 mg qday) are at Least 3x Too High
        • Low Cortisol Response to Corticotropin Stimulation Does Not Necessarily Reflect Adrenal Failure, Since Cortisol Production in Critically Ill Patients is Not Subnormal and the Suppressed Clearance Maintains Hypercortisolemia
    • Belgian Study of the Features of Adrenal Dysfunction in the Setting of Critical Illness (NEJM, 2013) [MEDLINE]
      • Critical Illness Resulted in an 83% Increase in Cortisol Synthesis, as Compared to Controls
      • Critical Illness Also Decreased Expression/Activity of Cortisol-Metabolizing Enzymes, Resulting in Decreased Cortisol Degradation
      • These Two Factors Result in Hypercortisolemia (with Elevated Total and Free Cortisol)
        • Hypercortisolemia Then Subsequently Suppressed Corticotropin Release

Microbiology

Common Organisms

Multidrug-Resistant Organisms

  • Study of Multidrug-Resistant Gram-Negative Bacterial in Elderly Patients with Bacterial Bloodstream Infection (Infect Control Hosp Epidemiol, 2009) [MEDLINE]
    • Multidrug-Resistant Gram-Negative Bacteria were Isolated from 8% of Elderly Patients with Gram-Negative Bloodstream Infection
      • Over the 8.5 Year Study Period, the Percentage of Multidrug-Resistant Gram-Negative Bacteria in Bloodstream Isolates Increased from 1% to 16% of Cases
    • Variables Associated with Bloodstream Infection Due to Multidrug-Resistant Gram-Negative Bacteria
      • Residency in a Long-Term Care Facility (Odds Ratio, 4.9 [95% confidence interval {CI} 1.6-14.9]; P= .006)
      • Presence of an Invasive Device (Odds Ratio, 6.0 [95% CI, 1.5-23.5]; P= .01)
      • Severe Sepsis (Odds Ratio, 7.9 [95% CI, 1.7-37.1]; P= .009)
      • Delayed Initiation of Effective Therapy (Odds Ratio, 12.8 [95% CI, 3.9-41.1]; P= .001)

Candida (see Candida)

  • Candida Species are the 4th Most Common Etiology of Nosocomial Bloodstream Infections in North America (Diagn Microbiol Infect Dis, 2007) [MEDLINE]
    • Approximately 23% of Patients with Candidemia Have a Polymicrobial Bloodstream Infection and 4% Have More than One Species of Candida

Culture-Negative Sepsis

  • Culture-Negative Severe Sepsis is Common in Hospitalized Patients (47.1% of Cases) and its Incidence Has Been Increasing (Increased from 33.9% in 2000 to 43.5% in 2010) (Chest, 2016) [MEDLINE]
    • Culture-Negative Severe Sepsis is Associated with Higher Number of Comorbidities, Greater Risk of Acute Organ (Respiratory, Cardiac, Hepatic, and Renal) Dysfunction, and Increased In-Hospital Mortality Rate
    • Culture-Negativity is an Independent Predictor of Death in Severe Sepsis

Microbiology of Sepsis in Pregnancy and Postpartum (Aust N Z J Obstet Gynaecol, 2017) [MEDLINE]


Diagnosis

Cultures and Microbiologic Assays

Rationale

  • Isolation of the Etiologic Organism(s) Allows for Identification of the Responsible Microorganism, Determination of the Sensitivity Pattern, and Allows for Later Antibiotic De-Escalation

Types of Cultures and Microbiologic Assays

  • General Comments
    • In General, Routine “Panculture” of All Available Sites is Not Recommended (Unless the Clinical Source of Sepsis is Not Readily Apparent), Due to the Risk of Inappropriate Antimicrobial Use (BMJ Qual Saf, 2017) [MEDLINE]
  • Ascites Culture
    • Ascites Culture is Required in Patient with Liver Disease and Ascites with a Suspicion of Spontaneous Bacterial Peritonitis, etc
  • Blood Culture (see Blood Culture)
    • Protocol
      • Two Sets (Aerobic and Anaerobic) of Blood Cultures are Recommended to Assess for Bacteremia
      • In Patient with Intravascular Catheter (Present for >48 hrs), One Set of Blood Cultures Should Be Obtained from the Catheter and One Set Peripherally
      • Blood Culture Yield Has Not Been Shown to Be Improved with Sequential Draws or Timing to Fever Spikes
    • Presence of Bacteremia
      • Only 50% of Patients are Bacteremic at the Time of Sepsis Diagnosis (Crit Care Med, 1989) [MEDLINE]
      • Canadian Study of Blood Cultures for Sepsis in the Emergency Department Before and After Antibiotic Administration (Ann Intern Med, 2019) [MEDLINE]: n = 325
        • Pre-Antimicrobial Blood Cultures were Positive for ≥1 Microbial Pathogens in 31.4% of Patients
        • When the Results of Other Microbiological Cultures were Included, Microbial Pathogens were Found in 67.6% of Patients (CI: 57.7% to 76.6%)
    • Sterilization of Cultures
      • Sterilization of Blood Cultures May Occur within Minutes-Hours of Antibiotic Administration (Clin Infect Dis, 2013) [MEDLINE]
      • Canadian FABLED Study of Blood Cultures for Sepsis in the Emergency Department Before and After Antibiotic Administration (Ann Intern Med, 2019) [MEDLINE]: n = 325
        • Pre-Antimicrobial Blood Cultures were Positive for ≥1 Microbial Pathogens in 31.4% of Patients
        • Post-Antimicrobial Blood Cultures were Positive for ≥1 Microbial Pathogens in 19.4% of Patients: sensitivity of post-antimicrobial culture was 52.9% (CI: 42.8% to 62.9%)
    • Blood Cultures are Required to Facilitate Future Antibiotic De-Escalation When the Organism is Identified and its Sensitivity is Elucidated
      • De-Escalation of Antibiotic Therapy is Associated with Less Resistant Microorganisms, Fewer Side Effects, and Lower Costs (Clin Infect Dis, 2016) [MEDLINE]
    • Blood Culture Antigen Detection Assays (VERIGENE, etc) are Routinely Utilized to Rapidly Identify the Organism and its Resistance Pattern
  • Bronchoscopy with Bronchoalveolar Lavage (BAL) with Culture and Other Assays (see Bronchoscopy)
    • Bronchoscopy with Bronchoalveolar Lavage is Often Performed in Patient with Severe Pneumonia of Unclear Etiology (Especially in an Immunocompromised Host)
    • Bronchoalveolar Lavage is Analyzed with Stains, Cultures, and Respiratory Pathogen Panel (GenMark, etc)
  • Lumbar Puncture (LP) with Cerebrospinal Fluid Culture and Other Assays (see Lumbar Puncture)
    • Lumbar Puncture is Required to Analyze Cerebrospinal Fluid in a Patient with Altered Mental Status with Suspicion for Meningitis/Encephalitis
    • Cerebrospinal Fluid is Analyzed with Stains, Cultures, and Antigen Assays
    • Sterilization of Cultures
      • Sterilization of Cerebrospinal Fluid Cultures May Occur within 2-4 Hours of Antibiotic Administration (Pediatrics, 2001) [MEDLINE]
  • Nasopharyngeal Swab with Respiratory Pathogen Panel (GenMark, etc)
    • Respiratory Pathogen Panels Can Be Utilized with Either Nasopharyngeal Swab or Lower Respiratory Tract (Bronchoalveolar Lavage, etc) Specimens
  • Pericardial Fluid Culture
    • Pericardial Fluid Culture is Required in a Patient with a Pericardial Effusion as a Potential Source of Infection
  • Pleural Fluid Culture (see Thoracentesis)
    • Pleural Fluid Culture is Required in a Patient with a Pleural Effusion (Complicated Parapneumonic Effusion/Empyema) as a Potential Source of Infection
  • Sputum Culture and Other Assays (see Sputum Culture)
    • Sputum Gram Stain and Culture is Required in Patient with Pneumonia
  • Urinalysis, Urine Culture, and Other Assays (see Urine Culture)
    • Urinalysis and Urine Culture is Required in Patient with Suspected Urinary Tracy Source
    • Urine Antigen Assays are Utilized to Detect Histoplasma, Pneumococcal, and Legionella Antigens
  • Wound/Skin Abscess Culture
    • Wound/Skin Abscess Cultures are Required in Patient with Suspected Skin Source

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

  • Routine (Appropriate) Cultures are Recommended Prior to Starting Antibiotic Therapy in Patients with Suspected Sepsis (Best Practice Statement): assuming that this results in no significant delay (<45 min) in starting antibiotics
  • At Least Two Sets of Blood Cultures (Aerobic and Anaerobic) with a Single Time of Draw are Recommended (Best Practice Statement)
  • In Patients with an Intravascular Catheter in Place with a Suspicion of Line-Related Sepsis, at Least One Set of Blood Cultures Should Be Obtained from the Catheter (with Simultaneous Peripheral Blood Cultures)
  • In Patients with an Intravascular Catheter in Place without a Suspicion of Line-Related Sepsis, at Least One Set of Blood Cultures Should Be Obtained Peripherally (No Recommendation is Made Regarding the Second Site of Blood Culture)

Serum Lactate (see Serum Lactate)

Rationale

  • Measurement of Serum Lactate (Arterial Preferred Over Venous, When Possible) is Critical to the Diagnosis and Management of Sepsis

Clinical Efficacy-Arterial vs Venous Serum Lactate

  • Agreement Between Arterial and Venous Lactate is Poor at Abnormal Values, But if the Venous Lactate is Normal, the Arterial Lactate is Generally Also Normal (Eur J Emerg Med, 2014) [MEDLINE]
  • Study of Arterial and Venous Serum Lactate in Patients with Sepsis and Septic Shock (J Intensive Care Med, 2018) [MEDLINE]
    • While There is a Strong Correlation Between Arterial and Venous Lactate Values, Agreement Between Both Parameters was Poor
    • Authors Suggest Not Using the Venous Lactate as a Substitute for the Arterial Lactate in Sepsis Regarding Due to Disparities in Absolute Value and Clearance Rate, But Venous Lactate ≥4.5 mmol/L May Be Used for Predicting the Arterial Lactate ≥4 mmol/L

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

  • Resuscitation Should Target the Normalization of Serum Lactate in Patients with Hyperlactatemia (Which is a Marker of Tissue Hypoperfusion) (Weak Recommendation, Low Quality Evidence)

Complete Blood Count (CBC) (see Complete Blood Count)

  • Useful to Assess for Leukocytosis, Anemia, and Thrombocytopenia

Serum Chemistry (see Serum Chemistry)

  • Useful to Assess Serim Bicarbonate, Serum Creatinine, etc

Arterial Blood Gas (ABG (see Arterial Blood Gas)

  • Useful to Evaluate for Hypoxemia, Hypercapnia, and Acidosis

Serum Procalcitonin (see Serum Procalcitonin)

Clinical Efficacy

  • Systematic Review and Meta-Analysis Studying the Value Serum Procalcitonin in Differentiating Sepsis from Non-Infectious Etiologies of Systemic Inflammatory Response Syndrome (SIRS) (Lancet Infect Dis, 2007) [MEDLINE]: n = 18 studies
    • Sensitivity of Serum Procalcitonin for Diagnosis of Sepsis: 71%
      • Area Under the Summary Receiver Operator Characteristic Curve of 0.78 (95% CI 0.73-0.83)
    • Specificity of Serum Procalcitonin for Diagnosis of Sepsis: 71%
    • Conclusion: serum procalcitonin cannot reliably differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome in critically ill adult patients
  • Study of Diagnostic Efficacy and Prognostic Value of Serum Procalcitonin in Patients with Suspected Sepsis (J Intensive Care Med, 2009) [MEDLINE]
    • Diagnostic Accuracy of Procalcitonin was Higher than C-Reactive Protein and Complement Proteins
    • Procalcitonin in Combination with Sequential Organ Failure Assessment was Useful to Diiagnose Infection
    • C-Reactive Protein, Sequential Organ Failure Assessment Score, Age, and Gender were Shown to Be Helpful to Improve the Prediction of Mortality Risk, But Not Procalcitonin
  • 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 a Diagnostic Marker for Sepsis (Lancet Infect Dis, 2013) [MEDLINE]
    • Procalcitonin is a Helpful Biomarker for the Early Diagnosis of Sepsis in Critically Ill Patients
      • Sensitivity = 77% (95% CI: 72-81%)
      • Specificity = 79% (95% CI: 74-84%)
      • Area Under ROC = 0.85 (95% CI: 0.81-0.88)
  • 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
  • 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
  • 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
  • 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

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

  • Role of Serum Procalcitonin in De-Escalation of Antimicrobials
    • Serum Procalcitonin Can Be Used to Shorten the Duration of Antimicrobial Therapy in Sepsis Patients (Weak Recommendation, Low Quality Evidence): however, no specific algorithm appears to be superior to the other algorithms
    • Serum Procalcitonin Can Be Used to Support the Discontinuation of Empiric Antimicrobials in Patients Who Initially Appeared to Have Sepsis, But Subsequently Have Limited Clinical Evidence of Infection (Weak Recommendation, Low Quality of Evidence)

Serum Galactomannan (see Serum Galactomannan)

Clinical Efficacy

  • Randomized Trial of Serum Galactomannan in High-Risk Hematology Patients (Clin Infect Dis, 2015) [MEDLINE]
    • Combined Monitoring Strategy Based on Serum Galactomannan and Aspergillus DNA was Associated with an Earlier Diagnosis and a Lower incidence of Invasive Aspergillosis in High-Risk Hematology Patients

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

  • Use of 1,3 Beta-D-Glucan Assay (Grade 2B Recommendation) and/or Mannan/Anti-Mannan Assays (Grade 2C Recommendation) are Recommended, if Candida/Fungi are Potential Etiologies of Infection

Serum (1,3)-β-D-Glucan (see Serum (1–3)-β-D-Glucan)

Clinical Efficacy

  • Meta-Analysis of Serum (1–3)-β-D-Glucan in the Diagnosis of Invasive Fungal Disease (PLoS One, 2015) [MEDLINE]: 11 studies
    • Serum (1–3)-β-D-Glucan Had Sensitivity of 75% and Specificity of 87%

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

  • Use of 1,3 Beta-D-Glucan Assay (Grade 2B Recommendation) and/or Mannan/Anti-Mannan Assays (Grade 2C Recommendation) are Recommended, if Candida/Fungi are Potential Etiologies of Infection

Serum Mid-Regional Proadrenomedullin (MR-proADM) (see Serum Mid-Regional Proadrenomedullin)

Clinical Efficacy

  • Study of Serum Mid-Regional Proadrenomedullin in the Diagnosis of Sepsis (Crit Care, 2018) [MEDLINE]
    • MR-proADM identified Sepsis Severity and Treatment Response More Accurately than Established Biomarkers and Scores

Thromboelastograph (TEG) (see Thromboelastograph)

Clinical Efficacy

  • 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 Hemorrhage and Death

Imaging

Typical Types of Imaging

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

  • Specific Anatomic Diagnosis of Infection Requiring Emergent Source Control Should Be Identified as Rapidly as Possible in Patients with Sepsis/Septic Shock (Best Practice Statement)
    • Required Source Control Interventions Should Be Implemented as Soon as Medically/Logistically Practical After the Diagnosis is Made (Generally Within 6-12 hrs)
  • Prompt Removal of Intravascular Access Devices Which are Possible Sources of Sepsis/Septic Shock Should Be Removed as Soon as Possible After Other Vascular Access Has Been Secured (Best Practice Statement)

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

Rationale

  • CVC Allows for Intravenous Fluid Resuscitation, Antibiotic Administration, and Measurement of Central Venous Pressure (CVP) (see Hemodynamics)

Technique of Central Venous Pressure (CVP) Measurement

  • CVP is Measured at Right Atrium or Superior Vena Cava Via the Distal (End) Port of CVC (or PICC Line)
  • Determinants of Central Venous Pressure
    • Atrial and Ventricular Compliance
    • Right Ventricular (RV) Function
    • Venous Return

Clinical Efficacy-Use of Central Venous Catheter

  • Retrospective Study of Central Venous Catheter Use in Septic Shock (Crit Care Med, 2013) [MEDLINE]: n = 203,481 admitted through the ED 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

