Sepsis

Definitions

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 persisting vasopressor-dependent hypotension (to maintain MAP ≥65 mm Hg) and serum lactate level >2 mmol/L despite adequate volume resuscitation
    • Septic Shock Mortality Rate: >40% mortality rate

Old Definitions (No Longer Recommended)

SEPSIS GRAPHIC

  • Systemic Inflammatory Response Syndrome (SIRS)
    • Fever
    • Leukocytosis
    • Tachycardia
    • Tachypnea
  • Sepsis: SIRS + known or suspected infection
  • Severe Sepsis: sepsis + organ dysfunction (hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia, altered mental status)
  • Septic Shock: severe sepsis + hypotension despite IV fluid resuscitation

Etiology

Cardiovascular Sources

Dermatologic Sources

Gastrointestinal Sources

Head/Neck Sources

Hematologic Sources

Neurologic Sources

Pulmonary Sources

  • Lung Abscess (see Lung Abscess , [[Lung Abscess ]])
  • Necrotizing Pneumonia/Pulmonary Gangrene (see Necrotizing Pneumonia and Pulmonary Gangrene, [[Necrotizing Pneumonia and Pulmonary Gangrene]])
  • Pneumonia (see Pneumonia, [[Pneumonia]])
  • Complicated Parapneumonic Effusion/Empyema (see Pleural Effusion-Parapneumonic, [[Pleural Effusion-Parapneumonic]]): may or may not be associated with concomitant pneumonia at the time of diagnosis (ie: pneumonia may may resolve prior to the development of the parapneumonic effusion)

Renal Sources

Rheumatologic/Orthopedic Sources


Physiology

  • Peripheral Vasodilation
  • Hypotension: probably due to vasodilation mediated by IL-1/TNF/nitric oxide/C5 anaphylatoxin
  • Myocardial Depression: probably mediated by IL-1/TNF/nitric oxide

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

  • General Comments
    • Hypercortisolemia in Critical Illness is Proportionate to the Severity of Illness (see Hypercortisolemia, [[Hypercortisolemia]])
  • Clinical Data
    • 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 Results in 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 Suppresses Corticotropin Release
      • Implications
        • Stress Dose Steroids (Hydrocortisone 200 mg qday) Which are Given in the Setting of Critical Illness with Presumed Adrenal Failure are at Least 3x Too High (J Clin Endocrinol Metab, 2006) [MEDLINE]
      • 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

Diagnosis

Cultures

Rationale

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

Types of Cultures

  • Ascites Culture: required in patients with ascites and suspicion of spontaneous bacterial peritonitis, etc
  • Blood Culture (see Blood Culture, [[Blood Culture]])
    • Two Sets (Aerobic and Anaerobic) Blood Cultures are Recommended to Assess for Bacteremia
    • In Patients 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
  • Lumbar Puncture with Cerebrospinal Fluid Culture (see Lumbar Puncture, [[Lumbar Puncture]]): required in the setting of altered mental status with suspicion for meningitis/encephalitis
  • Urine Culture (see Urine Culture, [[Urine Culture]]): often required to rule out a urinary source
  • Wound Culture: may be required in presence of skin source

Clinical Efficacy

  • Sterilization of Cultures May Occur within Minutes-Hours of Antibiotic Administration (Clin Infect Dis, 2013) [MEDLINE] (Pediatrics, 2001) [MEDLINE]
  • Antibiotic Stewardship Data from the 2014 National Healthcare Safety Network Annual Hospital Survey (Clin Infect Dis, 2016) [MEDLINE]
    • De-Escalation of Antibiotic Therapy is Associated with Less Resistant Microorganisms, Fewer Side Effects, and Lower Costs
  • Blood Culture Yield is Not Improved with Sequential Draws or Timing with Fever Spikes

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 Procalcitonin (see Serum Procalcitonin, [[Serum Procalcitonin]])

Clinical Efficacy

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

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)

Serum Lactate (see Serum Lactate, [[Serum Lactate]])

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, 2106) [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

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)

Central Venous Catheter (CVC) (see Central Venous Catheter, [[Central Venous Catheter]])

Rationale

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

Intraosseous (IO) Vascular Access (see Intraosseous Vascular Access, [[Intraosseous Vascular Access]])

