MD Nexus

Sepsis-Part 1

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) (see Fever)
    • Leukocytosis (White Blood Cell >12k) or Leukopenia (WBC <4k) or Bandemia (Bands >10%) (see Leukocytosis)
    • Tachycardia (Heart Rate >90 bpm) (see Sinus Tachycardia)
    • Tachypnea (Respiratory Rate >20 breaths/min) (see Tachypnea)
  • 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
  • Septic Shock: including both of the following
    • Severe Sepsis
    • Hypotension Persisting in the Hour After the Intravenous Fluid Bolus as Evidenced By Either of the Following (see Hypotension)
      • 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

Etiology

Cardiovascular Sources

Dermatologic Sources

  • Burn (see Burns)
  • 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 or Other 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
  • Gastrointestinal/Hepatic
    • Impaired Gastrointestinal Barrier Function, Resulting in Bacterial/Endotoxin Translocation into the Systemic Circulation
    • Hepatic Dysfunction, Resulting in Impaired Clearance of Endotoxin and Other Bacterial Products
  • Hematologic
  • 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
  • Pulmonary
    • Interstitial/Alveolar Pulmonary Edema with Ventilation/Perfusion Mismatch
      • Due to Endothelial Injury with Increased Vascular Permeability
  • 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

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 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
        • 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 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 (see xxxx)
    • 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

  • The Association of Serum Lactate Level with Mortality Rate in Patients with Suspected Infection and Sepsis is Well-Established
    • 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 (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]

  • For Adults Suspected of Having Sepsis, Measurement of Blood Lactate is Recommended (Weak Recommendation, Low Quality of 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 (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021)(Crit Care Med, 2021) [MEDLINE]

  • For Adults with Septic Shock, Invasive Arterial Blood Pressure Monitoring is Recommended Over Noninvasive Arterial Blood Pressure Monitoring, as Soon as Practical and if Resources are Available (Weak Recommendation, Very Low Quality of Evidence)

Swan-Ganz Catheterization (see Swan-Ganz Catheter)

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

Systemic Inflammatory Response Syndrome (SIRS) Score

  • 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) Score (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) Score

  • 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

National Early Warning Score (NEWS)

Scoring Criteria (Infect Drug Resist, 2020) [MEDLINE]

  • Respiratory Rate (Breaths/min)
    • ≤8 Breaths/min = 3 pts
    • 9-11 Breaths/min = 1 pts
    • 12-20 Breaths/min = 0 pt
    • 21-24 Breaths/min = 2 pts
    • ≥25 Breaths/min = 3 pts
  • Oxygen Saturation
    • ≤91% = 3 pts
    • 92-93% = 2 pts
    • 94-95% = 1 pt
    • ≥96% = 0 pts
  • Any Supplemental Oxygen
    • Yes = 2 pts
    • No = 0 pts
  • Temperature
    • ≤35°C = 3 pts
    • 35.1-36.0°C = 1 pts
    • 36.1-38°C = 0 pts
    • 38.1-39.0°C = 1 pts
    • ≤39.1°C = 2 pts
  • Systolic Blood Pressure (SBP)
    • ≤90 mm Hg = 3 pts
    • 91-100 mm Hg = 2 pts
    • 101-110 = 1 pts
    • 111-219 mm Hg = 0 pts
    • ≥220 mm Hg = 3 pts
  • Heart Rate (Beats/min)
    • ≤40 Beats/min = 3 pts
    • 41-50 Beats/min = 1 pts
    • 51-90 Beats/min = 0 pts
    • 91-110 Beats/min = 1 pt
    • 111-130 Beats/min = 2 pts
    • ≥131 Beats/min = 3 pts
  • Level of Consciousness
    • Alert = 0 pts
    • Unresponsive/React to Pain or Loud Voice = 3 pts

Scoring

  • Score Range: 0-20
  • Low Score = NEWS 1–4
  • Medium Score = NEWS 5–6
  • High Score = NEWS ≥7

Modified Early Warning Score (MEWS)

Scoring Criteria (Am J Respir Crit Care Med, 2017) [MEDLINE]