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

  • 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

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

  • Arterial Line is Recommended in All Patients Requiring Vasopressors for Sepsis (Weak Recommendation, Very Low Quality of Evidence)

Swan-Ganz Catheterization (see Swan-Ganz Catheter)

Classical Hemodynamic Findings in Sepsis

  • High Cardiac Output + Low 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)

Dynamic Hemodynamic Variables

Rationale

  • Dynamic Variables are Better Predictors of Fluid Responsiveness Than Traditional Static Variables (CVP, PCWP)
    • However, the Measurement of Dynamic Variables is Limited to Sedated Patients Who are Mechanically Ventilated and Not Breathing Spontaneously or in Atrial Fibrillation

Clinical Efficacy

  • Systematic Review of Dynamic Variables in Predicting Fluid Responsiveness in Mechanically Ventilated Patients (Crit Care Med, 2009) [MEDLINE]
    • Pulse Pressure Variation
      • r = 0.78 (correlation with change in stroke/cardiac index)
      • ROC = 0.94
      • Sensitivity: 89%
      • Specificity: 88%
    • Stroke Volume Variation (SVV)
      • r = 0.72 (correlation with change in stroke/cardiac index)
      • ROC = 0.84
      • Sensitivity: 82%
      • Specificity: 86%
    • Baseline Systolic Pressure Variation
      • r = 0.72 (correlation with change in stroke/cardiac index)
      • ROC = 0.86
    • LV End-Diastolic Volume Area Index
      • ROC = 0.64
    • Global End-Diastolic Volume Index
      • ROC = 0.56
    • Central Venous Pressure (CVP)
      • ROC = 0.55

FloTrac (see FloTrac)

Rationale

  • Cardiac Output Measurement Using Arterial Line (Instead of Swan-Ganz Catheter)

Technique

Echocardiogram (see Echocardiogram)

Physiology

  • Mechanical Ventilation in the Passive Patient
    • Inspiration -> Increases Intrathoracic Pressure and RA Pressure, Resulting in IVC Distention
    • Expiration -> Decreases Intrathoracic Pressure and RA Pressure, Resulting in IVC Collapse

Rationale

  • A Fluid-Responsive Circulation Will Demonstrate Significant Cyclic Respiratory Variation in IVC Volume and Left Ventricular Stroke Volume
  • In Contrast, if Circulation is Not Fluid-Responsive, Only Small Respirophasic Changes Will Be Seen in the IVC or Left Ventricular Stroke Volume
  • Caveats
    • Lung Distention Increases the Pressure Around Pulmonary Capillaries, Increasing RV Afterload
      • Normally, this Doesn’t Have Significant Consequence for the Circulation
      • However, in the Setting of RV Failure, this will Result in Fluid-Unresponsiveness Despite Significant Respiratory Variation in the Left Ventricular Stroke Volume

Technique of IVC Diameter Measurement

  • IVC is Imaged in a Subxiphoid, Long-Axis View (Either off the Frozen Image with Caliper Function or with M-Mode Imaging)
  • IVC Diameter is Measured 2-3 cm Below the Right Atrium or Just Caudad to the Inlet of the Hepatic Veins: allows an estimation of right atrial pressure
  • IVC Diameter Should Be Measured at End-Expiration

Clinical Efficacy

  • Minimal/Maximal IVC Diameter as a Guide to Fluid Responsiveness in Sedated, Mechanically-Ventilated Patients (Intensive Care Med, 2004) [MEDLINE]
    • Correlations: r = 0.58 (minimal IVC diameter) and r = 0.44 (maximal IVC diameter)
    • Variation in IVC Diameter = Max Diameter-Min Diameter/Mean Diameter
    • Respiratory Variation in IVC Diameter was Greater in Fluid Responders than in Fluid Non-Responders
    • Threshold Variation in IVC Diameter of 12% (Max Diameter-Min Diameter/Mean Diameter) or 18% (Max Diameter-Min Diameter/Min Diameter) Separated Fluid Responders (Positive Predictive Value: 93%) from Fluid Non-Responders (Positive Predictive Value: 92%)
  • In Spontaneously Breathing Patient, A Dilated IVC (>2 cm) without a >50% Decrease in IVC Diameter with Gentle Sniffing Usually Indicates an Elevated Right Atrial Pressure (Chest, 2005) [MEDLINE]
    • However, this is Less Specific in Mechanically-Ventilated Patients, Since there is a High Prevalence of IVC Dilation in These Patients

General Features of Echocardiogram Which Predict Fluid Responsiveness (Chest, 2012) [MEDLINE]

  • Assumptions: patient is either on mechanical ventilation with respiratory efforts or is breathing spontaneously
  • If the Left Ventricle is Hyperdynamic with End-Systolic Effacement, There is a High Probability of Fluid Responsiveness
  • If the IVC is <1 cm in Diameter, There is a High Probability of Fluid Responsiveness
  • If the IVC is Between 1-2.5 cm, There is an Indeterminate Probability of Fluid Responsiveness
  • If the IVC is >2.5 cm in Diameter, There is a Low Probability of Fluid Responsiveness

Serum Cortisol (see Serum Cortisol)

Cosyntropin (Cortrosyn) Stimulation Test (see Cosyntropin Stimulation Test)

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]

  • Adrenocorticotrophic Hormone (ACTH) Stimulation Testing Should Not Be Used to Identify Those Patients with Septic Shock/ARDS Who Should Receive Glucocorticoids

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

  • Adrenocorticotrophic Hormone (ACTH) Stimulation Testing Should Not Be Used to Identify Adults with Septic Shock Who Should Receive Hydrocortisone (Grade 2B Recommendation)

Serum C-Reactive Protein (CRP) (see Serum C-Reactive Protein)

  • May Be Elevated

Clinical Criteria for Sepsis from 2012 Surviving Sepsis Guidelines (Crit Care Med, 2013) [MEDLINE]

General Variables

Inflammatory Variables

Hemodynamic Variables

  • Hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or an SBP Decrease >40 mm Hg in Adults or <2 SD Below the Normal Value for Age) (see Hypotension)

Organ Dysfunction Variables

  • Acute Oliguria (Urine Output <0.5 mL/kg/hr for at Least 2 hrs, Despite Adequate Fluid Resuscitation)
  • Coagulopathy (INR >1.5 or PTT >60 s) (see Coagulopathy)
  • Hyperbilirubinemia (Total Bilirubin >4 mg/dL or 70 μmol/L) (see Hyperbilirubinemia)
  • Hypoxemia (pO/FiO2 <300) (see Hypoxemia)
  • Ileus (see Ileus): absent bowel sounds
  • Increased Creatinine (>0.5 mg/dL or 44.2 μmol/L)
  • Thrombocytopenia (Platelet Count <100,000k) (see Thrombocytopenia)

Tissue Perfusion Variables

  • Decreased Capillary Refill or Mottling
  • Hyperlactatemia (>1 mmol/L) (see Lactic Acidosis)

Clinical-Sepsis Scoring

Scoring Based on Systemic Inflammatory Response Syndrome (SIRS) Criteria

  • SIRS Criteria were Originally Developed in 1991 (Chest, 1992) [MEDLINE]
    • Severe Sepsis: sepsis complicated by organ dysfunction
    • Septic Shock: sepsis-induced hypotension persisting despite adequate fluid resuscitation
  • Systemic Inflammatory Response Syndrome (SIRS) Criteria
    • Fever (Temperature >100.9° F) or Hypothermia (Temperature <96.8° F)
    • Leukocytosis (White Blood Cell >12k) or Leukopenia (WBC <4k) or Bandemia (Bands >10%)
    • Tachycardia (Heart Rate >90 bpm)
    • Tachypnea (Respiratory Rate >20 breaths/min)
  • Sepsis Criteria: including both of the following
    • Suspected or Possible Source of Infection
    • ≥2 Systemic Inflammatory Response Syndrome (SIRS) Criteria
  • Severe Sepsis Criteria: including both of the following
    • Sepsis
    • Organ Dysfunction as Evidenced by 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/hr for 2 hrs
      • Serum Bilirubin >2 mg/dL
      • Platelet Count <100k
      • International Normalized Ratio >1.5 or Activated Partial Thromboplastin Time >60 sec (in a Non-Anticoagulated Patient)
      • Serum Lactate >2 mmol/L
  • Septic Shock Criteria: including both of the following
    • 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

Sequential Organ Failure Assessment (SOFA) Criteria (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]

  • Background
    • The Sequential Organ Failure Assessment (SOFA) Score was Originally Developed (as the “Sepsis-Related Organ Failure Assessment”) in 1994 to Provide a Scoring System for Sepsis Severity (Intensive Care Med, 1996) [MEDLINE] (Crit Care Med. 1998) [MEDLINE]
      • SOFA was Developed Using Data from 1,449 Patients in 40 ICU’s in 16 Countries
    • SOFA Has Been Used to Predict Mortality from Multiple Organ Failure in a Number of Disorders, Including Sepsis, Acute Liver Failure Associated with Acetaminophen Intoxication, Chronic Liver Failure (CLIF-SOFA), Cancer, Post-Cardiac Surgery, and Post-Hematopoietic Stem Cell Transplant
    • In Sepsis, the SOFA Score is Used to Predict Mortality and Should Not Be Used to Diagnose Sepsis
  • Calculation
    • SOFA Score is Initially Calculated 24 hrs After ICU Admission, then q48hrs Thereafter (Characterizing it as a “Sequential” Score)
    • In Sepsis, Baseline SOFA Score Can Be Assumed to Be Zero in Patients Not Known to Have Preexisting Organ Dysfunction

Quick Sequential Organ Failure Assessment (qSOFA) Criteria

  • General Comments
    • The qSOFA was Originally Designed and Validated in 2016 as a Tool to Predict Sepsis Mortality Outside of the Intensive Care Unit (JAMA, 2016) [MEDLINE]
      • Similar to SOFA, the qSOFA was Not Designed as a Tool to Diagnose Sepsis
      • In Patients Outside of the ICU, Any 2 of 3 Clinical qSOFA Variables Offered Predictive Validity (Area Under ROC = 0.81; 95% CI, 0.80-0.82), Similar to that of the Full SOFA Score (JAMA, 2016) [MEDLINE]
  • Poor Outcome is Associated with at Least Two of the Following Clinical Criteria

Clinical Efficacy-Sepsis Scoring

General

  • Australian/New Zealand Study of SIRS Criteria for Sepsis (N Engl J Med, 2015) [MEDLINE]
    • Of 1,171,797 Patients, a Total of 109,663 Had Infection and Organ Failure
      • Approximately 87.9% of Patients Had SIRS-Positive Severe Sepsis
      • Approximately 12.1% of Patients Had SIRS-Negative Severe Sepsis
    • Over the 14 Years of the Study, These Groups Had Similar Characteristics and Changes in Mortality (SIRS-Positive Group: from 36.1% to 18.3%, P<0.001; SIRS-Negative Group: from 27.7% to 9.3%, P<0.001)
    • This Pattern Remained Similar After Adjustment for Baseline Characteristics (Odds Ratio in the SIRS-Positive Group, 0.96; 95% confidence interval [CI], 0.96 to 0.97; Odds Ratio in the SIRS-Negative Group, 0.96; 95% CI, 0.94 to 0.98; P=0.12 for Between-Group Difference)
    • In the Adjusted Analysis, Mortality Rate Increased Linearly with Each Additional SIRS Criterion (Odds Ratio for Each Additional Criterion, 1.13; 95% CI, 1.11 to 1.15; P<0.001) without Any Transitional Increase in Risk at a Threshold of Two SIRS Criteria: the need for two or more SIRS criteria to define severe sepsis excluded one in eight otherwise similar patients with infection, organ failure, and substantial mortality and failed to define a transition point in the risk of death
  • Study of SIRS Criteria in Hospital Ward Patients (Am J Respir Crit Care Med, 2015) [MEDLINE]
    • Almost Half of Patients Hospitalized on the Wards Developed SIRS at Least Once During Their Ward Stay
    • Study Findings Suggest that Screening Ward Patients Using SIRS Criteria for Identifying Those with Sepsis is Impractical
  • 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
  • Study of Value of qSOFA in the Emergency Department (JAMA, 2017) [MEDLINE]
    • In Patients Presenting to the Emergency Department with Suspected Infection, the Use of qSOFA Resulted in Greater Prognostic Accuracy for In-Hospital Mortality Than Did Either SIRS or Severe Sepsis Criteria
  • Post Hoc Subgroup Analysis of qSOFA in Patients with Sepsis Outside of the Intensive Care Unit (J Infect Chemother, 2017) [MEDLINE]: n = 387
    • Area Under the ROC Curve for the qSOFA Score was 0.615, Which was Superior to SIRS Score (0.531, P = 0.019), But Inferior to the SOFA Score (0.702, P = 0.005)
    • Multivariate Logistic Regression Analysis Demonstrated that Hypothermia Might Be Associated with Poor Outcome Independently of qSOFA Criteria
    • Findings Suggested that qSOFA had a Suboptimal Level of Predictive Value Outside of the ICU and Could Not Identify 16.3% of Patients Who were Once Actually Diagnosed with Sepsis
    • Hypothermia Might Be Associated with an Increased Risk of death that Cannot Be Identified by qSOFA
  • Retrospective Study of qSOFA and SIRS Criteria in the Emergency Department (Am J Emerg Med, 2017)
    • Although qSOFA May Be Valuable in Predicting Sepsis-Related Mortality, it Performed Poorly as a Screening Tool for Identifying Sepsis in the Emergency Department
    • As the Time to Meet qSOFA Criteria was Significantly Longer than for SIRS, Relying on qSOFA Alone May Delay Initiation of Evidence-Based Interventions Known to Improve Sepsis-Related Outcomes
  • Retrospective, Single-Center Study of Value of qSOFA in the Emergency Department (Ann Emerg Med, 2018) [MEDLINE]
    • The Diagnostic Performance of Positive qSOFA Score for Predicting 28-Day Mortality was Low in Critically Ill Septic Patients, Particularly dDuring the Early Period After ED Presentation
  • 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 60.8% Sensitivity and 72% Specificity 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

Hospitalized Patients in Low/Middle-Income Countries

  • Sepsis Assessment and Identification in Low Resource Settings (SAILORS) Study of qSOFA Score in Hospitalized Adults With Suspected Infection in Low/Middle-Income Countries (JAMA, 2018) [MEDLINE]
    • In Hospitalized Adults With Suspected Infection in Low/Middle-Income Countries, the qSOFA Score Identified Infected Patients at Risk of Death Beyond that Explained by Baseline Factors
    • However, the Predictive Validity Varied Among Cohorts and Settings, and Further Research is Required to Better Understand Potential Generalizability

Sepsis Scoring in Pregnant Patients (see Pregnancy)

Obstetrically-Modified SOFA (omSOFA) Score (Aust N Z J Obstet Gynaecol, 2017) [MEDLINE]

  • Respiration
    • pO2/FIO2 Ratio ≥400: 0 points
    • pO2/FIO2 Ratio 300-399: 1 point
    • pO2/FIO2 Ratio ≤299: 2 points
  • Coagulation
    • Platelets ≥150k: 0 points
    • Platelets 100-149k: 1 point
    • Platelets ≥99k: 2 points
  • Liver
    • Total Bilirubin ≤20 μmol/L: 0 points
    • Total Bilirubin 21-32 μmol/L: 1 point
    • Total Bilirubin >32 μmol/L: 2 points
  • Cardiovascular
    • MAP ≥70 mm Hg: 0 points
    • MAP <70 mm Hg: 1 point
    • Vasopressors Required: 2 points
  • Central Nervous System
    • Alert: 0 points
    • Arousable by Voice: 1 point
    • Arousable by Pain: 2 points
  • Renal
    • Serum Cr ≤90 μmol/L: 0 points
    • Serum Cr 90-120 μmol/L: 1 point
    • Serum Cr >120 μmol/L: 2 points

Obstetrically-Modified qSOFA (omqSOFA) Score (Aust N Z J Obstet Gynaecol, 2017) [MEDLINE]

  • Respiration
    • RR <25/min: 0 points
    • RR ≥25/min: 1 point
  • Cardiovascular
    • SBP ≥90 mm Hg: 0 points
    • SBP <90 mm Hg: 1 point
  • Central Nervous System
    • Alert: 0 points
    • Not Alert: 1 point