Rationale

  • IO Vascular Access Allows for Intravenous Fluid Resuscitation and Antibiotic Administration

Arterial Line (see Arterial Line, [[Arterial Line]])

Rationale

  • Arterial Line Allows for Accurate Hemodynamic Monitoring of Arterial Blood Pressure: cuff measurement (especially automated cuff measurement) of blood pressure may be inaccurate 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, [[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 CVC in Acute Lung Injury (NEJM, 2006) [MEDLINE]
    • Swan-Ganz Catheter Did Not Improve Mortality Rate vs Using a CVC, 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

Dynamic Hemodynamic Variables

  • Rationale
    • Dynamic Variables are Better Predictors of Fluid Responsiveness Than Traditional Static Variables (CVP, PCWP) however, 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, [[FloTrac]])

  • Rationale: cardiac output measurement using arterial line (instead of Swan-Ganz catheter)
  • Technique

Echocardiogram (see Echocardiogram, [[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, [[Serum Cortisol]])

Cosyntropin (Cortrosyn) Stimulation Test (see Cosyntropin Stimulation Test, [[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)

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

General Variables

  • Altered Mental Status (see Altered Mental Status, [[Altered Mental Status]])
  • Fever (>38.3°C) (see Fever, [[Fever]])
  • Hyperglycemia (Plasma Glucose >140 mg/dL in the Absence of Diabetes) (see Hyperglycemia, [[Hyperglycemia]])
  • Hypothermia (<36°C) (see Hypothermia, [[Hypothermia]])
  • Significant Edema or Positive Fluid Balance (>20 mL/kg over 24 hrs) (see Peripheral Edema, [[Peripheral Edema]])
  • Tachycardia (HR >90 bpm or >2 SD Above the Normal Value for Age) (see Sinus Tachycardia, [[Sinus Tachycardia]])
  • Tachypnea (see Tachypnea, [[Tachypnea]])

Inflammatory Variables

  • Elevated Plasma C-Reactive Protein (CRP) (>2 SD Above the Normal Value) (see Serum C-Reactive Protein, [[Serum C-Reactive Protein]])
  • Elevated Plasma Procalcitonin (>2 SD Above the Normal Value) (see Serum Procalcitonin, [[Serum Procalcitonin]])
  • Leukocytosis (WBC >12k) (see Leukocytosis, [[Leukocytosis]])
  • Leukopenia (WBC <4K) (see Leukopenia, [[Leukopenia]])
  • Normal WBC Count with >10% Immature Forms

Hemodynamic Variables

  • Hypotension (SBP <90mm Hg, MAP <70mm Hg, or an SBP Decrease >40mm Hg in Adults or <2 SD Below the Normal Value for Age) (see Hypotension, [[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, [[Coagulopathy]])
  • Hyperbilirubinemia (Total Bilirubin >4mg/dL or 70 μmol/L) (see Hyperbilirubinemia, [[Hyperbilirubinemia]])
  • Hypoxemia (pO/FiO2 <300) (see Hypoxemia, [[Hypoxemia]])
  • Ileus (see Ileus, [[Ileus]]): absent bowel sounds
  • Increased Creatinine (>0.5mg/dL or 44.2 μmol/L)
  • Thrombocytopenia (Platelet Count <100,000k) (see Thrombocytopenia, [[Thrombocytopenia]])

Tissue Perfusion Variables

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

Clinical Sepsis Scoring

Sequential Organ Failure Assessment (SOFA) (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]

  • General Comments: baseline SOFA score can be assumed to be zero in patients not known to have preexisting organ dysfunction

SEPSIS SOFA

Quick Sequential Organ Failure Assessment (qSOFA)

  • Poor Outcome is Associated with at Least Two of the Following Clinical Criteria

Clinical Manifestations

Cardiovascular Manifestations

Atrial Fibrillation (AF) (see Atrial Fibrillation, [[Atrial Fibrillation]])

  • Epidemiology: 6-20% of patients with severe sepsis develop new-onset AF
  • Clinical
    • 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 6-fold 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 CVA risk, as compared with patients without AF

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

  • Physiology: due to sepsis-related myocardial depression
    • Evidence Suggests that Circulating Histones May Be Implicated in the Pathogenesis of Septic Cardiomyopathy [MEDLINE]

Hypotension (see Hypotension, [[Hypotension]])