  • Respiratory Rate (Breaths/min)
    • <8 Breaths/min = 2 pts
    • 9-14 Breaths/min = 0 pts
    • 15-20 Breaths/min = 1 pts
    • 21-29 Breaths/min = 2 pts
    • ≥29 Breaths/min = 3 pts
  • Temperature
    • <35°C = 2 pts
    • 35.1–36.0°C = 1 pts
    • 36.1–38.0°C (95–101.1°F) = 0 pts
    • 38.1-38.5°C = 1 pts
    • ≥38.6°C = 2 pts
  • Systolic Blood Pressure (SBP)
    • ≤70 mm Hg = 3 pts
    • 71-80 mm Hg = 2 pts
    • 81-100 mm Hg = 1 pts
    • 101-199 mm Hg = 0
    • ≥200 mm Hg = 2 pts
  • Heart Rate (Beats/min)
    • <40 Beats/min = 2 pts
    • 41-50 Beats/min = 1 pts
    • 51-100 Beats/min = 0 pts
    • 101-110 Beats/min = 1 pts
    • 111-129 Beats/min = 2 pts
    • >129 Beats/min = 3 pts
  • Alert/Voice/Pain/Unresponsive (AVPU) Score
    • Alert = 0 pts
    • Reacts to Voice = 1 pts
    • Reacts to Pain = 2 pts
    • Unresponsive = 3 pts
  • Urine Output (ml/kg/hr)
    • <0.5 ml/kg/hr= 2 pts
    • 0 ml/kg/hr = 3 pts

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
  • Study of Quick Sepsis-Related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores for Detecting Clinical Deterioration in Infected Patients Outside of the Intensive Care Unit (in Emergency Department or Hospital Wards) (Am J Respir Crit Care Med, 2017) [MEDLINE]: n = 30,677
    • NEWS/MEWS were More Accurate than qSOFA for for Predicting Death and Intensive Care Unit Transfer in Non-Intensive Care Unit Patients
      • Discrimination for In-Hospital Mortality was Highest for NEWS (Area Under the Curve 0.77; 95% CI: 0.76–0.79), followed by MEWS (Area Under the Curve 0.73; 95% CI: 0.71–0.74), qSOFA (Area Under the Curve 0.69; 95% CI: 0.67–0.70), and SIRS (Area Under the Curve 0.65; 95% CI: 0.63–0.66) (P , 0.01 for All Pairwise Comparisons)
      • Using the Highest Non-ICU Score of Patients, >2 SIRS had a Sensitivity of 91% and Specificity of 13% for the Composite Outcome Compared with 54% and 67% for qSOFA >2, 59% and 70% for MEWS >5, and 67% and 66% for NEWS >8, Respectively
      • Most Patients Met >2 SIRS Criteria 17 hrs Before the Combined Outcome Compared with 5 hrs for >2 and 17 hrs for >1 qSOFA Criteria
  • 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
  • Meta-Analysis of Machine Learning for Detection of Sepsis in Hospitalized Patients (Comput Methods Programs Biomed. 2019 Mar;170:1-9. doi: 10.1016/j.cmpb.2018.12.027 [MEDLINE]: = n = 42,623 (7 studies)
    • For Machine Learning, the Pooled Area Under the Receiving Operating Curve (SAUROC) was 0.89 (95% CI, 0.86−0.92), the Sensitivity was 81% (95% CI, 80−81), and the Specificity was 72% (95% CI, 72−72)
      • These were All Higher for Machine Learning than the SAUROC for Traditional Screening Tools (SIRS 0.70, MEWS 0.50, and SOFA 0.78)*
  • Study of Oxygen Saturation (SpO2) in SOFA Sepsis Scoring (Crit Care Med, 2021) [MEDLINE]: n = 19,396 sepsis episodes (main cohort) and n = 10,586 episodes (validation cohort)
    • Oxygen Saturations 96-95% Were Not Significantly Associated with Increased Mortality Rate in the Main or Validation Cohorts
    • Oxygen Saturation 94%, the Adjusted Odds Ratio of Death was 1.56 (95% CI: 1.10-2.23) in the Main Cohort and 1.36 (95% CI: 1.00-1.85) in the Validation Cohorts and Increased Gradually Below This Level
    • Oxygen Saturation/FIO2 Ratio Had Slightly Better Predictive Performance, as Compared with Oxygen Saturation Alone
    • These Findings Provide Evidence for Assessing Respiratory Function with Oxygen Saturation in the Sequential Organ Failure Assessment (SOFA) Score and the Sepsis-3 Criteria

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 Efficacy

  • 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

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

  • Systemic Inflammatory Response Syndrome (SIRS), National Early Warning Score (NEWS), or Modified Early Warning System (MEWS) Should Be Used Instead of qSOFA as a Single-Screening Tool for Sepsis/Septic Shock (Strong Recommendation, Moderate Quality of Evidence

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

Sepsis-Induced Coagulopathy (SIC)/Disseminated Intravascular Coagulation (DIC) (see Coagulopathy and Disseminated Intravascular Coagulation)