Clinical Data

  • Conventional Sepsis Scoring Systems (Both SIRS and SOFA) Have Excluded Pregnant Patients, Since the Physiology of Pregnancy is Unique with Normal Physiologic Parameters in Pregnancy Overlap with the Clinical Criteria for Sepsis (Obstet Gynecol, 2014) [MEDLINE]
    • Sepsis in Obstetrics Score Has Been Alternatively Proposed and Validated to Identify Pregnant Patients with Sepsis (Obstet Gynecol, 2017) [MEDLINE]
  • Society of Obstetric Medicine Australia and New Zealand (SOMANZ) Sepsis Guidelines in Pregnant Patients (Aust N Z J Obstet Gynaecol, 2017) [MEDLINE]
    • Alternative Guidelines Proposed (But Not Validated) to Diagnose and Manage Sepsis in Pregnant Patients

Clinical Manifestations

General Comments

  • Up to 40% of Patients Admitted to the ICU with Suspected Sepsis Do Not Actually Have Sepsis (Crit Care, 2015) [MEDLINE]
    • Since the Benefit of Treating The Patients Who Do Not Have Sepsis with the Recommended Sepsis Resuscitation Procedures and Antibiotics is Unclear (and May Be Harmful), the Infectious Diseases Society of America (IDSA) Did Not Endorse the 2016 Surviving Sepsis Guidelines (Clin Infect Dis, 2018) [MEDLINE]
    • The Surviving Sepsis Campaign Guidelines Also Do Not Differentiate Between Patients with Suspected Sepsis and Suspected Septic Shock (Clin Infect Dis, 2018) [MEDLINE]

Cardiovascular Manifestations

Atrial Fibrillation (AF) (see Atrial Fibrillation)

  • Epidemiology
    • Approximately 6-20% of Patients with Severe Sepsis Develop New-Onset Atrial Fibrillation
      • Exacerbation of Pre-Existing Atrial Fibrillation or the Occurrence of New-Onset Atrial Fibrillation May Occur Due to Sepsis Itself or May Be Due to Catecholamine Vasopressors Used in the Treatment of Septic Shock
        • The Addition of Vasopressin to Catecholamine Vasopressors (as Compared with Catecholamines Alone) was Associated with a Lower Risk of Atrial Fibrillation ( JAMA, 2018) [MEDLINE]
  • Clinical Data
    • 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
    • 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

Elevation of Serum Brain Natriuretic Peptide (BNP) (see Serum Brain Natriuretic Peptide)

  • Physiology
    • Elevation of Serum Brain Natriuretic Peptide is Likely Due to Sepsis-Related Inflammatory Myocardial Dysfunction (Crit Care Med, 2004) [MEDLINE]
  • Clinical Data
    • BNP Does Not Appear to Reliably Predict the Pulmonary Capillary Wedge Pressure (PCWP) in ICU Patients (Especially in Patients with Shock) (Crit Care Med 2004) [MEDLINE] and (J Am Coll Cardiol, 2005) [MEDLINE]

Elevation of Serum Troponin (see Serum Troponin)

  • Epidemiology
    • Troponin Elevation is Common in Adult Patients with Septic Shock (Crit Care, 2013) [MEDLINE]
  • Clinical Data
    • Study of Troponin in Critically Ill ICU Patients (Arch Intern Med, 2006) [MEDLINE]: n = 23 studies
      • Elevated Troponin was Associated with Increased ICU Mortality Rate and Length of Stay
    • Retrospective Study of the Value of Troponin-I in Predicting Sepsis Mortality Rate (Using Data from the Prowess Trial) (J Crit Care, 2010) [MEDLINE]: n = 598
      • Positive Troponin-I was Associated with Increased Age (61 y/o), as Compared to Negative Troponin-I (56 y/o)
      • Positive Troponin-I was Associated with Higher APACHE II Score (26.1), as Compared to Negative Troponin-I (22.3)
      • Troponin-I Elevation was Associated with an Increased 28-Day Sepsis Mortality Rate
        • After Adjusting for Other Variables, Elevated Troponin-I Had Odds Ratio of 2.020 for Mortality (95% CI: 1.153-3.541)
    • Study of Troponin-T in Sepsis (Am J Med, 2013) [MEDLINE]: n = 645
      • Troponin-T Elevation was Associated with In-Hospital Mortality Rate 30-Day Mortality Rate (But Not Long-Term 1/2/3-Year Mortality Rates) in Sepsis Patients Admitted to the Intensive Care Unit
    • Prospective Substudy of a Randomized Trial in Septic Shock (Crit Care, 2013) [MEDLINE]: n = 121 patients
      • Troponin Elevation was Commonly Observed in Adult Patients with Septic Shock
      • No Differences were Observed in Troponin Elevation, CK Elevation, or EKG Changes in Patients Treated with Vasopressin vs Epinephrine

Hypotension (see Hypotension)

  • Epidemiology
    • Hypotension is a Common Manifestation of Sepsis
  • Physiology
    • Due to Endothelial Cell Release of Prostacyclin and Nitric Oxide-Induced Vasodilation
    • Due to Increased Endothelial Permeability and Decreased Arterial Vascular Tone with to Increased Capillary Pressure, Resulting in Redistribution of Intravascular Fluid
    • Due to Impaired Compensatory Secretion of the Antidiuretic Hormone, Vasopressin
    • Due to Myocardial Depression (Decreased Systolic and Diastolic Function)
    • Due to Regional Microvascular Dysfunction Resulting in Impaired Redistribution of Blood Flow from the Splanchnic Organs to the Core Organs (Brain, Heart)
  • Clinical
    • Note that Patients with Chronic Hypertension May Develop Critical End-Organ Hypoperfusion at Higher Blood Pressures than Healthy Patients (i.e. Relative Hypotension)

Septic Cardiomyopathy/Congestive Heart Failure-Systolic/Cardiogenic Shock (see Congestive Heart Failure and Cardiogenic Shock)

  • Physiology
    • Septic Cardiomyopathy is Due to Sepsis-Related Myocardial Depression
      • Evidence Suggests that Circulating Histones May Be Implicated in the Pathogenesis of Septic Cardiomyopathy (Crit Care Med, 2015) [MEDLINE]

Sinus Tachycardia (see Sinus Tachycardia)

  • Epidemiology
    • Tachycardia is Common in Sepsis
      • However, it May Be Absent in Older Patients, in Diabetics, and in Patients Who Have Been Taking β-Blockers
    • Tachycardia May Be Pronounced and Prolonged (Prior to the Development of Hypotension) in Younger Patients
  • Physiology
    • Tachycardia is Due to Vasodilation-Induced Increased in Heart Rate

Takotsubo Cardiomyopathy (Stress-Induced Cardiomyopathy) (see Takotsubo Cardiomyopathy)

  • Epidemiology
    • Systematic Review of 26 Case Reports of Sepsis-Associated Takotsubo Cardiomyopathy (Angiology, 2017) [MEDLINE]
      • Mean Age of 62.8 y/o (SD 14 yrs)
      • Female Predominance (16/26 Cases)
      • Favorable Outcome in 92.3% of Cases Once the Sepsis was Treated

Dermatologic Manifestations

Clinical Changes Due to Alteration in Skin Perfusion

  • Warm, Flushed Skin (Erythroderma) (see Erythroderma)
    • Epidemiology: may be observed early in the course
    • Physiology: peripheral vasodilation
  • Cool Skin/Mottling/Cyanosis (see Cyanosis)
    • Epidemiology: observed as shock develops
    • Physiology: peripheral vasoconstriction

Endocrinologic Manifestations

Abnormal Thyroid Function Tests (see Abnormal Thyroid Function Tests in Non-Thyroidal Illness)

  • Epidemiology
    • May Occur in Some Cases

Hyperglycemia (see Hyperglycemia)

  • Epidemiology
    • Hyperglycemia (“Stress Hyperglycemia”) is Common During Critical Illness
  • Mechanisms of Hyperglycemia
    • Catecholamine Secretion
    • Cortisol Secretion
    • Glucagon Secretion
    • Growth Hormone Secretion
    • Gluconeogenesis
    • Glycogenolysis
    • Insulin Resistance: overt insulin resistance was noted on admission in 67% of critically ill patients, with the percentage of patients having insulin resistance increasing to 70% when assessed later in the course (J Parenter Enteral Nutr, 2008) [MEDLINE]
  • Prognosis
    • Retrospective Study of Hyperglycemia in Critically Ill (Medical and Surgical) Patients (Mayo Clin Proc, 2003 )[MEDLINE]
      • Hyperglycemia (as Assessed by Admission, Mean, and Maximal Blood Glucose Levels) was Associated with Increased Mortality Rate: there was a dose-response effect
    • 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

Gastrointestinal Manifestations

Hyperbilirubinemia (see Hyperbilirubinemia)

  • Epidemiology
    • May Occur in Some Cases
  • Prognosis
    • Early Hepatic Dysfunction (Hyperbilirubinemia >2 mg/dL within 48 hrs of Admission) Occurred in 11% of Patients and was Associated with an Increased Mortality Rate (30.4% vs. 16.4%; p < 0.001) (Crit Care Med, 2007) [MEDLINE]

Ileus (see Ileus)

  • Physiology
    • Due to Bowel Hypoperfusion
  • Clinical
    • Decreased Bowel Sounds

Ischemic Hepatitis (see Ischemic Hepatitis)

  • Epidemiology
    • May Occur in Septic Shock (or Any Other Type of Shock)

Hematologic Manifestations

Coagulopathy/Disseminated Intravascular Coagulation (DIC) (see Coagulopathy and Disseminated Intravascular Coagulation)

  • Epidemiology
    • May Occur in Some Cases
    • 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

Leukocytosis (see Leukocytosis)

  • Epidemiology
    • Leukocytosis is Common
  • Clinical: WBC >12k

Leukopenia (see Leukopenia)

  • Epidemiology
    • May Occur in Some Cases
  • Clinical: WBC <4k
  • Clinical Data
    • 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

Methemoglobinemia (see Methemoglobinemia)

  • Epidemiology
    • Methemoglobin Levels May Increase in Sepsis (Acta Anaesthesiol Scand, 1998) [MEDLINE]
  • Physiology
    • May Be Related to the Synthesis of Nitric Oxide Which Occurs in Sepsis: nitric oxide is converted to methemoglobin and nitrate

Thrombocytopenia (see Thrombocytopenia)

  • Epidemiology
    • Thrombocytopenia Has Been Reported in 14.5% of Severe Sepsis Patients in the ICU and is Associated with Worse Outcome (9.9% in Survivors, 22.5% in Non-Survivors) (Crit Care Med, 2009) [MEDLINE]
  • Mechanisms of Thrombocytopenia
    • Consumptive Coagulopathy: related to sepsis-induced platelet activation with/without frank disseminated intravascular coagulation (DIC)
    • Hemodilution: associated with intravenous fluid resuscitation
    • Increased Circulating Histones (JAMA, 2016) [MEDLINE]
    • Platelet Sequestration
  • Prognosis
    • Thrombocytopenia is Associated with Worse Outcome in Severe Sepsis (9.9% in Survivors, 22.5% in Non-Survivors) (Crit Care Med, 2009) [MEDLINE]
    • Thrombocytopenia During the First 24 hrs is Associated with Worse 28-Day Mortality Rate in Septic Shock (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)

Infectious Manifestations

Fever (see Fever)

  • Clinical: temperature >38.5 degrees C
    • 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%)

Hypothermia (see Hypothermia)

  • Clinical: temperature <36 degrees C
  • Clinical Data
    • 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%)

Increased Risk of Acquiring Other Infections

  • Clinical Data
    • Study of Acquisition of Secondary Infections After Intensive Care Unit Admission for Sepsis (JAMA, 2016) [MEDLINE]
      • Intensive Care Unit-Acquired Infections Occurred More Commonly in Patients with Sepsis with Higher Disease Severity, But Such Infections Contributed Only Modestly to Overall Mortality
      • The Genomic Response of Patients with Sepsis was Consistent with Immune Suppression (Decreased Expression of Genes Involved in Gluconeogenesis and Glycolysis) at the Onset of Secondary Infection

Rigors (see Rigors)

  • Epidemiology
    • Common

Neurologic Manifestations

Altered Mental Status/Encephalopathy (see Altered Mental Status)

  • Epidemiology
    • Encephalopathy is Common in Sepsis
  • Clinical
    • Delirium (see Delirium)
      • BRAIN-ICU Study of Patients with Respiratory Failure or Shock in the Medical or Surgical Intensive Care Unit (NEJM, 2013) [MEDLINE]: 74% of patients had delirium
    • Obtundation/Coma (see Obtundation/Coma)

Focal Neurologic Signs

  • Epidemiology
    • May Be Seen in Some Cases
  • Physiology
    • Due to Cerebral Hypoperfusion

Akathisia/Restlessness (see Akathisia)

  • Epidemiology
    • May Be Seen in Some Cases
  • Physiology
    • Due to Cerebral Hypoperfusion

Pulmonary Manifestations

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)

  • Epidemiology
    • Sepsis is the Most Common Etiology of ARDS
    • Risk Factors for the Development of Sepsis-Associated ARDS
      • Acute Abdomen (Ann Intensive Care, 2017) [MEDLINE]
      • Acute Pancreatitis (Ann Intensive Care, 2017) [MEDLINE]
      • Alcohol Abuse (Crit Care Med, 2003) [MEDLINE] and (Crit Care Med, 2008) [MEDLINE]: ethanol may decrease glutathione concentrations in the epithelial lining fluid, increasing the risk of oxidative injury to the lung
      • Delayed Antibiotics (Crit Care Med, 2008) [MEDLINE]
      • Delayed Goal-Directed Resuscitation (Crit Care Med, 2008) [MEDLINE]
      • Diabetes Mellitus (Crit Care Med, 2008) [MEDLINE]
      • Higher APACHE II Score (Ann Intensive Care, 2017) [MEDLINE]
      • Higher Intravenous Fluid Resuscitation within the First 6 hrs (Ann Intensive Care, 2017) [MEDLINE]: in stratified analysis, the total fluid infused within the first 6 hrs was a risk factor in the non-shock group, but not in the shock group
      • Increased Baseline Respiratory Rate (Crit Care Med, 2008) [MEDLINE]
      • Older Age (Ann Intensive Care, 2017) [MEDLINE]
      • Pneumonia as the Site of Infection (Ann Intensive Care, 2017) [MEDLINE]
      • Recent Chemotherapy (Crit Care Med, 2008) [MEDLINE]
      • Shock (Ann Intensive Care, 2017) [MEDLINE]
      • Transfusion (Crit Care Med, 2008) [MEDLINE]
  • Clinical

Hypoxemia (see Hypoxemia)

  • Epidemiology
    • Hypoxemia is Common in Sepsis
  • Physiology
    • Pulmonary Vascular Endothelial Injury with Impairment of Capillary Blood Flow and Increased Microvascular Permeability (with Development of Interstitial and Alveolar Edema)

Renal Manifestations

Acute Kidney Injury (AKI) (see Acute Kidney Injury)