  • Physiology: due to vasodilation and capillary leak

Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])

  • Physiology: due to vasodilation-induced increased in heart rate

Takotsubo Cardiomyopathy (Stress-Induced Cardiomyopathy) (see Takotsubo Cardiomyopathy, [[Takotsubo Cardiomyopathy]])

  • Epidemiology: case reports

Troponin Elevation (see Serum Troponin, [[Serum Troponin]])

  • Epidemiology
    • Troponin Elevation is Common in Septic Shock (Crit Care, 2013) [MEDLINE]: no differences were observed in troponin elevation, CK elevation, or EKG changes in patients treated with vasopressin vs epinephrine

Endocrinologic Manifestations

Hyperglycemia (see Hyperglycemia, [[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

Hematologic Manifestations

Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation, [[Disseminated Intravascular Coagulation]])

  • Physiology: xxx

Leukocytosis (see Leukocytosis, [[Leukocytosis]])

  • Physiology: xxx

Leukopenia (see Leukopenia, [[Leukopenia]])

  • Physiology: xxx

Thrombocytopenia (see Thrombocytopenia, [[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) [MEDLINE]
  • Physiology: multiple mechanisms have been implicated
    • 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

Neurologic Manifestations

Delirium (see Delirium, [[Delirium]])

  • Epidemiology
    • 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

Focal Neurologic Signs

  • xxx

Pulmonary Manifestations

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])

  • Epidemiology: xxx
  • Tachypnea (see Tachypnea, [[Tachypnea]])

Renal Manifestations

Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])

  • Epidemiology: xxxxxxx
  • Measures to Prevent AKI in the ICU (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, [[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
      • Using 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

Lactic Acidosis (see Lactic Acidosis, [[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

Toxicologic Manifestations

Methemoglobinemia (see Methemoglobinemia, [[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

Other Manifestations

  • Fever (see Fever, [[Fever]])
  • xxxx

Treatment

Compliance with Surviving Sepsis Guidelines

  • Compliance with the Surviving Sepsis Campaign Bundle is Variable, But Generally Low in Most Studies (Crit Care Med, 2010) [MEDLINE] and (Lancet Infect Dis, 2012) [MEDLINE]

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, [[Chlorhexidine Gluconate]])

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

  • No Recommendations Made

Source Identification and Control

Potential Sources Which May Require Intervention

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

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

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)

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-Antimicrobial De-Escalation

  • 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
  • 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

Clinical Efficacy-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. 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
  • 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

Clinical Efficacy-Antimicrobial Therapy in the Setting of Burns (see Burns, [[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, [[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, [[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 Co-Morbid 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, [[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, [[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

Bicarbonate Therapy (see Sodium Bicarbonate, [[Sodium Bicarbonate]])

Clinical Efficacy

  • Prospective, Randomized Trial of Bicarbonate in Critically Ill Patients with Lactic Acidosis (Ann Intern Med 1990) [MEDLINE]
    • Sodium Bicarbonate Did Not Improve Hemodynamics, Tissue Oxygenation, or Response to Infused Catecholamines in Critically Ill Patients with Lactic Acidosis
    • Sodium Bicarbonate Decreased Plasma Ionized Calcium and Increased pO2
  • Prospective, Randomized Trial of Bicarbonate in Critically Ill Patients with Lactic Acidosis (Crit Care Med, 1991) [MEDLINE]
    • Sodium Bicarbonate Did Not Improve Hemodynamics, But Did Not Worsen Tissue Oxygenation in Critically Ill Patients with Lactic Acidosis

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: 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

  • Increased 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]
    • 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
  • 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 to 60-days 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%)
  • Meta-Analysis and Systematic Review of Early Goal-Directed Therapy (J Crit Care, 2106) [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 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, 2106) [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 of Fluid Balance/Targeted Fluid Minimization

  • 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
  • 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

Clinical Efficacy of Central Venous Pressure (CVP) Monitoring (see Hemodynamics, [[Hemodynamics]])

  • Systematic Review of the Clinical Utility of CVP (Chest, 2008) [MEDLINE]: systematic review of 24 studies (which 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)
    • There was a 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 to 20 mm Hg
    • CVP in the Normal Range (Especially in the -12 mm Hg Range) Does Not Predict Fluid Responsiveness