  • Epidemiology
    • Either Sepsis-Induced Coagulopathy (SIC)/Disseminated Intravascular Coagulation (DIC) May Occur
    • 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
  • Physiology (J Thromb Haemost, 2019) [MEDLINE]
    • Sepsis‐Associated Disseminated Intravascular Coagulation (DIC) is Characterized by Overproduction of Plasminogen Activator Inhibitor‐1 with Excessive Suppression of Fibrinolysis, Resulting in Prothrombotic Effects
      • In Contrast, This Suppression of Plasminogen Activator Inhibitor‐1 is Rarely Observed in Malignancy‐Associated Disseminated Intravascular Coagulation (DIC)
    • Consequently, Organ Dysfunction Frequently Develops in Sepsis‐Associated Disseminated Intravascular Coagulation (DIC) Due to Decreased Tissue Perfusion
      • In Contrast, Systemic Bleeding is a More Common Feature in (Non-Sepsis) Fibrinolytic Phenotype Disseminated Intravascular Coagulation (DIC)
    • Consequently, Hypofibrinogenemia is Not Common in Sepsis‐Associated Disseminated Intravascular Coagulation (DIC) and Elevation in Fibrin‐Related Markers is Not Associated with Sepsis Severity
      • In Contrast, Thrombocytopenia and Prolongation of the INR are Correlated with an Increase in the Sepsis Mortality Rate
  • Clinical Scoring (International Society on Thrombosis and Haemostasis) (Thromb Haemost, 2001) [MEDLINE] (J Thromb Haemost, 2019) [MEDLINE]
    • Sepsis-Induced Coagulopathy (SIC)
      • Platelet Count (see Complete Blood Count)
        • 100-149k -> 1 pt
        • <100k -> 2 pts
      • International Normalized Ratio (INR) (see Prothrombin Time)
        • 1.3-1.4 -> 1 pt
        • >1.4 -> 2 pts
      • SOFA Score
        • 1 -> 1 pt
        • ≥2 -> 2 pts
      • Total ≥4 Indicates Sepsis-Induced Coagulopathy
    • Overt Disseminated Intravascular Coagulation (DIC)

    Leukocytosis (see Leukocytosis)

    • Epidemiology
      • Leukocytosis is Common
    • Clinical
      • White Blood Cell (WBC) Count >12k

    Leukopenia (see Leukopenia)

    • Epidemiology
      • May Occur in Some Cases
    • Clinical
      • White Blood Cell (WBC) Count <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
      • Nitric Oxide is Synthesized in Sepsis and 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

    Vascular Manifestations

    Symmetrical Peripheral Gangrene (SPG)

    • Physiology
      • Disturbed Procoagulant-Anticoagulant Balance in Susceptible Tissue Beds Secondary to Shock (Cardiogenic, Septic)
      • A Causal Role of Vasopressor Therapy in Symmetrical Peripheral Gangrene is Unproven and is Unlikely
        • Since Critically Ill Patients Who Develop Symmetrical Peripheral Gangrene Do So Usually After >36–48 hrs of Vasopressor Therapy, Implicating Some Type of Time-Dependent Pathophysiological Mechanism (Transfus Apher Sci, 2021) [MEDLINE]
    • Clinical
      • Tissue Necrosis of Acral (Distal) Extremities
      • Characteristic Triad
        • Shock
        • Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)
        • Natural Anticoagulant (Protein C, Antithrombin) Depletion
          • Acute Ischemic Hepatitis (“Shock Liver”) is Observed in >90% of Patients Who Develop Symmetrical Peripheral Gangrene and Likely Plays a Role in Natural Anticoagulant Depletion (see Ischemic Hepatitis)
          • Characteristic Time Interval of 2–5 Days (Median: 3 Days) Between the Onset of Shock/Shock Liver and the Beginning of Ischemic Injury Secondary to Peripheral Microthrombosis (“Limb Ischemia with Pulses”), Consistent with the Time Required to Develop Depletion in Hepatically-Synthesized Natural Anticoagulants
          • Other Risk Factors for Natural Anticoagulant Depletion Include Chronic Liver Disease (i.e Cirrhosis) and, Possibly Colloid (Albumin, High-Dose Immunoglobulin) Transfusion (Which Cause Hemodilution, Since They Lack Lack Coagulation Factors)

    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

    References

    General

    Epidemiology

    Risk Factors

    Physiology

    General

    Microbiology

    Diagnosis

    General

    Culture

    Serum Galactomannan (see Serum Galactomannan)

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

    Serum Procalcitonin (see Serum Procalcitonin)

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

    Serum Lactate (see Serum Lactate)

    Central Venous Pressure (CVP) (see Hemodynamics)

    Arterial Line (see Arterial Line)

    Swan-Ganz Catheter (see Swan-Ganz Catheter)

    Ultrasound

    Passive Leg Raise Effect on Cardiac Output and Pulse Pressure

    Other

    Clinical Sepsis Scoring

    Clinical Manifestations

    General

    Cardiovascular Manifestations

    Endocrinologic Manifestations

    Gastrointestinal Manifestations

    Hematologic Manifestations

    Infectious Manifestations

    Pulmonary Manifestations

    Renal Manifestations

    Toxicologic Manifestations

    Vascular Manifestations

    Prevention