  • Epidemiology
    • Retrospective Cohort Study of Acute Kidney Injury Requiring Dialysis in Severe Sepsis (from 2000-2009) (Am J Respir Crit Care Med, 2015) [MEDLINE]
      • Approximately 6.1% of Patients with Severe Sepsis Develop AKI Requiring Dialysis: the odds of requiring dialysis increased by 14% from 2000-2009 (while the odds of mortality decreased by 61% from 2000-2009)
      • Mortality Rate was Higher in Patients Requiring Dialysis (43.6% vs. 24.9%)
  • Mechanisms
    • Acute Tubular Necrosis (ATN): due to renal hypoperfusion, hypoxemia, etc
    • Hypotension with Renal Hypoperfusion
    • Neutrophil Activation by Endotoxin and the Chemotactic Peptide, fMet-Leu-Phe (FMLP) Released from Bacterial Cell Walls
    • Renal Vasoconstriction
    • Tumor Necrosis Factor-α (TNFα)
    • Clinical
    • Oliguria/Anuria
  • Prevention of Acute Kidney Injury
    • Measures to Prevent Acute Kidney Injury in the Intensive Care Unit (ATS/ERS/ESICM/SCCM/SRLF Statement-Prevention and Management of Acute Renal Failure in the ICU Patient; Am J Resp Crit Care Med, 2010) [MEDLINE]
      • Avoid Nephrotoxic Exposure (NSAID’s, Aminoglycosides, etc)
      • Avoid Radiographic Contrast Exposure (see Radiographic Contrast)
      • Avoid Hyper-Oncotic Resuscitation Fluids (Hydroxyethyl Starch, Dextrans, 20-25% Albumin), Due to Their Risk of Renal Dysfunction
      • Maintain MAP >65 mm Hg with Intravenous Fluids/Vasopressors
        • Higher MAP May Be Required in Patients with Long-Standing Hypertension (Where Autoregulation of Renal Blood Flow Might Be Impaired)
      • Vasopressors are Recommended in Patients with Hypotension (MAP <65) Despite Intravenous Fluid Resuscitation: there is no data to support the use of any specific vasopressor over another
        • Use of Inotropic Agents to Increase Cardiac Output to Supraphysiologic Levels to Improve Renal Function is Not Recommended
        • Low-Dose Dopamine (Intended to Improve Renal Function) is Not Recommended
  • Complications and Prognosis
    • Prospective Observational Study of Septic Acute Kidney Injury (J Intensive Care Med, 2018) [MEDLINE]
      • Patients with Septic AKI Had a 40% 1-Year Mortality
      • Factors Associated with Increased 1-Year Mortality
        • Older Age
        • Ischemic Heart Disease
        • Higher Simplified Acute Physiology Score II
        • Central Nervous System or Musculoskeletal Primary Infections
        • Higher Daily Fluid Balance
        • Furosemide Administration During ICU Stay
      • Risk of Progression to Chronic Kidney Disease is High
        • Initial AKI Reversal: 21% progressed to CKD
        • Initial AKI Recovery: 30% progressed to CKD
        • Initial AKI Non-Recovery: 79% progressed to CKD

Lactic Acidosis (see Lactic Acidosis)

  • Physiology
    • Decreased Lactate Clearance, Likely Due to Inhibition of Pyruvate Dehydrogenase
    • Epinephrine-Induced β2-Adrenergic Receptor Stimulation with/without Decreased Oxygen Delivery to Tissues

Special Clinical Situation-Sepsis in Pregnancy

Non-Infectious Conditions Which Can Mimic Sepsis in Pregnancy (Aust N Z J Obstet Gynaecol, 2017) [MEDLINE]


Prevention

Clinical Data

Decontamination Strategies

  • Randomized Trial of Decontamination in the Prevention of ICU-Acquired Bloodstream Infection in Mechanically-Ventilated Intensive Care Unit Patients (with Moderate-High Antibiotic Resistance Prevalence) (JAMA, 2018) [MEDLINE]
    • Chlorhexidine Gluconate 2% Mouthwash, Selective Oropharyngeal Decontamination (Mouth Paste with Colistin, Tobramycin, and Nystatin), and Selective Digestive Tract Decontamination (Same Mouth Paste and Gastrointestinal Suspension with the Same Antibiotics) Were Not Associated with a Decrease in ICU-Acquired Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Bacteria, as Compared to Standard Care

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

Triage

Clinical Efficacy

  • Study of Association Between 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

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

  • 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)

Opinions

  • Paul Marik Editorial Regarding Use of Lactate in SEP-1 Bundle (Crit Care Med, 2018) [MEDLINE]
    • 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

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

  • Goals of Care and Prognosis Should Be Discussed with Patient and Family (Best Practice Statement)
  • Goals of Care Should Be Incorporate into End-of-Life Care Planning, Utilizing Palliative Care Principles When Appropriate (Strong Recommendation, Moderate Quality of Evidence)
  • Goals of Care Should Be Discussed as Early as Feasible, But No Later than 72 hrs After ICU Admission (Weak Recommendation, Low Quality of Evidence)

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

  • Hospitals Should Have a Performance Improvement Program for Sepsis, Including Sepsis Screening for Acutely Ill, High-Risk Patients (Best Practice Statement)

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

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 ED 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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
    • Arterial Line is Recommended in All Patients Requiring Vasopressors for Sepsis (Weak Recommendation, Very Low Quality of Evidence)

Swan-Ganz Catheterization (see Swan-Ganz Catheter)

  • Findings
    • High Cardiac Output + Low 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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Specific Anatomic Diagnosis of Infection Requiring Emergent Source Control Should Be Identified as Rapidly as Possible in Patients with Sepsis/Septic Shock (Best Practice Statement)
    • Required Source Control Interventions Should Be Implemented as Soon as Medically/Logistically Practical After the Diagnosis is Made (Generally Within 6-12 hrs)
  • Prompt Removal of Intravascular Access Devices Which are Possible Sources of Sepsis/Septic Shock Should Be Removed as Soon as Possible After Other Vascular Access Has Been Secured (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]

  • Timing of Antimicrobial Administration
    • Intravenous Antimicrobials Should Be Administered as Soon as Possible (and Within 1 hr) of Sepsis/Septic Shock Diagnosis (Strong Recommendation, Moderate Quality 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
  • 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)
        • 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
        • Risk Factors for Candida (see Candida): immunocompromised state (neutropenia, chemotherapy, transplant, diabetes mellitus, liver disease, renal failure), invasive vascular devices (central venous catheters, hemodialysis catheters), total parenteral nutrition, necrotizing pancreatitis, recent major surgery (especially abdominal), prolonged broad-spectrum antibiotic administration, prolonged hospital/ICU admission, recent fungal infection, multisite Candida colonization)
    • Dosing Strategies for Antimicrobials Should Be Optimized in Sepsis/Septic Shock Based on Pharmacokinetic/Pharmacodynamic Principles and Specific Drug Properties
      • 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 the 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)
      • 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 above 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
      • Continuous Infusion of β-Lactams (vs Intermittent Dosing) is Probably Beneficial in Sepsis
    • Empiric Combination Antimicrobial Therapy (with at Least Two Agents from Different Antimicrobial Classes) Targeted Toward the Likely Bacterial Pathogens is Recommended for the Initial Management of Septic Shock (Weak Recommendation, Low Quality of Evidence)
      • Combination Therapy is Utilized to Cover the Suspected Pathogen with More Than One Antibiotic to Facilitate Pathogen Clearance (Rather to Than to Broaden the Spectrum of Antimicrobial Coverage): provides “double coverage”
        • Example: use of piperacillin/tazobactam + aminoglycoside or fluoroquinolone to enhance the clearance of Gram-negative pathogens
        • Example: clindamycin with β-lactams for streptococcal toxic shock (due to the inhibition of bacterial toxin by clindamycin)
        • Example: macrolides with a β-lactam for pneumococcal pneumonia (due to the potential immunomodulatory effect of macrolides)
    • Combination Therapy is Not Recommended for Bacteremia or Sepsis without Shock (Weak Recommendation, Low Quality of Evidence)
    • Combination Therapy is Not Recommended for the Routine Treatment of Neutropenic Sepsis/Bacteremia without Shock (Strong Recommendation, Moderate Quality Evidence)
  • Duration of Antimicrobial Therapy
    • Antimicrobial Therapy of 7-10 Days is Adequate for Most Serious Infections Associated with Sepsis/Septic Shock (Weak Recommendation, 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) (Weak Recommendation, Low Quality of Evidence)
        • 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 (Weak Recommendation, Low Quality of 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)
      • Daily Assessment for De-Escalation of Antimicrobial Therapy is Recommended in Sepsis/Septic Shock (Best Practice Statement)
      • If Combination Therapy is Initially Utilized for Septic Shock, De-Escalation is Recommended within the First Few Days After Clinical Improvement and/or Evidence of Resolution of Infection (Best Practice Statement): this applies to both culture-positive infections and culture-negative empiric treatment
    • Role of Serum Procalcitonin in De-Escalation of Antimicrobials
      • Serum Procalcitonin Can Be Used to Shorten the Duration of Antimicrobial Therapy in Sepsis Patients (Weak Recommendation, Low Quality Evidence): however, no specific algorithm appears to be superior to the other algorithms
      • Serum Procalcitonin Can Be Used to Support the Discontinuation of Empiric Antimicrobials in Patients Who Initially Appeared to Have Sepsis, But Subsequently Have Limited Clinical Evidence of Infection (Weak Recommendation, Low Quality of Evidence)

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 May 1. doi: 10.1097/SHK.0000000000001368 [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]: 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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Sodium Bicarbonate is Not Recommended to Improve Hemodynamics or Decrease Vasopressor Requirements in Hypoperfusion-Associated Lactic Acidosis with pH ≥ 7.15 (Weak Recommendation, Moderate 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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • MAP Target of ≥65 mm Hg is Recommended in Patients with Septic Shock Requiring Vasopressors (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]
    • Arterial Line is Recommended in Patients Requiring Vasopressors (Weak Recommendation, Very Low Quality Evidence): if resources are available

Intravenous Fluid Resuscitation Strategy

Rationale

  • In the Setting of Sepsis, Increased Serum Lactate is a Marker of Impaired Microcirculatory Flow with Tissue Hypoxia
    • 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 ED 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

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

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

Recommendations (European Society of Intensive Care Medicine Task Force Consensus on Circulatory Shock and Hemodynamic Monitoring; Intensive Care Med, 2014) [MEDLINE]

  • XXXXXXXX

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

  • Initial Intravenous Fluid Resuscitation of ≥30 mL/kg with Crystalloid is Recommended within the First 3 hrs (Strong Recommendation, Low Quality Evidence)
    • Additional Intravenous Fluid Resuscitation Should Be Contingent on Frequent Reassessment of Hemodynamic Status (Using Heart Rate, Blood Pressure, SaO2, Respiratory Rate, Temperature, Urine Output, Results of Non-Invasive Monitoring, Results of Invasive Monitoring, and Other Variables) (Best Practice Statement)
    • Intravenous Fluid Challenge Should Be Continued as Long as Hemodynamic Parameters Continue to Improve (Best Practice Statement): however, fluid should not be given after the initial resuscitation without some likelihood that the patient will respond positively (due to defined risk of fluid overload impacting the mortality rate)
  • Assessment of Cardiac Function is Recommended if Clinical Examination Does Not Indicate a Clear Diagnosis (Best Practice Statement)
  • Assessment of Dynamic Hemodynamic Variables (Passive Leg Raise/Fluid Challenge Against Stroke Volume, Variation in Systolic Blood Pressure/Pulse Pressure/Stroke Volume in Response to Changes in Intrathoracic Pressure Associated with Mechanical Ventilation, etc) is Recommended Over Assessment of Static Hemodynamic Variables (CVP, etc) to Predict Fluid Responsiveness (Weak Recommendation, Low Quality Evidence)
    • Static Hemodynamic Variables with Target
      • CVP 8-12 mm Hg
      • ScvO2 ≥70% (Obtained from Central Venous Catheter)
      • SvO2 ≥65% (Obtained from Swan-Ganz Catheter)
    • Use of CVP Alone to Guide Resuscitation is Not Recommended: due to the fact that the CVP has limited ability in the normal range (8-12 mm Hg) to predict fluid responsiveness
  • Resuscitation Should Target the Normalization of Serum Lactate in Patients with Hyperlactatemia (Which is a Marker of Tissue Hypoperfusion) (Weak Recommendation, Low Quality Evidence)

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 = 7942 (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

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

  • Crystalloids are Recommended as the Initial Intravenous Fluid for Resuscitation in Sepsis/Septic Shock (Strong Recommendation, Moderate Quality of Evidence)
    • Balanced Crystalloids or Saline are Recommended for Resuscitation in Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence)
    • Crystalloids are Recommended Over Gelatins for Resuscitation in Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence)
    • Hyperchloremia Should Be Avoided (Regardless of Which Fluid is Used): due to concern that hyperchloremia may induce renal vasoconstriction
  • When Patient Requires a Substantial Amount of Crystalloids, Albumin is Recommended in Addition to Crystalloids for the Initial and Subsequent Resuscitation of Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence)
  • Hydroxyethyl Starches are Not Recommended for Resuscitation in Sepsis/Septic Shock (Strong Recommendation, High Quality of Evidence): due to concerns related to an increased mortality rate and increased risk for hemodialysis

Choice of Vasopressor

Agents

  • Angiotensin II (Giapreza) (see Angiotensin II)
    • Pharmacology: synthetic human angiotensin II
    • Clinical: FDA approved in 2018
  • 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
  • Methylene Blue (see Methylene Blue)
    • Physiology: methylene blue selectively inhibits the action of nitric oxide on guanylate cyclase, decreasing endotoxin-mediated vasodilation
      • Result in an Increase in Systemic Blood Pressure
    • Contraindications
    • Administration: single intravenous bolus dose of 2 mg/kg (continuous infusion can alternatively be used in some cases)
      • Indicated for Septic Shock and Hypotension Refractory to Multiple Vasopressors without Evidence of Acute Respiratory Distress Syndrome
      • Duration of Action: 2-3 hrs
  • 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 IV drip
      • 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-Other 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
    • However, in Subgroup Analysis, as Compared to the More Severely Hypotensive Group (≥15 μg/min) Where Mortality Rates were Comparable, Vasopressin Demonstrated a Lower Mortality Rate than Norepinephrine in the Less Severely Hypotensive Group (<15 μg/min): authors concluded that this finding required further study
  • 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

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

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)
  • Norepinephrine is the Recommended First Choice Vasopressor (Strong Recommendation, Moderate Quality of Evidence)
    • Vasopressin (Up to 0.03 U/min) (Weak Recommendation, Moderate Quality of Evidence) or Epinephrine Can Be Added to Norepinephrine, as Required, to Increase the Mean Arterial Pressure (Weak Recommendation, Low Quality of Evidence)
    • Vasopressin (Up to 0.03 U/min) Can Be Used to Decrease the Norepinephrine Dosage (Weak Recommendation, Moderate Quality of Evidence)
  • Dopamine is Suggested as an Alternative Vasopressor in Select Patients with Low Risk of Tachyarrhythmias and Absolute/Relative Bradycardia (Weak Recommendation, Low Quality of Evidence)
  • Dopamine (Low Dose) is Not Recommended for Renal Protection (Strong Recommendation, High Quality of Evidence)
  • Dobutamine is Recommended for Patients with Persistent Hypoperfusion Despite Adequate Intravenous Fluid Loading and the Use of Vasopressors (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
  • 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]

Inotropic Therapy

Agents

Clinical Efficacy

  • 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]

  • Dobutamine is Recommended for Patients with Persistent Hypoperfusion Despite Adequate Intravenous Fluid Loading and the Use of Vasopressors (Weak Recommendation, Low Quality of Evidence)
    • Dobutamine Should Not Be Used to Target a Supranormal Cardiac Output
    • Monitoring Response in Indices of Perfusion to a Measured Dobutamine-Induced Increase in Cardiac Output is Recommended

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

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

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

  • Intravenous Hydrocortisone Should Only Be Used in Septic Shock if Hemodynamic Stability Cannot Be Restored with Adequate Intravenous Fluid Resuscitation and Vasopressor Therapy (Weak Recommendation, Low Quality of Evidence)
    • Recommended Hydrocortisone Dose: 200 mg qday (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

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 (American College of Physicians Guideline for Intensive Insulin Therapy in Hospitalized Patients, 2011) (Ann Intern Med, 2011) [MEDLINE]

  • Intensive Insulin Therapy (Glucose 80-180 mg/dL) is Not Recommended to Control Blood Glucose in Non-SICU/MICU Patients with or without Diabetes Mellitus (Strong Recommendation, Moderate-Quality Evidence)
  • Intensive Insulin Therapy (Glucose 80-180 mg/dL) is Not Recommended to Normalize Blood Glucose in SICU/MICU Patients with or without Diabetes Mellitus (Strong Recommendation, High-Quality Evidence)
  • Target Blood Glucose Level of 140-200 mg/dL is Recommended if Insulin Therapy is Used in SICU/MICU Patients (Weak Recommendation, Moderate-Quality Evidence)

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

  • Use Protocolized Glucose Management, Targeting a Blood Glucose ≤180 mg/dL (Strong Recommendation, High Quality of Evidence): this is recommended over intensive insulin therapy protocols targeting a glucose ≤110 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 (Best Practice Statement)
    • 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 (Best Practice Statement)
      • 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 (Weak Recommendation, Low Quality of Evidence)

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
  • Red Blood Cell Transfusion is Recommended Only When the Hemoglobin is <7 g/dL (in the Absence of Myocardial Ischemia/Severe Hypoxemia/Acute Hemorrhage) (Strong Recommendation, High Quality of Evidence)

