Prospective Trial of Sodium Bicarbonate in Critically Ill Patients with Lactic Acidosis (Ann Intern Med, 1990) [MEDLINE]
Sodium Bicarbonate Did Not Improve Hemodynamics in Critically Ill Patients with Metabolic Acidosis and Hyperlactatemia
Sodium Bicarbonate Did Not Increase the Cardiovascular Response to Infused Catecholamines in in Critically Ill Patients with Metabolic Acidosis and Hyperlactatemia
Sodium Bicarbonate Decreased Plasma Ionized Calcium and Increased the pCO2
Prospective, Randomized Trial of Sodium Bicarbonate in Lactic Acidosis (Crit Care Med, 1991) [MEDLINE]
Sodium Bicarbonate Administration Did Not Improve Hemodynamic Variables in Patients with Lactic Acidosis, But Did Not Worsen Tissue Oxygenation
French Multi-Center, Randomized BICAR-ICU Trial of Sodium Bicarbonate for ICU Patients with Severe Acidemia and Lactic Acidosis (Lancet, 2018) [MEDLINE]: n = 389 (from 26 French ICU’s)
Total Group
Sodium Bicarbonate Therapy for Severe Acidemia (pH ≤7.20, pCO2 ≤45 mm Hg, Serum Bicarbonate ≤20 mmol/L, SOFA ≥4. Arterial Lactate ≥2 mmol/L) Targeting a Serum pH >7.30 Did Not Significantly Decrease the 28-Day Mortality Rate (45%), as Compared to Control (54%)
Sodium Bicarbonate Did Not Decrease the Occurrence of at Least One Organ Failure at Day 7
Prespecified Acute Kidney Injury Network Group (with a Score of 2-3)
Sodium Bicarbonate Therapy Decreased the Mortality Rate (46%), as Compared to Control (63%)
Sodium Bicarbonate Decreased the Occurrence of at Least One Organ Failure at Day 7
Metabolic Alkalosis, Hypernatremia, and Hypocalcemia were Observed More Frequently in the Bicarbonate Group than in the Control Group
Pilot Randomized Double-Blind Clinical Trial of Sodium Bicarbonate Therapy for Metabolic Acidosis in the Intensive Care Unit (Crit Care Med, 2023) [MEDLINE]: n = 30
At Day 7, Patients in the Sodium Bicarbonate and Placebo Group Had a Median of 132.2 (85.6-139.1) and 97.1 (69.3-132.4) Hours Alive and Vasopressor-Free, Respectively (Median Difference 35.07; 95% CI: -9.14 to 79.28; p = 0.131)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Septic Shock and Hypoperfusion-Induced Lactic Acidemia, Sodium Bicarbonate Therapy to Improve Hemodynamics or to Decrease Vasopressor Requirement is Not Recommended (Weak Recommendation, Low Quality of Evidence)
For Adults with Septic Shock and Severe Metabolic Acidemia (pH ≤ 7.2) and Acute Kidney Injury (AKIN Score 2-3), Sodium Bicarbonate Therapy is Recommended (Weak Recommendation, Low Quality of Evidence)
Blood Pressure Target
Clinical Efficacy
French SEPSISPAM Trial Examining Blood Pressure Targets in Septic Shock (NEJM, 2014) [MEDLINE]
MAP Target 80-95 mm Hg Had No 28-day Mortality (and 90-Day Mortality) Benefit, as Compared to MAP Target 65-70 mm Hg
Incidence of Newly Diagnosed Atrial Fibrillation was Higher in the MAP Target 80-95 mm Hg Group
In Patients with Chronic Hypertension, Those in the MAP Target 80-95 mm Hg Group Required Less Hemodialysis than Those in the MAP Target 65-70 mm Hg Group: however, no difference in mortality rate was observed
Systematic Review of Blood Pressure Target in Sepsis (Shock, 2015) [MEDLINE]
MAP Target of 80-85 mm Hg vs 65-70 mm Hg Had No Effect on 28-Day Mortality Rate
MAP Target of 80-85 mm Hg Increased the Risk of Atrial Fibrillation and a Lower Risk of Hemodialysis in Hypertensive Patients
Crossover Trials Suggested MAP Target of 80-85 mm Hg (Achieved by Increasing Vasopressor Doses) Increased Heart Rate and Cardiac Index Without an Effect on Serum Lactate