Clinical Efficacy of Passive Leg Raise

  • Systematic Review and Meta-Analysis of Passive Leg Raise in Predicting Fluid Responsiveness (Intensive Care Med, 2016) [MEDLINE]: n = 991 (21 studies)
    • CO 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 CO ≥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 CO 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

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

  • xxxx

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)
    • 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, [[Traumatic Brain Injury]])
    • Colloid Use in Septic Shock Subgroup Demonstrated a Trend Toward Lower Mortality Rate
  • 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
  • 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

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 (LJPC-501): currently experimental
    • Pharmacology: synthetic human angiotensin II
  • Dopamine (see Dopamine, [[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, [[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
  • Norepinephrine (Levophed) (see Norepinephrine, [[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, [[Phenylephrine]])
    • Pharmacology: α1-Adrenergic Receptor Agonist -> Vasoconstriction with Increase in Mean Arterial Pressure
  • Vasopressin (see Vasopressin, [[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

  • 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
  • Meta-Analysis Comparing Dopamine with Norepinenephrine in Septic Shock (Crit Care Med, 2012) [MEDLINE]: in septic shock, dopamine increased arrhythmias and mortality, as compared to norepinephrine
  • Vasopressin and Septic Shock Trial (VASST): Comparison of Vasopressin and Norepinephrine in Septic Shock (Chest, 2012) [MEDLINE]
    • 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
  • 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
  • Study of Myocardial Ischemia in Septic Shock (Crit Care, 2013) [MEDLINE]
    • Troponin Elevation is Common in 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
  • 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

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

  • Dobutamine (Dobutrex) (se Dobutamine, [[Dobutamine]])
    • Pharmacology
      • XXXXXX
  • Levosimendan (see Levosimendan, [[Levosimendan]])
    • Pharmacology
      • XXXXXX
  • Milrinone (XXXX) (see Milrinone, [[Milrinone]])
    • Pharmacology
      • XXXXXX

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

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, [[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

Corticosteroids (see Corticosteroids, [[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
  • German HYPRESS Trial of Hydrocortisone in Severe Sepsis (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

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]

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)

Erythropoietin (see Erythropoietin, [[Erythropoietin]])

Clinical Efficacy

  • 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

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

Packed Red Blood Cell (PRBC) Transfusion (see Packed Red Blood Cells, [[Packed Red Blood Cells]])

Rationale

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

Adverse Effects

  • Acute Hemolytic Transfusion Reaction (see Acute Hemolytic Transfusion Reaction, [[Acute Hemolytic Transfusion Reaction]])
  • Delayed Hemolytic Transfusion Reaction (see Delayed Hemolytic Transfusion Reaction, [[Delayed Hemolytic Transfusion Reaction]])
  • Fluid Overload
  • Increased Plasma Viscosity: doubling the Hct (from 20 to 40%) will double plasma viscosity -> increases oxygen delivery to coronary arteries but increases myocardial work
  • Increased Risk of Specific Infections
  • Transfusion-Associated Acute Lung Injury (TRALI) (see Transfusion-Associated Acute Lung Injury, [[Transfusion-Associated Acute Lung Injury]])

Clinical Efficacy

  • 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
  • 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

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

  • 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, [[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, [[Platelet Transfusion]])

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

  • Platelet Tranfusion Threshold of 10k/mm3 is Recommended in the Absence of Bleeding (Weak Recommendation, Very Low Quality of Evidence
  • Platelet Tranfusion Threshold of 20k/mm3 is Recommended if the Patient Has Significant Risk of Bleeding (Weak Recommendation, Very Low Quality of Evidence
  • Platelet Tranfusion 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, [[Deep Venous Thrombosis]])

Agents

  • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]])
  • Enoxaparin (Lovenox) SQ (see Enoxaparin, [[Enoxaparin]])
  • Heparin SQ (see Heparin, [[Heparin]])

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 Last 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 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 (A.S.P.E.N.) (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 (A.S.P.E.N.) (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)

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)

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 Indicatons for Hemodialysis (Weak Recommendation, Low Quality of Evidence)
  • Either Continuous Renal Replacement Therapy (CRTT) 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, [[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 the Decreased Mortality Rate, as Compared to the Conventional Oxygen Strategy