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]

  • Unfractionated Heparin or Low Molecular Weight Heparin (Enoxaparin, etc) are Recommended for DVT Prophylaxis, in the Absence of Contraindications (Strong Recommendation, Moderate Quality of Evidence)
    • Low Molecular Weight Heparin (Enoxaparin, etc) is Recommended Over Unfractionated Heparin for DVT Prophylaxis, in the Absence of Contraindications (Strong Recommendation, Moderate Quality of Evidence)
  • Combination Pharmacologic and Mechanical Prophylaxis is Recommended Whenever Possible (Weak Recommendation, Low Quality of Evidence
    • When Pharmacologic Prophylaxis is Contraindicated, Mechanical Prophylaxis is Recommended (Weak 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)

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

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

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 ARDS (Strong Recommendation, Moderate Quality of Evidence)
  • Fluid Management in ARDS
    • Conservative Fluid Management Strategy is Recommended in Established Sepsis-Associated 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)
    • Low Tidal Volume (6 mL/kg PBW) is Recommended Over High Tidal Volume (12 mL/kg PBW) in Sepsis-Associated ARDS (Strong Recommendation, High Quality of Evidence)
    • Low Tidal Volume (6 mL/kg PBW) is Recommended Over High Tidal Volume (12 mL/kg PBW) in Sepsis-Associated Respiratory Failure without ARDS (Weak Recommendation, Low Quality of Evidence)
    • Plateau Pressure Upper Limit of 30 cm H2O is Recommended in Sepsis-Associated Severe ARDS (Strong Recommendation, Moderate Quality of Evidence)
    • 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)
  • Ventilation Mode
    • No Ventilator Mode is Recommended Over Another
    • No Recommendation is Made Regarding the Use of Noninvasive Positive-Pressure Ventilation (NIPPV) in Sepsis-Induced ARDS (see Noninvasive Positive-Pressure Ventilation)
    • However, High-Frequency Oscillation Ventilation is Not Recommended in Adult Patients with Sepsis-Associated ARDS (Strong Recommendation, Moderate Quality of Evidence) (see High-Frequency Ventilation)
  • Positive End-Expiratory Pressure (PEEP) (see Invasive Mechanical Ventilation-General)
    • Higher PEEP is Recommended Over Lower PEEP in Adults with Sepsis-Associated Moderate-Severe ARDS (Weak Recommendation, Moderate Quality of 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
    • Recruitment Maneuvers are Recommended in Sepsis-Associated ARDS (Weak Recommendation, Moderate Quality of Evidence): selected patients with severe hypoxemia may benefit from recruitment maneuvers in conjunction with higher levels of PEEP
  • Proning
    • Prone Position is Recommended Over Supine Position in Sepsis-Associated ARDS and pO2/FIO2 Ratio <150 (Strong Recommendation, Moderate Quality of Evidence)
  • Venovenous Extracorporeal Membrane Oxygenation (VV-EMCO) (see Venovenous Extracorporeal Membrane Oxygenation)
    • VV-EMCO May Be Considered in Centers with Local Expertise
  • Sedation and Paralysis (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)
    • Neuromuscular Junction Blockade (for ≤48 hrs) is Suggested for Adult Patients with Sepsis-Associated ARDS and pO2/FIO2 Ratio <150 (Weak Recommendation, Moderate Quality of Evidence)
  • 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 ARDS (Strong Recommendation, High Quality of 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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Stress Ulcer Prophylaxis is Recommended for Patients Who Have Risk Factors for Gastrointestinal Bleeding (Strong Recommendation, Low Quality of Evidence)
    • Either Proton Pump Inhibitor (PPI) or H2-Blockers are Recommended When Stress Ulcer Prophylaxis is Indicated (Weak Recommendation, Low Quality of Evidence)
    • Stress Ulcer Prophylaxis is Not Recommended for Patients without Risk Factors for Gastrointestinal Bleeding (Best Practice Statement)

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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
    • No Recommendations are Made with Regard to Blood Purification in Sepsis

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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
    • Intravenous Immunoglobulin is Not Recommended in Sepsis/Septic Shock (Weak Recommendation, Low Quality of 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

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 Risk of Death

  • 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

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

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

References

General

  • Cardiovascular management of septic shock. Crit Care Med 2003; 31:946-955
  • Management of sepsis. N Engl J Med. 2006;355:1699-1713
  • Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med. 2009 Oct;37(10 Suppl):S331-6. doi: 10.1097/CCM.0b013e3181b6ed58 [MEDLINE]
  • Bundled care for septic shock: an analysis of clinical trials. Crit Care Med. 2010;38(2):668–78 [MEDLINE]
  • The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38(2):367–74 [MEDLINE]
  • Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af [MEDLINE]
  • Novel therapies for septic shock over the past 4 decades. JAMA. 2011 Jul 13;306(2):194-9 [MEDLINE]
  • Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012;12(12):919–24 [MEDLINE]
  • The Surviving Sepsis Campaign’s Revised Sepsis Bundles. Curr Infect Dis Rep. 2013 Oct;15(5):385-93 [MEDLINE]
  • Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623 [MEDLINE]
  • Current controversies in the support of sepsis. Curr Opin Crit Care. 2014 Dec;20(6):681-4. doi: 10.1097/MCC.0000000000000154 [MEDLINE]
  • Severe sepsis during pregnancy. Clin Obstet Gynecol. 2014 Dec;57(4):827-34. doi: 10.1097/GRF.0000000000000066 [MEDLINE]
  • Sepsis: a roadmap for future research. Lancet Infect Dis. 2015 May;15(5):581-614 [MEDLINE]
  • Assessment of Clinical Criteria for Sepsis For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):762-74. doi: 10.1001/jama.2016.0288 [MEDLINE]
  • Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289 [MEDLINE]
  • The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287 [MEDLINE]
  • Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Jan 18. doi: 10.1007/s00134-017-4683-6 [MEDLINE]
  • Infectious Diseases Society of America (IDSA) POSITION STATEMENT: Why IDSA Did Not Endorse the Surviving Sepsis Campaign Guidelines. Clin Infect Dis. 2018;66(10):1631 [MEDLINE]

Epidemiology

  • The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA. 1995;274(8):639 [MEDLINE]
  • The systemic inflammatory response syndrome as a predictor of bacteraemia and outcome from sepsis. QJM. 1996;89(7):515 [MEDLINE]
  • Caring for the critically ill patient. Current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population? JAMA. 2000;284(21):2762 [MEDLINE]
  • Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303 [MEDLINE]
  • The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546 [MEDLINE]
  • Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care. Crit Care. 2004;8(5):R291 [MEDLINE]
  • The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34(1):15 [MEDLINE]
  • Severe sepsis in community-acquired pneumonia: when does it happen, and do systemic inflammatory response syndrome criteria help predict course? Chest. 2006;129(4):968 [MEDLINE]
  • Obesity and infection. Lancet Infect Dis. 2006;6(7):438 [MEDLINE]
  • Is severe sepsis increasing in incidence AND severity? Crit Care Med. 2007;35(5):1414 [MEDLINE]
  • Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007;35(5):1244 [MEDLINE]
  • Seasonal variation in the epidemiology of sepsis. Crit Care Med. 2007;35(2):410 [MEDLINE]
  • Immunodeficiency and genetic defects of pattern-recognition receptors. N Engl J Med. 2011;364(1):60 [MEDLINE]
  • Severe sepsis cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population. Crit Care Med. 2013;41(4):945 [MEDLINE]
  • Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13):1308 [MEDLINE]
  • Hospitalization Type and Subsequent Severe Sepsis. Am J Respir Crit Care Med. 2015 Sep;192(5):581-8 [MEDLINE]
  • Estimating Ten-Year Trends in Septic Shock Incidence and Mortality in United States Academic Medical Centers Using Clinical Data. Chest. 2017;151(2):278 [MEDLINE]
  • Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016 Feb 1;193(3):259-72. doi: 10.1164/rccm.201504-0781OC [MEDLINE]
  • Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017 Apr 12;357:j1415. doi: 10.1136/bmj.j1415 [MEDLINE]
  • Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017 Oct 3;318(13):1241-1249 [MEDLINE]

Risk Factors

  • Cirrhosis as a risk factor for sepsis and death: analysis of the National Hospital Discharge Survey. Chest. 2003 Sep;124(3):1016-20 [MEDLINE]
  • Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care. 2003;26(2):510–3. doi: 10.2337/diacare.26.2.510 [MEDLINE]
  • Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients. Crit Care. 2016 Aug 6;20(1):252. doi: 10.1186/s13054-016-1429-8 [MEDLINE]
  • Diabetes Mellitus and Sepsis: A Challenging Association. Shock. 2017 Mar;47(3):276-287. doi: 10.1097/SHK.0000000000000778 [MEDLINE]

Physiology

General

  • Thiamine deficiency in the critically ill. Intensive Care Med 1988; 14:384–387 [MEDLINE]
  • Thiamine deficiency in critically ill patients with sepsis. J Crit Care 2010; 25:576–581 [MEDLINE]
  • Age- and sex-associated trends in bloodstream infection: a population-based study in Olmsted County, Minnesota. Arch Intern Med. 2007 Apr;167(8):834-9 [MEDLINE]
  • Polymicrobial bloodstream infections involving Candida species: analysis of patients and review of the literature. Diagn Microbiol Infect Dis. 2007 Dec;59(4):401-6 [MEDLINE]
  • Influx of multidrug-resistant, gram-negative bacteria in the hospital setting and the role of elderly patients with bacterial bloodstream infection. Infect Control Hosp Epidemiol. 2009 Apr;30(4):325-31 [MEDLINE]
  • Center for Resuscitation Science Research Group: Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: A pilot study. Crit Care Med 2016; 44:360–367 [MEDLINE]

Microbiology

  • Age- and sex-associated trends in bloodstream infection: a population-based study in Olmsted County, Minnesota. Arch Intern Med. 2007 Apr;167(8):834-9 [MEDLINE]
  • Polymicrobial bloodstream infections involving Candida species: analysis of patients and review of the literature. Diagn Microbiol Infect Dis. 2007 Dec;59(4):401-6 [MEDLINE]
  • Influx of multidrug-resistant, gram-negative bacteria in the hospital setting and the role of elderly patients with bacterial bloodstream infection. Infect Control Hosp Epidemiol. 2009 Apr;30(4):325-31 [MEDLINE]
  • Culture-Negative Severe Sepsis: Nationwide Trends and Outcomes. Chest. 2016;150(6):1251 [MEDLINE]

Diagnosis

General

  • Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Jan 18. doi: 10.1007/s00134-017-4683-6 [MEDLINE]

Culture

  • Sepsis syndrome: a valid clinical entity. Methylprednisolone Severe Sepsis Study Group. Crit Care Med. 1989;17(5):389 [MEDLINE]
  • Comparison of 2 blood culture media shows significant differences in bacterial recovery for patients on antimicrobial therapy. Clin Infect Dis 2013; 56(6):790–797 [MEDLINE]
  • Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001; 108(5):1169–1174 [MEDLINE]
  • Revisiting the panculture. BMJ Qual Saf. 2017 Mar;26(3):236-239. doi: 10.1136/bmjqs-2015-004821. Epub 2016 Feb 19 [MEDLINE]
  • Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis: A Diagnostic Study. Ann Intern Med. 2019 Sep 17. doi: 10.7326/M19-1696 [MEDLINE]

Serum Galactomannan (see Serum Galactomannan)

  • Serum galactomannan versus a combination of galactomannan and polymerase chain reaction‐based Aspergillus DNA detection for early therapy of invasive aspergillosis in high‐risk hematological patients: a randomized controlled trial. Clin Infect Dis 2015, 60(3):405–414 [MEDLINE]

Serum 1,3-β-D-Glucan (see Serum 1,3-β-D-Glucan)

  • The screening performance of serum 1,3‐beta‐D‐glucan in patients with invasive fungal diseases: a meta‐analysis of prospective cohort studies. PLoS One 2015, 10(7):e0131602 [MEDLINE]

Serum Procalcitonin (see Serum Procalcitonin)

  • Differential diagnostic value of procalcitonin in surgical and medical patients with septic shock. Crit Care Med. 2006;34(1):102 [MEDLINE]
  • Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis. 2007;7(3):210 [MEDLINE]
  • Diagnostic efficacy and prognostic value of serum procalcitonin concentration in patients with suspected sepsis. J Intensive Care Med. 2009;24(1):63 [MEDLINE]
  • Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta‐analysis. Clin Infect Dis 2012: 55(5):651–662 [MEDLINE]
  • An ESICM systematic review and meta‐analysis of procalcitonin‐guided antibiotic therapy algorithms in adult critically ill patients. Intensive Care Med 2012: 38(6):940–949 [MEDLINE]
  • Procalcitonin‐guided therapy in intensive care unit patients with severe sepsis
and septic shock—a systematic review and meta‐analysis. Crit Care 2013: 17(6):R291 [MEDLINE]
  • Procalcitonin‐guided antibiotic therapy: a systematic review and meta‐analysis. J Hosp Med 2013: 8(9):530–540 [MEDLINE]
  • Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta‐analysis. Lancet Infect Dis 2013: 13(5):426–435 [MEDLINE]
  • Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost‐effectiveness analysis. Health Technol Assess 2015: 19(96):v–xxv, 1–236 [MEDLINE]
  • Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016 Jul;16(7):819-27. doi: 10.1016/S1473-3099(16)00053-0. Epub 2016 Mar 2 [MEDLINE]

Serum Mid-Regional Proadrenomedullin (MR-proADM) (see Serum Mid-Regional Proadrenomedullin)

  • The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis – a secondary analysis of a large randomised controlled trial. Crit Care. 2018;22(1):79 [MEDLINE]

Serum Lactate (see Serum Lactate)

  • The role of venous blood gas in the emergency department: a systematic review and meta-analysis. Eur J Emerg Med. 2014 Apr;21(2):81-8. doi: 10.1097/MEJ.0b013e32836437cf [MEDLINE]
  • Lactate measurements in sepsis‐induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med 2015; 43(3):567–573 [MEDLINE]
  • The Correlation Between Arterial Lactate and Venous Lactate in Patients With Sepsis and Septic Shock. J Intensive Care Med. 2018;33(2):116 [MEDLINE]

Central Venous Pressure (CVP) (see Hemodynamics)

  • Central venous pressure measurements: peripherally inserted catheters versus centrally inserted catheters. Crit Care Med. 2000 Dec;28(12):3833-6 [MEDLINE]
  • Intraoperative peripherally inserted central venous catheter central venous pressure monitoring in abdominal aortic aneurysm reconstruction. Ann Vasc Surg. 2006 Sep;20(5):577-81. Epub 2006 Jul 27 [MEDLINE]
  • Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008 Jul;134(1):172-8. doi: 10.1378/chest.07-2331 [MEDLINE]
  • An in vitro study comparing a peripherally inserted central catheter to a conventional central venous catheter: no difference in static and dynamic pressure transmission. BMC Anesthesiol. 2010 Oct 12;10:18. doi: 10.1186/1471-2253-10-18 [MEDLINE]
  • Comparison of the central venous pressure from internal jugular vein and the pressure measured from the peripherally inserted antecubital central catheter (PICCP) in liver transplantation recipients. Korean J Anesthesiol. Oct 2011; 61(4): 281–287. Published online Oct 22, 2011. doi: 10.4097/kjae.2011.61.4.281 [MEDLINE]
  • Peripherally inserted central catheters are equivalent to centrally inserted catheters in intensive care unit patients for central venous pressure monitoring. J Clin Monit Comput. 2012 Apr;26(2):85-90. doi: 10.1007/s10877-012-9337-1 [MEDLINE]\
  • Utilization patterns and outcomes associated with central venous catheter in septic shock: a population-based study. Crit Care Med. 2013;41(6):1450 [MEDLINE]
  • Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014; 40(12):1795–1815 [MEDLINE]
  • Systematic review including re‐analyses of 1148 individual data sets of central venous pressure as a predictor of fluid responsiveness. Intensive Care Med 2016, 42(3):324–332 [MEDLINE]

Arterial Line (see Arterial Line)