Critical Review of the Currently Recommended Blood Pressure Target of 65 mm Hg in Sepsis (Crit Care Med, 2015) [MEDLINE]
While MAP Target of >65 mm Hg is Appropriate in Most Patients, MAP Target of 75-85 mm Hg Decreases the Risk of Acute Kidney Injury in Patients with a History of Hypertension
Trial of Higher vs Lower Blood Pressure Targets for Vasopressor Therapy in Shock (Intensive Care Med, 2016) [MEDLINE]
In the Subgroup of Patients >75 y/o, Mortality was Decreased with MAP Target of 60–65 mmg Hg (13%) vs 75–80 mm Hg (60%)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Septic Shock (on Vasopressors), Initial Mean Arterial Pressure (MAP) Target of ≥65 mm Hg is Recommended Over a Higher MAP Target (Strong Recommendation, Moderate Quality of Evidence)
However, Consideration of a Higher MAP Target (75-85 mm Hg) Might Be Appropriate in Patients with a History of Hypertension as This Intervention Might Decrease the Risk of Acute Kidney Injury Requiring Hemodialysis (NEJM, 2013) [MEDLINE]
Intravenous Fluid Resuscitation Strategy
History
Intravenous Fluid Resuscitation was First Described During the Cholera Outbreaks of the 1830’s (Emerg Med Clin North Am, 2020) [MEDLINE] (Open Access Emerg Med, 2022) [MEDLINE]
Intravenous Fluid Resuscitation Became Standard Practice During the Early 1900’s
Rationale
In the Setting of Sepsis, Increased Serum Lactate is a Marker of Impaired Microcirculatory Flow with Tissue Hypoxia (see Lactic Acidosis)
However, There are Scant Data that Tissue Hypoxia Occurs in Patients with Sepsis
In Addition, Increasing Oxygen Delivery in Patients with Sepsis Does Not Increase Oxygen Consumption
Increased Serum Lactate Levels are Associated with Worse Outcome (Crit Care Med, 2015) [MEDLINE]
Clinical Efficacy of Early Goal-Directed Therapy
Rivers Early Goal-Directed Therapy Trial (NEJM, 2001) [MEDLINE]
Goal-Directed Therapy Protocol was Triggered by Presence of SIRS Criteria + Systolic BP ≤90 mm Hg or Serum Lactate ≥4 mmol/L
Protocol Consisted of Continuous ScvO2 Monitoring and Early Goal-Directed Therapy for ≥6 hrs with Goals to Maintain CVP ≥8–12 mm Hg, Maintain MAP ≥65 mm Hg, Maintain Urine Output ≥0.5 mL/kg/hr, Maintain ScvO2 ≥70% (Using SaO2 ≥93%, Hematocrit ≥30%, Cardiac Index, and VO2)
Early Goal-Directed Therapy (Used for First 6 hrs of Emergency Department Care) Decreased 28-Day Mortality in Severe Sepsis and Septic Shock
As Compared to Standard Therapy, Early Goal-Directed Therapy Group (from 7-72 hrs) Resulted in Higher pH, Lower Base Deficit, Lower Lactate Concentration, and Significantly Higher Mean Central Venous Oxygen Saturation (ScvO2)
In Patients with Severe Sepsis/Septic Shock Treated to Normalize Central Venous Pressure/Mean Arterial Pressure, Additional Management to Normalize Lactate Clearance vs Management to Normalize Central Venous Oxygen Saturation Did Not Improve In-Hospital Mortality
US Protocolized Care for Early Septic Shock (PROCESS) Trial (NEJM, 2014) [MEDLINE]: tertiary care, multi-center trial (n = 1,341) from 2008-2013 -> 439 were randomly assigned to protocol-based early goal-directed therapy (transfusion threshold hematocrit >10 g/dL when the ScvO2 was <70% after the initial resuscitation), 446 to protocol-based standard therapy (transfusion threshold hemoglobin >7.5 g/dL when the ScvO2 was <70% after the initial resuscitation), and 456 to usual care
Average Volume of Intravenous Fluid Given in the PROCESS Trial Pre-Randomization was 30 mL/kg (Intensive Care Med, 2017) [MEDLINE]