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

  • Beta Agonists (see β2-Adrenergic Receptor Agonists, [[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 without Evidence 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 Mechanical Ventilation-General, [[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 Max 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, [[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, [[High-Frequency Ventilation]])
  • PEEP (see PEEP and Auto-PEEP, [[PEEP and Auto-PEEP]])
    • 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 (EMCO) (see Venovenous Extracorporeal Membrane Oxygenation, [[Venovenous Extracorporeal Membrane Oxygenation]])
    • VV-EMCO May Be Considered in Centers with Local Expertise
  • Sedation and Paralysis (see Sedation, [[Sedation]] and Neuromuscular Junction Antagonists, [[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) are Suggested for Adult Patients with Sepsis-Associated ARDS and pO2/FIO2 Ratio <150 (Weak Recommendation, Moderate Quality of Evidence)
  • Weaning (see Ventilator Weaning, [[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]])
    • 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, [[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)

Antithrombin III (see Antithrombin III, [[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 Re, 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)

Thrombomodulin (see Thrombomodulin, [[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

Heparin (see Heparin, [[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

Drotecogin Alfa (Xigris) (see Drotrecogin Alfa, [[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, [[Eritoran]])

Clinical Efficacy

  • ACCESS Trial of Eritoran (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

Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin, [[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)

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

Prognosis

Mortality Data

  • Study of Severe Sepsis Mortality Rates in Australia/New Zealand (JAMA, 2014) [MEDLINE]: from 2000 to 2012, there was a decrease in absolute mortality 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)

Sequelae of 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
      • 40% had impaired had global cognition scores that were 1.5 SD below the population mean (similar to scores for patients with moderate traumatic brain injury)
      • 26% had scores 2 SD below the population mean (similar to scores for patients with mild Alzheimer’s disease)
    • At 12 Months
      • Similar persistent cognitive dysfunction occurs as in those with moderate traumatic brain injury
      • Similar persistent cognitive dysfunction occurs 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]
  • 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]

Diagnosis

Culture

  • 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]

Serum Galactomannan (see Serum Galactomannan, [[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, [[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, [[Serum Procalcitonin]])

  • 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 Lactate (see Serum Lactate, [[Serum Lactate]])

  • Lactate measurements in sepsis‐induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med 2015; 43(3):567–573 [MEDLINE]

Central Venous Pressure (CVP) (see xxxx, [[xxxx]])

  • 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]
  • 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, [[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, [[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

  • 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

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

Treatment

General

  • Foreword. The future of sepsis performance improvement. Crit Care Med 2015; 43(9):1787–1789 [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]

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

  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]

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]

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]

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]
  • 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]
  • 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]
  • 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]
  • Early goal‐directed therapy for severe sepsis and septic shock: a living systematic review. J Crit Care 2016; 36:43–48 [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 36:43–48 [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]
  • 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]
  • 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]
  • 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]

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
  • Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122-1125
  • 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
  • SOAP II Trial. Comparison of dopamine and norepinephrine in the treatment of shock.  N Engl J Med 2010; 362:779-789 [MEDLINE]
  • Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis. Crit Care Med 2012;40:725-730 [MEDLINE]
  • Vasopressin and Septic Shock Trial (VASST): 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. Epub 2013 Jun 6 [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]
  • 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]
  • 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]
  • 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]

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, [[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]

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • 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
  • 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]
  • 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]
  • Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016;316(17):1775 [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]

Erythropoietin (see Erythropoietin, [[Erythropoietin]])

  • 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]
  • Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002, 288(22):2827–2835 [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]
  • 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]

Packed Red Blood Cell (PRBC) Transfusion (see Packed Red Blood Cells, [[Packed Red Blood Cells]])

  • A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-417 [MEDLINE]
  • Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009 Apr;7(2):132-50. doi: 10.2450/2009.0005-09 [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]
  • 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]

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]

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]

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, [[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, [[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 Immunoglobuin (IVIG) (see Intravenous Immunoglobuin, [[Intravenous Immunoglobuin]])

  • 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]

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]

Atrial Fibrillation

  • Incident Stroke and Mortality Associated With New-Onset Atrial Fibrillation in Patients Hospitalized With Severe Sepsis. JAMA 2011;306(20) [MEDLINE]

Prognosis

  • BRAIN-ICU: Long-Term Cognitive Impairment after Critical Illness. N Engl J Med. 2013 Oct 3;369(14):1306-1316 [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]
  • 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]