  • Blood pressure measurement in shock. Mechanism of inaccuracy in ausculatory and palpatory methods. JAMA 1967: 199(13):118–122 [MEDLINE]
  • Arterial catheters as a source of bloodstream infection: a systematic review and meta-analysis. Crit Care Med. 2014 Jun;42(6):1334-9. doi: 10.1097/CCM.0000000000000166 [MEDLINE]

Swan-Ganz Catheter (see Swan-Ganz Catheter)

  • French Pulmonary Artery Catheter Study Group: Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: A randomized controlled trial. JAMA 2003; 290:2713–2720 [MEDLINE]
  • Impact of the pulmonary artery catheter in critically ill patients: Meta-analysis of randomized clinical trials. JAMA 2005; 294:1664–1670 [MEDLINE]
  • PAC-Man study collaboration: Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): A randomised controlled trial. Lancet 2005; 366:472–477 [MEDLINE]
  • Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:2213–2224 [MEDLINE]
  • A systematic review and meta-analysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients. Anesth Analg 2011; 112:1392–1402 [MEDLINE]

Ultrasound

  • The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med. 2004;30(9):1834-1837 [MEDLINE]
  • Bedside ultrasonography in the ICU: part 1. Chest. 2005 Aug;128(2):881-95 [MEDLINE]
  • Shock: Ultrasound to guide diagnosis and therapy.  Chest  2012; 142(4):1042-1048. Doi:10.1378/chest.12-1297 [MEDLINE]
  • Bedside ultrasonography for the intensivist. Crit Care Clin. 2015 Jan;31(1):43-66. doi: 10.1016/j.ccc.2014.08.003. Epub 2014 Oct 3 [MEDLINE]

Passive Leg Raise Effect on Cardiac Output and Pulse Pressure

  • Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med. 2000 Jul;162(1):134-8 [MEDLINE]
  • Does pulse pressure variation predict fluid responsiveness in critically ill patients? A systematic review and meta-analysis. Crit Care. 2014 Nov 27;18(6):650. doi: 10.1186/s13054-014-0650-6 [MEDLINE]
  • Passive leg raising for predicting fluid responsiveness: a systematic review and meta‐analysis. Intensive Care Med 2016; 42(12):1935–1947 [MEDLINE]

Other

  • Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: A systematic review of the literature. Crit Care Med 2009; 37:2642–2647 [MEDLINE]

Clinical Sepsis Scoring

  • Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55 [MEDLINE]
  • 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530-8 [MEDLINE]
  • The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10 [MEDLINE]
  • Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med. 1998;26(11):1793 [MEDLINE]
  • Application of the Sequential Organ Failure Assessment (SOFA) score to patients with cancer admitted to the intensive care unit. Am J Hosp Palliat Care. 2009 Oct-Nov;26(5):341-6 [MEDLINE]
  • Sequential Organ Failure Assessment predicts the outcome of SCT recipients admitted to intensive care unit. Bone Marrow Transplant. 2010 Apr;45(4):682-8 [MEDLINE]
  • The sequential organ failure assessment (SOFA) score is prognostically superior to the model for end-stage liver disease (MELD) and MELD variants following paracetamol (acetaminophen) overdose. Aliment Pharmacol Ther. 2012 Mar;35(6):705-13 [MEDLINE]
  • Comparison between Sequential Organ Failure Assessment score (SOFA) and Cardiac Surgery Score (CASUS) for mortality prediction after cardiac surgery. Thorac Cardiovasc Surg. 2012 Feb;60(1):35-42 [MEDLINE]
  • Maternal physiologic parameters in relationship to systemic inflammatory response syndrome criteria: a systematic review and meta-analysis. Obstet Gynecol. 2014;124(3):535 [MEDLINE]
  • Scoring systems for 6-month mortality in critically ill cirrhotic patients: a prospective analysis of chronic liver failure – sequential organ failure assessment score (CLIF-SOFA). Aliment Pharmacol Ther. 2014 Nov;40(9):1056-65 [MEDLINE]
  • Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015 Apr;372(17):1629-38 [MEDLINE]
  • Incidence and Prognostic Value of the Systemic Inflammatory Response Syndrome and Organ Dysfunctions in Ward Patients. Am J Respir Crit Care Med. 2015 Oct;192(8):958-64 [MEDLINE]
  • Predictors of outcome in decompensated liver disease: validation of the SOFA-L score. Ir Med J. 2015 Apr;108(4):114-6 [MEDLINE]
  • Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):762-74. doi: 10.1001/jama.2016.0288 [MEDLINE]
  • Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289 [MEDLINE]
  • Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017 Jan 17;317(3):290-300. doi: 10.1001/jama.2016.20328 [MEDLINE]
  • Internal Validation of the Sepsis in Obstetrics Score to Identify Risk of Morbidity From Sepsis in Pregnancy. Obstet Gynecol. 2017;130(4):747 [MEDLINE]
  • Assessment of mortality by qSOFA in patients with sepsis outside ICU: A post hoc subgroup analysis by the Japanese Association for Acute Medicine Sepsis Registry Study Group. J Infect Chemother. 2017 Nov;23(11):757-762. doi: 10.1016/j.jiac.2017.07.005 [MEDLINE]
  • SOMANZ guidelines for the investigation and management sepsis in pregnancy. Aust N Z J Obstet Gynaecol. 2017;57(5):540 [MEDLINE]
  • Prognostic Accuracy of Sepsis-3 Criteria for In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department. JAMA. 2017;317(3):301 [MEDLINE]
  • Comparison of QSOFA score and SIRS criteria as screening mechanisms for emergency department sepsis. Am J Emerg Med. 2017;35(11):1730 [MEDLINE]
  • Accuracy of Positive qSOFA Criteria for Predicting 28-Day Mortality in Critically Ill Septic Patients During the Early Period After Emergency Department Presentation. Ann Emerg Med. 2018;71(1):1 [MEDLINE]
  • A Comparison of the Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality: A Systematic Review and Meta-Analysis. Chest. 2018;153(3):646 [MEDLINE]
  • SAILORS Study. Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries. JAMA. 2018;319(21):2202 [MEDLINE]

Clinical Manifestations

General

  • A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis Treatment and Response Registry. Crit Care Med. 2009 Jan;37(1):81-8. doi: 10.1097/CCM.0b013e31819285f0 [MEDLINE]
  • Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Crit Care. 2015 Sep 7;19:319. doi: 10.1186/s13054-015-1035-1 [MEDLINE]

Cardiovascular Manifestations

  • Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 2004;32:660–5 [MEDLINE]
  • Utility of B-type natriuretic peptide for the evaluation of intensive care unit shock. Crit Care Med 2004;32:1643–7 [MEDLINE]
  • Relationship between B-type natriuretic peptides and pulmonary capillary wedge pressure in the intensive care unit. J Am Coll Cardiol 2005;45:1667–71 [MEDLINE]
  • Elevated cardiac troponin measurements in critically ill patients. Arch Intern Med. 2006 Dec 11-25;166(22):2446-54 [MEDLINE]
  • Troponin-I as a prognosticator of mortality in severe sepsis patients. J Crit Care. 2010 Jun;25(2):270-5. doi: 10.1016/j.jcrc.2009.12.001. Epub 2010 Feb 10 [MEDLINE]
  • Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA. 2011 Nov;306(20):2248-54 [MEDLINE]
  • Elevated cardiac troponin T levels in critically ill patients with sepsis. Am J Med. 2013 Dec;126(12):1114-21. doi: 10.1016/j.amjmed.2013.06.029. Epub 2013 Sep 28 [MEDLINE]
  • Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine. Crit Care. 2013 Jun 20;17(3):R117. doi: 10.1186/cc12789 [MEDLINE]
  • Atrial Fibrillation Is an Independent Predictor of Mortality in Critically Ill Patients. Crit Care Med. 2015 Oct;43(10):2104-11. doi: 10.1097/CCM.0000000000001166 [MEDLINE]
  • Practice Patterns and Outcomes of Treatments for Atrial Fibrillation During Sepsis: A Propensity-Matched Cohort Study. Chest. 2016 Jan;149(1):74-83. doi: 10.1378/chest.15-0959. Epub 2016 Jan 6 [MEDLINE]
  • Incidence, Predictors, and Outcomes of New-Onset Atrial Fibrillation in Critically Ill Patients with Sepsis. A Cohort Study. Am J Respir Crit Care Med. 2017 Jan;195(2):205-211 [MEDLINE]
  • Takotsubo Cardiomyopathy and Sepsis. Angiology. 2017 Apr;68(4):288-303. doi: 10.1177/0003319716653886 [MEDLINE]

Endocrinologic Manifestations

  • Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003;78(12):1471 [MEDLINE]
  • Prevalence, incidence, and clinical resolution of insulin resistance in critically ill patients: an observational study. JPEN J Parenter Enteral Nutr. 2008;32(3):227 [MEDLINE]

Gastrointestinal Manifestations

  • Incidence and prognosis of early hepatic dysfunction in critically ill patients–a prospective multicenter study. Crit Care Med. 2007 Apr;35(4):1099-104 [MEDLINE]

Hematologic Manifestations

  • Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis. Crit Care Med. 2015 Oct;43(10):2094-103. doi: 10.1097/CCM.0000000000001162 [MEDLINE]
  • Sepsis-associated thrombocytopenia. Thromb Res. 2016 May;141:11-6. doi: 10.1016/j.thromres.2016.02.022. Epub 2016 Mar 2 [MEDLINE]
  • Histone-Associated Thrombocytopenia in Patients Who Are Critically Ill. JAMA. 2016;315(8):817-819. doi:10.1001/jama.2016.0136 [MEDLINE]

Infectious Manifestations

  • Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis. JAMA. 2016;315(14):1469 [MEDLINE]

Pulmonary Manifestations

  • Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med. 2003;31(3):869 [MEDLINE]
  • Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med. 2008;36(5):1518 [MEDLINE]
  • Early risk factors and the role of fluid administration in developing acute respiratory distress syndrome in septic patients. Ann Intensive Care. 2017;7(1):11. Epub 2017 Jan 23 [MEDLINE]

Renal Manifestations

  • Acute Kidney Injury Requiring Dialysis in Severe Sepsis. Am J Respir Crit Care Med. 2015 Oct 15;192(8):951-7. doi: 10.1164/rccm.201502-0329OC [MEDLINE] -Extended Mortality and Chronic Kidney Disease After Septic Acute Kidney Injury. J Intensive Care Med. 2018 Jan 1:885066618764617. doi: 10.1177/0885066618764617 [MEDLINE]

Toxicologic Manifestations

  • Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand. 1998 Jul;42(6):713-6 [MEDLINE]

Prevention

  • Decontamination Strategies and Bloodstream Infections With Antibiotic-Resistant Microorganisms in Ventilated Patients: A Randomized Clinical Trial. JAMA. 2018;320(20):208 [MEDLINE]

Treatment

General

  • Foreword. The future of sepsis performance improvement. Crit Care Med 2015; 43(9):1787–1789 [MEDLINE]
  • Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015 Jan;43(1):3-12. doi: 10.1097/CCM.0000000000000723 [MEDLINE]
  • Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. PLoS One. 2015 May 6;10(5):e0125827. doi: 10.1371/journal.pone.0125827. eCollection 2015 [MEDLINE]
  • Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Jan 18. doi: 10.1007/s00134-017-4683-6 [MEDLINE]
  • Surviving Sepsis Guidelines: A Continuous Move Toward Better Care of Patients With Sepsis. JAMA. 2017 Feb 28;317(8):807-808. doi: 10.1001/jama.2017.0059 [MEDLINE]
  • Implementation of the Surviving Sepsis Campaign guidelines. Curr Opin Crit Care. 2017 Oct;23(5):412-416. doi: 10.1097/MCC.0000000000000438 [MEDLINE]
  • SOMANZ guidelines for the investigation and management sepsis in pregnancy. Aust N Z J Obstet Gynaecol. 2017;57(5):540 [MEDLINE]

Triage

  • Association of Intensive Care Unit Admission With Mortality Among Older Patients With Pneumonia. JAMA. 2015 Sep;314(12):1272-9 [MEDLINE]
  • ICE-CUB 2Trial. Effect of Systematic Intensive Care Unit Triage on Long-term Mortality Among Critically Ill Elderly Patients in France: A Randomized Clinical Trial. JAMA. 2017;318(15):1450 [MEDLINE]

SEP-1

  • The CMS Sepsis Mandate: Right Disease, Wrong Measure. Ann Intern Med. 2016 Oct 4;165(7):517-518. doi: 10.7326/M16-0588 [MEDLINE]
  • The Past, Present, and Future of the Centers for Medicare and Medicaid Services Quality Measure SEP-1: The Early Management Bundle for Severe Sepsis/Septic Shock. Emerg Med Clin North Am. 2017 Feb;35(1):219-231. doi: 10.1016/j.emc.2016.09.006 [MEDLINE]
  • Sepsis National Hospital Inpatient Quality Measure (SEP-1): Multistakeholder Work Group Recommendations for Appropriate Antibiotics for the Treatment of Sepsis. Clin Infect Dis. 2017 Oct 16;65(9):1565-1569. doi: 10.1093/cid/cix603 [MEDLINE]
  • Accountability for Sepsis Treatment: The SEP-1 Core Measure. Chest. 2017 May;151(5):955-957. doi: 10.1016/j.chest.2017.01.011 [MEDLINE]
  • A quality improvement project to improve the Medicare and Medicaid Services (CMS) sepsis bundle compliance rate in a large healthcare system. BMJ Open Qual. 2017 Oct 21;6(2):e000080. doi: 10.1136/bmjoq-2017-000080. eCollection 2017 [MEDLINE]
  • Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017; 376:2235–2244 [MEDLINE]
  • The SEP-1 quality mandate may be harmful: How to drown a patient with 30 mL per kg fluid! Anaesthesiol Intensive Ther. 2017;49(5):323-328. doi: 10.5603/AIT.a2017.0056 [MEDLINE]
  • Variability in determining sepsis time zero and bundle compliance rates for the centers for medicare and medicaid services SEP-1 measure. Infect Control Hosp Epidemiol. 2018 Aug;39(8):994-996. doi: 10.1017/ice.2018.134 [MEDLINE]
  • Preliminary Performance on the New CMS Sepsis-1 National Quality Measure: Early Insights From the Emergency Quality Network (E-QUAL). Ann Emerg Med. 2018 Jan;71(1):10-15.e1. doi: 10.1016/j.annemergmed.2017.06.032 [MEDLINE]
  • Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study. Crit Care Med 2018; 46:1585–1591 [MEDLINE]
  • Implications of Centers for Medicare & Medicaid Services Severe Sepsis and Septic Shock Early Management Bundle and Initial Lactate Measurement on the Management of Sepsis. Chest. 2018 Aug;154(2):302-308. doi: 10.1016/j.chest.2018.03.025 [MEDLINE]
  • Evidence Underpinning the Centers for Medicare & Medicaid Services’ Severe Sepsis and Septic Shock Management Bundle (SEP-1): A Systematic Review. Ann Intern Med. 2018 Apr 17;168(8):558-568. doi: 10.7326/M17-2947 [MEDLINE]
  • SEP-1: A Sepsis Measure in Need of Resuscitation? Ann Emerg Med. 2018 Jan;71(1):18-20. doi: 10.1016/j.annemergmed.2017.08.057 [MEDLINE]

Setting Goals of Care

  • The impact of advance care planning on end of life care in elderly patients: randomised controlled trial. BMJ 2010, 340:c1345. doi:10.1136/bmj.c1345 [MEDLINE]
  • Randomized, controlled trials of interventions to improve communication in intensive care: a systematic review. Chest 2011, 139(3):543–554 [MEDLINE]
  • Estimating the effect of palliative care interventions and advance care planning on ICU utilization: a systematic review. Crit Care Med 2015, 43(5):1102–1111 [MEDLINE]

Source Control

  • Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect (Larchmt). 2010 Feb;11(1):79-109. doi: 10.1089/sur.2009.9930 [MEDLINE]

Antimicrobial Therapy

  • Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med. 2004;164(15):1669 [MEDLINE]
  • Edusepsis Trial. Effectiveness of treatments for severe sepsis. A prospective multicenter observational study. Am J Respir Crit Care Med 2009;180:861-866 [MEDLINE]
  • Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38:1045-1053 [MEDLINE]
  • Prophylactic antibiotics for burns patients: systematic review and meta‐analysis. BMJ 2010: 340:c241 [MEDLINE]
  • A survival benefit of combination antibiotic therapy for serious infectionsassociated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med. 2010 Aug;38(8):1651-64. doi: 10.1097/CCM.0b013e3181e96b91 [MEDLINE]
  • Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med. 2010 Sep;38(9):1773-85. doi: 10.1097/CCM.0b013e3181eb3ccd [MEDLINE]
  • De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit. Crit Care. 2010;14(6):R225 [MEDLINE]
  • Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171(15):1322 [MEDLINE]
  • Frequency of microbiologically correct antibiotic therapy increased by infectious disease consultations and microbiological results. J Clin Microbiol. 2012 Jun;50(6):2066-8. doi: 10.1128/JCM.06051-11. Epub 2012 Mar 14 [MEDLINE]
  • Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta‐analysis. Clin Infect Dis 2012: 55(5):651–662 [MEDLINE]
  • An ESICM systematic review and meta‐analysis of procalcitonin‐guided antibiotic therapy algorithms in adult critically ill patients. Intensive Care Med 2012: 38(6):940–949 [MEDLINE]
  • IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15. doi: 10.1016/j.pan.2013.07.063 [MEDLINE]
  • Procalcitonin‐guided therapy in intensive care unit patients with severe sepsis
and septic shock—a systematic review and meta‐analysis. Crit Care 2013: 17(6):R291 [MEDLINE]
  • Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta‐analysis. Lancet Infect Dis 2013: 13(5):426–435 [MEDLINE]
  • Procalcitonin‐guided antibiotic therapy: a systematic review and meta‐analysis. J Hosp Med 2013: 8(9):530–540 [MEDLINE]
  • Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection– 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2013;68(10):2183 [MEDLINE]
  • De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2013 [MEDLINE]
  • De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med. 2014 Jan;40(1):32-40. doi: 10.1007/s00134-013-3077-7. Epub 2013 Sep 12 [MEDLINE]
  • Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med. 2014;190(10):1102 [MEDLINE]
  • De‐escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non‐blinded randomized noninferiority trial. Intensive Care Med 2014, 40(10):1399–1408 [MEDLINE]
  • Excluding infection through procalcitonin testing improves outcomes of congestive heart failure patients presenting with acute respiratory symptoms: results from the randomized ProHOSP trial. Int J Cardiol. 2014;175(3):464 [MEDLINE]
  • Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost‐effectiveness analysis. Health Technol Assess 2015: 19(96):v–xxv, 1–236 [MEDLINE]
  • Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372(21):1996 [MEDLINE]
  • Failure of empirical systemic antifungal therapy in mechanically ventilated critically ill patients. Am J Respir Crit Care Med. 2015 May;191(10):1139-46 [MEDLINE]
  • Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016 Jul;16(7):819-27. doi: 10.1016/S1473-3099(16)00053-0. Epub 2016 Mar 2 [MEDLINE]
  • Antibiotic Stewardship Programs in U.S. Acute Care Hospitals: Findings From the 2014 National Healthcare Safety Network Annual Hospital Survey. Clin Infect Dis. 2016 Aug 15;63(4):443-9. doi: 10.1093/cid/ciw323. Epub 2016 May 19 [MEDLINE]
  • Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials. Am J Respir Crit Care Med. 2016 Sep 15;194(6):681-91. doi: 10.1164/rccm.201601-0024OC [MEDLINE]
  • Patients with Complicated Intra-Abdominal Infection Presenting with Sepsis Do Not Require Longer Duration of Antimicrobial Therapy. J Am Coll Surg. 2016;222(4):440 [MEDLINE]
  • Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial. JAMA. 2016;316(15):1555 [MEDLINE]
  • Antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis. Clin Microbiol Infect. 2016;22(12):960 [MEDLINE]
  • Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. Cochrane Database Syst Rev. 2016 Jan 16;(1):CD004920 [MEDLINE]
  • Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017; 376:2235–2244 [MEDLINE]
  • Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2017;1:CD010959 [MEDLINE]
  • Effect of Procalcitonin Testing on Health-care Utilization and Costs in Critically Ill Patients in the United States. Chest. 2017 Jan;151(1):23-33 [MEDLINE]
  • The Cost-Effectiveness of Rapid Diagnostic Testing for the Diagnosis of Bloodstream Infections with or without Antimicrobial Stewardship. Clin Microbiol Rev. 2018 May 30;31(3). pii: e00095-17. doi: 10.1128/CMR.00095-17 [MEDLINE]

Fever Control

  • Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012 May 15;185(10):1088-95 [MEDLINE]
  • Fever control and sepsis mortality. Chest. 2014 Mar 1;145(3):666-7. doi: 10.1378/chest.13-2644 [MEDLINE]
  • The Association of Fever and Antipyretic Medication with Outcomes in Mechanically Ventilated Patients: A Cohort Study. Shock. 2019 May 1. doi: 10.1097/SHK.0000000000001368 [MEDLINE]
  • Fever control in critically ill adults. An individual patient data meta-analysis of randomised controlled trials. Intensive Care Med. 2019 Apr;45(4):468-476. doi: 10.1007/s00134-019-05553-w [MEDLINE]

Bicarbonate Therapy

  • Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: a prospective, controlled clinical study. Ann Intern Med 1990; 112(7):492–498 [MEDLINE]
  • Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Crit Care Med 1991, 19(11):1352–1356 [MEDLINE]
  • Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018 Jul 7;392(10141):31-40. doi: 10.1016/S0140-6736(18)31080-8 [MEDLINE]

Blood Pressure Target

  • SEPSISPAM. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014;370:1583-1593 [MEDLINE]
  • Blood pressure targets for vasopressor therapy: a systematic review. Shock. 2015 Jun;43(6):530-9. doi: 10.1097/SHK.0000000000000348 [MEDLINE]
  • Optimizing mean arterial pressure in septic shock: a critical reappraisal of the literature. Crit Care. 2015 Mar 10;19:101. doi: 10.1186/s13054-015-0794-z [MEDLINE]
  • Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med 2016; 42(4):542–550 [MEDLINE]

Fluid Resuscitation Strategy (Including Early Goal-Directed Therapy)

  • Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001; 345:1368-1377 [MEDLINE]
  • Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564 [MEDLINE]
  • EMShockNet: Lactate clearance versus central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303(8):739-746 [MEDLINE]
  • PROCESS Trial: A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18 [MEDLINE]
  • The ProCESS trial: A new era of sepsis management. N Engl J Med 2014;370:1750-1751 [MEDLINE]
  • ARISE Trial: Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1 [MEDLINE]
  • SEPSISPAM. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014;370:1583-1593 [MEDLINE]
  • PROMISE Trial: Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. doi: 10.1056/NEJMoa1500896. Epub 2015 Mar 17. [MEDLINE]
  • A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015 Sep;41(9):1549-60 [MEDLINE]
  • Association between fluid balance and survival in critically ill patients. J Intern Med.  2015;277:468–477 [MEDLINE]
  • Targeted Fluid Minimization Following Initial Resuscitation in Septic Shock: A Pilot Study. Chest. 2015 Dec;148(6):1462-9. doi: 10.1378/chest.15-1525 [MEDLINE]
  • Fluid overload, de‐resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther 2014: 46(5):361–380 [MEDLINE]
  • A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care 2015: 19:251 [MEDLINE]
  • Volume overload: prevalence, risk factors, and functional outcome in survivors of septic shock. Ann Am Thorac Soc 2015: 12(12):1837–1844 [MEDLINE]
  • Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5‐year study. Crit Care Med 2015: 43 (1):3–12 [MEDLINE]
  • Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock. 2015;43(1):68 [MEDLINE]
  • Positive fluid balance as a prognostic factor for mortality and acute kidney injury in severe sepsis and septic shock. J Crit Care 2015: 30(1):97–101 [MEDLINE]
  • Positive fluid balance as a major predictor of clinical outcome of patients with sepsis/septic shock after ICU discharge. Am J Emerg Med 2016: 34(11):2122–2126 [MEDLINE]
  • A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016;116:339-49 [MEDLINE]
  • Early goal‐directed therapy for severe sepsis and septic shock: a living systematic review. J Crit Care 2016; 36:43–48 [MEDLINE]
  • Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017; 376:2235–2244 [MEDLINE]
  • Early, Goal-Directed Therapy for Septic Shock – A Patient-Level Meta-Analysis. N Engl J Med. 2017 Jun 8;376(23):2223-2234. doi: 10.1056/NEJMoa1701380 [MEDLINE]
  • Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA. 2017;318(13):1233 [MEDLINE]
  • Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155-170 [MEDLINE]
  • Intensive Monitoring of Urine Output Is Associated With Increased Detection of Acute Kidney Injury and Improved Outcomes. Chest. 2017 Nov;152(5):972-979. doi: 10.1016/j.chest.2017.05.011 [MEDLINE]
  • Evidence Underpinning the U.S. Government-Mandated Hemodynamic Interventions for Sepsis: A Systematic Review. Ann Intern Med. 2018 Feb 20. doi: 10.7326/M17-2947 [MEDLINE]
  • Treating Sepsis Is Complicated: Are Governmental Regulations for Sepsis Care Too Simplistic? Ann Intern Med. 2018 Feb 20. doi: 10.7326/M18-0290 [MEDLINE]
  • Early Goal-Directed Therapy in Severe Sepsis and Septic Shock: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. J Intensive Care Med. 2018;33(5):296 [MEDLINE]
  • FRESH Trial. Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. Chest. 2020 Apr 27;S0012-3692(20)30768-6. doi: 10.1016/j.chest.2020.04.025 [MEDLINE]

Lactate-Guided Therapy

  • Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32(8):1637-1642
  • Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009; 32(1):35-39
  • LACTATE Study. Early lactate-guided therapy in intensive care unit patients. Am J Respir Crit Care Med 2010; 182:752-761 [MEDLINE]
  • Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303(8):739–746 [MEDLINE]
  • The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2012; 24(1):42–45 [MEDLINE]
  • Comparison of the effect of fluid resuscitation as guided either by lactate clearance rate or by central venous oxygen saturation in patients with sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2013; 25(10):578–583 [MEDLINE]
  • Efficacies of fluid resuscitation as guided by lactate clearance rate and central venous oxygen saturation in patients with septic shock. Zhonghua Yi Xue Za Zhi 2015; 95(7):496–500 [MEDLINE]
  • Early lactate clearance‐guided therapy in patients with sepsis: a meta‐analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med 2015; 41(10):1862–1863 [MEDLINE]
  • Early goal‐directed therapy for severe sepsis and septic shock: a living systematic review. J Crit Care 2016: 36:43–48 [MEDLINE]
  • SEP-1: The Lactate Myth and Other Fairytales. Crit Care Med. 2018 Oct;46(10):1689-1690. doi: 10.1097/CCM.0000000000003313 [MEDLINE]

Choice of Resuscitation Fluid

  • SAFE Trial: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247–2256 [MEDLINE]
  • VISEP Trial. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125 [MEDLINE]
  • An Official ATS/ERS/ESICM/SCCM/SRLF Statement:  Prevention and Management of Acute Renal Failure in the ICU Patient: an international consensus conference in intensive care medicine.  Am J Respir Crit Care Med  2010;  181:1128-1155.  DOI:  10.1164/rccm.200711-1664ST [MEDLINE]
  • The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011 Feb;39(2):386-91. doi: 10.1097/CCM.0b013e3181ffe217 [MEDLINE]
  • Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev. Nov 9 2011;CD001208 [MEDLINE]
  • Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72. doi: 10.1001/jama.2012.13356 [MEDLINE]
  • 6S Trial. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124 [MEDLINE]
  • CHEST Trial. Hydroxyethyl starch or saline for fluid resuscitation in intensive care.  N Engl J Med  Nov 15, 2012;  367(20):1901-1911.  DOI: 10.1056/NEJMoa1209759.  Epub Oct 17, 2012 [MEDLINE]
  • Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013 Nov 6;310(17):1809-17. doi: 10.1001/jama.2013.280502 [MEDLINE]
  • Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care. 2014;18(6):702 [MEDLINE]
  • Albumin versus other fluids for fluid resuscitation in patients with sepsis: a meta-analysis. PLoS One. 2014;9(12):e114666 [MEDLINE]
  • Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis. Ann Intern Med. 2014 Jul 22. doi: 10.7326/M14-0178 [MEDLINE]
  • ALBIOS Study. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727. Epub 2014 Mar 18 [MEDLINE]
  • Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med. 2017;5(3):180 [MEDLINE]
  • Choice of resuscitative fluids and mortality in emergency department patients with sepsis. Am J Emerg Med. 2018;36(4):625 [MEDLINE]
  • Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):819-828. doi: 10.1056/NEJMoa1711586 [MEDLINE]
  • Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584 [MEDLINE]

Choice of Vasopressor

  • Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103:1826-1831
  • The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994; 272:1354-1357
  • Methylene blue increases myocardial function in septic shock. Crit Care Med 1995;23:1363–70
  • Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock. Intensive Care Med 1995;21: 1027–31
  • Methylene blue administration in septic shock: a clinical trial. Crit Care Med 1995;23:259–64
  • Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122-1125
  • Use of methylene blue in patients with refractory septic shock: impact on hemodynamics and gas exchange. J Crit Care 1998;13:164–8
  • Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue. Braz J Med Biol Res 1999;32:1505–13
  • Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors. Circulation 1999; 100 (suppl II):II-244-II-246
  • Low-dose vasopressin (VP) in the treatment of vasodilatory septic shock. J Trauma 1999; 47:699-703
  • The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 2001; 93:7-13
  • Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med 2001;29:1860–7 [MEDLINE]
  • Does methylene blue administration to septic shock patients affect vascular permeability and blood volume? Crit Care Med 2002;30: 2271–7
  • The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care 2002;30:755–62
  • Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 2002 Mar;96(3):576-82 [MEDLINE]
  • The effects of methylene blue on hemodynamic parameters and cytokine levels in refractory septic shock. Korean J Intern Med 2005;20:123–8
  • Use of methylene blue in sepsis: a systematic review. J Intensive Care Med. 2006 Nov-Dec;21(6):359-63 [MEDLINE]
  • VASST Trial. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373 [MEDLINE]
  • Short-term beneficial effects of methylene blue on kidney damage in septic shock patients. Intensive Care Med 2008;34:350–4
  • The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010 May;51(3):194-200 [MEDLINE]
  • SOAP II Trial. Comparison of dopamine and norepinephrine in the treatment of shock.  N Engl J Med 2010; 362:779-789 [MEDLINE]
  • Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock. Indian J Crit Care Med. 2010 Jan;14(1):29-34. doi: 10.4103/0972-5229.63033 [MEDLINE]
  • Discontinuation of vasopressin before norepinephrine increases the incidence of hypotension in patients recovering from septic shock: a retrospective cohort study. J Crit Care. 2010;25:362 e367–11 [MEDLINE]
  • Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis. Crit Care Med 2012;40:725-730 [MEDLINE]
  • The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock. Chest. 2012 Sep;142(3):593-605 [MEDLINE]
  • Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine. Crit Care. 2013 Jun 20;17(3):R117. doi: 10.1186/cc12789 [MEDLINE]
  • Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study. Intensive Care Med. 2013 Aug;39(8):1435-43. doi: 10.1007/s00134-013-2982-0 [MEDLINE]
  • Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol. 2013 Sep;9(3):242-9. doi: 10.1007/s13181-013-0298-7 [MEDLINE]
  • A review of methylene blue treatment for cardiovascular collapse. J Emerg Med. 2014 May;46(5):670-9 [MEDLINE]
  • Mortality benefit of vasopressor and inotropic agents in septic shock: a Bayesian network meta-analysis of randomized controlled trials. J Crit Care. 2014 Oct;29(5):706-10. doi: 10.1016/j.jcrc.2014.04.011. Epub 2014 Apr 26 [MEDLINE]
  • The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial. Crit Care Med. 2014 Jun;42(6):1325-33. doi: 10.1097/CCM.0000000000000212 [MEDLINE]
  • Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014 Oct 6;18(5):534. doi: 10.1186/s13054-014-0534-9 [MEDLINE]
  • Vasopressors in septic shock: a systematic review and network meta-analysis. Ther Clin Risk Manag. 2015 Jul 14;11:1047-59. doi: 10.2147/TCRM.S80060. eCollection 2015 [MEDLINE]
  • Angiotensin II in septic shock. Crit Care. 2015 Mar 16;19:98. doi: 10.1186/s13054-015-0802-3 [MEDLINE]
  • Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis. PLoS One. 2015 Aug 3;10(8):e0129305. doi: 10.1371/journal.pone.0129305. eCollection 2015 [MEDLINE]
  • The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. Br J Anaesth. 2015 Nov;115(5):656-75. doi: 10.1093/bja/aev284 [MEDLINE]
  • Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther. 2015 May;20(3):249-60. doi: 10.1177/1074248414559838. Epub 2014 Nov 28 [MEDLINE]
  • Vasopressors for the treatment of septic shock: systematic review and meta-analysis. PloS One. 2015;10(8):e0129305 [MEDLINE]
  • Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485 [MEDLINE]
  • Comparative safety and efficacy of vasopressors for mortality in septic shock: A network meta-analysis. J Intensive Care Soc. 2016;17(2):136 [MEDLINE]
  • Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016;2:CD003709 [MEDLINE]
  • ATHOS-3 trial. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154 [MEDLINE]
  • Severe Undifferentiated Vasoplegic Shock Refractory to Vasoactive Agents Treated with Methylene Blue. Case Rep Crit Care. 2017;2017:8747326. doi: 10.1155/2017/8747326 [MEDLINE]
  • Angiotensin II in Refractory Septic Shock. Shock. 2017 May;47(5):560-566. doi: 10.1097/SHK.0000000000000807 [MEDLINE]
  • A systematic analysis of methylene blue for drug-induced shock in humans. Clin Toxicol (Phila). 2017 Mar;55(3):228. doi: 10.1080/15563650.2016.1271885 [MEDLINE]
  • Discontinuation of vasopressin before norepinephrine in the recovery phase of septic shock. J Intensive Care Med. 2017: 885066617714209 [MEDLINE]
  • Intraoperative vasoplegia: methylene blue to the rescue! Curr Opin Anaesthesiol. 2018;31(1):43 [MEDLINE]
  • Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Crit Care Med. 2018 Jun;46(6):949-957. doi: 10.1097/CCM.0000000000003092 [MEDLINE]
  • Intraoperative vasoplegia: methylene blue to the rescue! Curr Opin Anaesthesiol. 2018;31(1):43 [MEDLINE]
  • Angiotensin in Critical Care. Crit Care. 2018 Mar 20;22(1):69. doi: 10.1186/s13054-018-1995-z [MEDLINE]
  • Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA. 2018 May 8;319(18):1889-1900. doi: 10.1001/jama.2018.4528 [MEDLINE]
  • Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial (DOVSS). Crit Care. 2018 May 21;22(1):131. doi: 10.1186/s13054-018-2034-9 [MEDLINE]
  • Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med. 2019 Feb 1. doi: 10.1164/rccm.201806-1034OC [MEDLINE]

Inotropic Therapy

  • Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330:1717–1722 [MEDLINE]
  • A trial of goal-oriented hemodynamic therapy in critically ill patients. Svo2 Collaborative Group. N Engl J Med 1995; 333:1025–1032 [MEDLINE]

Midodrine (see Midodrine)

  • Feasibility, utility, and safety of midodrine during recovery phase from septic shock. Chest. 2016 Mar 4. pii: S0012-3692(16)41575-8. doi: 10.1016/j.chest.2016.02.657 [MEDLINE]

Arrhythmia Management

  • Practice Patterns and Outcomes of Treatments for Atrial Fibrillation During Sepsis: A Propensity-Matched Cohort Study. Chest. 2016 Jan;149(1):74-83. doi: 10.1378/chest.15-0959. Epub 2016 Jan 6 [MEDLINE]

Corticosteroids (see Corticosteroids)

  • Steroids in the treatment of clinical septic shock. Ann Surg 1976; 184:333-41 [MEDLINE]
  • The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984;311:1137-43 [MEDLINE]
  • A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317:653-8 [MEDLINE]
  • A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317:653-658 [MEDLINE]
  • Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71 [MEDLINE]
  • Steroids for septic shock: back from the dead? (Con). Chest 2003; 123:482S-489S
  • Cortisol response to critical illness: effect of intensive insulin therapy. J Clin Endocrinol Metab 2006;91:3803-13 [MEDLINE]
  • CORTICUS Trial. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366 [MEDLINE]
  • Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008 Jun;36(6):1937-49 [MEDLINE]
  • The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med. 2009 Nov;35(11):1868-76. doi: 10.1007/s00134-009-1603-4. Epub 2009 Aug 4 [MEDLINE]
  • Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009 Jun 10;301(22):2362-75 [MEDLINE]
  • Global utilization of low-dose corticosteroids in severe sepsis and septic shock: a report from the PROGRESS registry. Crit Care 2010;14:R102 [MEDLINE]
  • Systemic steroids in severe sepsis and septic shock. Am J Respir Crit Care Med. 2012 Jan 15;185(2):133-9 [MEDLINE]
  • Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign. Intensive Care Med. 2012 Dec;38(12):1946-54 [MEDLINE]
  • Reduced cortisol metabolism during critical illness. N Engl J Med. 2013 Apr 18;368(16):1477-88. doi: 10.1056/NEJMoa1214969. Epub 2013 Mar 19 [MEDLINE]
  • Adrenal dysfunction in critically ill patients. N Engl J Med 2013;368(16):1547-1548 [MEDLINE]
  • Corticosteroids for treating sepsis. Cochrane Database Syst Rev 2015;12:CD002243 [MEDLINE]
  • Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 2015;41: 1220-34 [MEDLINE]
  • Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016;316(17):1775 [MEDLINE]
  • ADRENAL trial. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/NEJMoa1705835. Epub 2018 Jan 19 [MEDLINE]
  • APROCCHSS Trial. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716 [MEDLINE]
  • Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2018;44(7):1003 [MEDLINE]
  • Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis. Crit Care Med. 2018 Sep;46(9):1411-1420. doi: 10.1097/CCM.0000000000003262 [MEDLINE]
  • HYVCTTSSS Trial. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. Chest 2020 Jul;158(1):174-182. doi: 10.1016/j.chest.2020.02.065 [MEDLINE]
  • Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049 [MEDLINE]

Vitamin C (see Vitamin C)

  • Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036 [MEDLINE]
  • Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest. 2017 Nov;152(5):954-962. doi: 10.1016/j.chest.2017.07.014 [MEDLINE]
  • Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Ther. 2018 Sep;189:63-70. doi: 10.1016/j.pharmthera.2018.04.007 [MEDLINE]
  • Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis. Crit Care. 2018 Oct 11;22(1):258. doi: 10.1186/s13054-018-2191-x [MEDLINE]
  • Bet 2: Does intravenous vitamin C improve mortality in patients with severe sepsis? Emerg Med J. 2018 Apr;35(4):272-274. doi: 10.1136/emermed-2018-207608.3 [MEDLINE]
  • Vitamin C: The next step in sepsis management? J Crit Care. 2018 Feb;43:230-234. doi: 10.1016/j.jcrc.2017.09.031 [MEDLINE]
  • Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270. doi: 10.1001/jama.2019.11825 [MEDLINE]
  • HYVCTTSSS Trial. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. Chest 2020 Jul;158(1):174-182. doi: 10.1016/j.chest.2020.02.065 [MEDLINE]
  • Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049 [MEDLINE]

Glycemic Control

  • Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367
  • Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461 [MEDLINE]
  • Insulin therapy for critically ill hospitalized patients. Arch Intern Med. 2004;164:2005-2011
  • German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139
  • VISEP Trial. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125 [MEDLINE]
  • NICE-SUGAR Trial. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283 [MEDLINE]
  • A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009;35(10):1738 [MEDLINE]
  • Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009;180(8):821 [MEDLINE]
  • Corticosteroid treatment and intensive insulin therapy for septic shock (COIITSS) in adults: a randomized controlled trial. JAMA. 2010;303(4):341 [MEDLINE]
  • Systematic review: intensive insulin therapy in hospitalized patients. Ann Intern Med. 2011;154: 268 [MEDLINE]
  • Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260 [MEDLINE]

Anemia Management (see Anemia)

  • Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double‐blind, placebo‐controlled trial. Crit Care Med 1999, 27(11):2346–2350 [MEDLINE]
  • A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-417 [MEDLINE]
  • Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001; 345:1368-1377 [MEDLINE]
  • Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002, 288(22):2827–2835 [MEDLINE]
  • Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009 Apr;7(2):132-50. doi: 10.2450/2009.0005-09 [MEDLINE]
  • Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012;157(1):49 [MEDLINE]
  • Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol. 2013 Feb;160(4):445-64. doi: 10.1111/bjh.12143. Epub 2012 Dec 27 [MEDLINE]
  • ARISE Trial: Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1 [MEDLINE]
  • Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617. Epub 2014 Oct 1 [MEDLINE]
  • An official American Thoracic Society/American Association of Critical-Care Nurses/American College of Chest Physicians/Society of Critical Care Medicine policy statement: the Choosing Wisely® Top 5 list in Critical Care Medicine. Am J Respir Crit Care Med. 2014 Oct 1;190(7):818-26. doi: 10.1164/rccm.201407-1317ST [MEDLINE]
  • Efficacy and Safety of Erythropoietin to Prevent Acute Kidney Injury in Patients With Critical Illness or Perioperative Care: A Systematic Review and Meta-analysis of Randomized Controlled Trials. J Cardiovasc Pharmacol. 2015 Jun;65(6):593-600. doi: 10.1097/FJC.0000000000000229 [MEDLINE]

Nutritional Support

  • Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863 [MEDLINE]
  • The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta‐analysis of randomized trials. Crit Care 2016, 20(1):259 [MEDLINE]
  • Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863 [MEDLINE]

Renal Support

  • Continuous versus intermittent renal replacement therapy: a meta‐analysis. Intensive Care Med 2002, 28(1):29–37 [MEDLINE]
  • Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002, 40(5):875–885 [MEDLINE]
  • IDEAL-ICU Trial. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018;379(15):1431 [MEDLINE]

Respiratory Support

  • Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016;316(15):1583 [MEDLINE]
  • Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018 Apr 28;391(10131):1693-1705. doi: 10.1016/S0140-6736(18)30479-3 [MEDLINE]

Stress Ulcer Prophylaxis

  • Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta‐ analysis and trial sequential analysis. Intensive Care Med 2014, 40(1):11–22 [MEDLINE]

Antithrombin III (see Antithrombin III)

  • Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286:1869-1878
  • KyberSept Trial: High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med. 2006 Feb;34(2):285-92 [MEDLINE]
  • Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD005370 [MEDLINE]
  • Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2016 Feb 8;2:CD005370. doi: 10.1002/14651858.CD005370.pub3 [MEDLINE]

Heparin (see Heparin)

  • The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med. 2015 Mar;43(3):511-8. doi: 10.1097/CCM.0000000000000763 [MEDLINE]

Drotrecogin Alfa (Xigris) (see Drotrecogin Alfa

  • Efficacy and safety of recombinant activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
  • Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003;31:12-19
  • PROWESS Trial: The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results. Crit Care Med 2003;31:2291-2301
  • ADDRESS Trial: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005 Sep 29;353(13):1332-41 [MEDLINE]
  • PROWESS Shock Trial: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31;366(22):2055-64 [MEDLINE]

Eritoran (see Eritoran)

  • Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis. JAMA. 2013 Mar 20;309(11):1154-62 [MEDLINE]

Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin)

  • Score‐based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 2007, 35(12):2693–2701 [MEDLINE]
  • Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev 2013, 9:CD001090 [MEDLINE]

Prognosis/Sequelae

  • Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med. 1980;68(3):344 [MEDLINE]
  • Urinary tract etiology of bloodstream infections in hospitalized patients. J Infect Dis. 1983;148(1):57 [MEDLINE]
  • Evaluation of definitions for sepsis. Chest. 1992;101(6):1656 [MEDLINE]
  • Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368 [MEDLINE]
  • Insights into severe sepsis in older patients: from epidemiology to evidence-based management. Clin Infect Dis. 2005;40(5):719 [MEDLINE]
  • The epidemiology of sepsis in patients with malignancy. Chest. 2006;129(6):1432 [MEDLINE]
  • Healthcare-associated bloodstream infection: A distinct entity? Insights from a large U.S. database. Crit Care Med. 2006;34(10):2588 [MEDLINE]
  • Alcohol dependence is independently associated with sepsis, septic shock, and hospital mortality among adult intensive care unit patients. Crit Care Med. 2007;35(2):34 [MEDLINE]
  • Risk factors for death after sepsis in patients immunosuppressed before the onset of sepsis. Scand J Infect Dis. 2009;41(6-7):469 [MEDLINE]
  • Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA. 2011 Nov;306(20):2248-54 [MEDLINE]
  • Impact of previous antibiotic therapy on outcome of Gram-negative severe sepsis. Crit Care Med. 2011;39(8):1859 [MEDLINE]
  • Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Crit Care Med. 2011;39(8):1886 [MEDLINE]
  • The determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment. Crit Care Med. 2012;40(7):2016 [MEDLINE]
  • BRAIN-ICU: Long-Term Cognitive Impairment after Critical Illness. N Engl J Med. 2013 Oct 3;369(14):1306-1316 [MEDLINE]
  • Long-term mortality and quality of life after septic shock: a follow-up observational study. Intensive Care Med. 2013 May;39(5):881-8 [MEDLINE]
  • A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med. 2014 Jun;40(6):839-45 [MEDLINE]
  • Subsequent infections in survivors of sepsis: epidemiology and outcomes. J Intensive Care Med. 2014;29(2):87 [MEDLINE]
  • Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med. 2014;190(1):62 [MEDLINE]
  • Sepsis severe or septic shock: outcome according to immune status and immunodeficiency profile. Chest. 2014 Nov;146(5):1205-13 [MEDLINE]
  • Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014;311(13):1308-1316 [MEDLINE]
  • Association between source of infection and hospital mortality in patients who have septic shock. Am J Respir Crit Care Med. 2014;189(10):1204 [MEDLINE]
  • Readmission diagnoses after hospitalization for severe sepsis and other acute medical conditions. JAMA. 2015 Mar;313(10):1055-7 [MEDLINE]
  • Post-Acute Care Use and Hospital Readmission after Sepsis. Ann Am Thorac Soc. 2015;12(6):904 [MEDLINE]
  • Impact of obesity on sepsis mortality: A systematic review. J Crit Care. 2015 Jun;30(3):518-24. doi: 10.1016/j.jcrc.2014.12.007 [MEDLINE]
  • Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients. Crit Care Med. 2015 Sep;43(9):1938-44 [MEDLINE]
  • Thromboelastography in patients with severe sepsis: a prospective cohort study. Intensive Care Med. 2015 Jan;41(1):77-85 [MEDLINE]
  • Late mortality after sepsis: propensity matched cohort study. BMJ. 2016;353:i2375 [MEDLINE]
  • Long-Term Mortality and Major Adverse Cardiovascular Events in Sepsis Survivors. A Nationwide Population-based Study. Am J Respir Crit Care Med. 2016 Jul;194(2):209-17 [MEDLINE]
  • Is Thrombocytopenia an Early Prognostic Marker in Septic Shock? Crit Care Med. 2016 Apr;44(4):764-72 [MEDLINE]
  • SMOOTH Trial. Effect of a Primary Care Management Intervention on Mental Health-Related Quality of Life Among Survivors of Sepsis: A Randomized Clinical Trial. JAMA. 2016 Jun;315(24):2703-11 [MEDLINE]
  • Severe hyperlactatemia, lactate clearance and mortality in unselected critically ill patients. Intensive Care Med. 2016 Feb;42(2):202-10 [MEDLINE]
  • Admission Hyperglycemia in Critically Ill Sepsis Patients: Association With Outcome and Host Response. Crit Care Med. 2016 Jul;44(7):1338-46 [MEDLINE]
  • Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017 Jan 17;317(3):290-300. doi: 10.1001/jama.2016.20328 [MEDLINE]
  • Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results From the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study. Crit Care Med. 2017;45(5):781 [MEDLINE]
  • Incidence, Predictors, and Outcomes of New-Onset Atrial Fibrillation in Critically Ill Patients with Sepsis. A Cohort Study. Am J Respir Crit Care Med. 2017 Jan;195(2):205-211 [MEDLINE]
  • Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection: A Systematic Review and Meta-analysis. Ann Intern Med. 2018;168(4):266. Epub 2018 Feb 6 [MEDLINE]
  • A Comparison of the Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality: A Systematic Review and Meta-Analysis. Chest. 2018;153(3):646 [MEDLINE]