With Diagnosis of Sepsis in the ED, Protocol-Based Resuscitation Did Not Improve In-Hospital Mortality Rate, 60 Day Mortality Rate or 1 Year Mortality Rate
Early Goal-Directed Protocol-Directed Therapy Significantly Increased IV Fluid Resuscitation During the First 6 hrs (2.8L), as Compared to Usual Care (2.3L)
Early Goal-Directed Protocol-Directed Therapy Significantly Increased ICU Admission Rates (91.3% of Cases), as Compared to Usual Care (86.2% of Cases)
Australasian Resuscitation in Sepsis Evaluation (ARISE) Trial (NEJM, 2014) [MEDLINE]: multi-center RCT in Australia/New Zealand (n = 1600)
Average Volume of Intravenous Fluid Given in the ARISE Trial Pre-Randomization was 30 mL/kg (Intensive Care Med, 2017) [MEDLINE]
With Diagnosis of Septic Shock in the ED, Early Goal-Directed Therapy Had No Impact on 90-day Mortality (18.6% mortality), as Compared to Usual Care (18.8% Mortality)
No Significant Differences in Survival Time, In-Hospital Mortality, Duration of Organ Support, or Length of Hospital Stay Between the Groups
Analysis of the Performance of Surviving Sepsis Guidelines from 2005-2012 in 218 Community/Academic/Tertiary Hospitals (Crit Care Med, 2015) [MEDLINE]
Increased Compliance with Surviving Sepsis Performance Bundles was Associated with 25% Relative Risk Reduction in the Mortality Rate
Protocolized Management in Sepsis (ProMISe) trial in the United Kingdom (NEJM, 2015) [MEDLINE]: randomized trial with integrated cost-effectiveness analysis in 56 hospitals in England (n = 1260)
Average Volume of Intravenous Fluid Given in the PROMISE Trial Pre-Randomization was 2L (Intensive Care Med, 2017) [MEDLINE]
With Early Diagnosis of Septic Shock, Early Goal-Directed Therapy Did Not Improve 90-Day All-Cause Mortality, as Compared to Usual Care
Early Goal-Directed Therapy Group Manifested Significantly Worse Organ-Failure Scores, More Days Receiving Advanced Cardiovascular Support, and Longer ICU Stays
Early Goal-Directed Therapy Increased Treatment Intensity (With Increased Use of Intravenous Fluids, Vasoactive Drugs, and Red Blood Cell Transfusions)
Early Goal-Directed Therapy Increased Costs (the Probability That it Was Cost-Effective Was <20%)
Systematic Review and Meta-Analysis of Early Goal-Directed Therapy in Septic Shock (by the the ARISE, ProCESS and ProMISe Investigators) (Intensive Care Med, 2015) [MEDLINE]
Early Goal-Directed Therapy was Not Superior to Usual Care for Emergency Department Patients with Septic Shock, But is Associated with Increased Utilization of ICU Resources
Meta-Analysis and Systematic Review of Early Goal-Directed Therapy (J Crit Care, 2016) [MEDLINE]
Early Goal-Directed Therapy Did Not Decrease the Mortality Rate
Benefit of Early Goal-Directed Therapy was Confined to Patients with a >35% Control Group Mortality Rate
Lactate-Guided Therapy Improved Outcome, as Compared to Usual Care or a ScvO2 Normalization Strategy
Patient-Level Meta-Analysis of Early Goal-Directed Therapy in Septic Shock (NEJM, 2017) [MEDLINE]
Early Goal-Directed Therapy Did Not Improve Outcome in Septic Shock Over Usual Care and was Associated with Higher Hospitalization Costs Across a Broad Range of Patient and Hospital Characteristics
Meta-Analysis and Trial Sequential Analysis of Early Goal-Directed Therapy in Septic Shock (J Intensive Care Med, 2018) [MEDLINE]
Adults with Severe Sepsis and Septic Shock Who Received Early Goal-Directed Therapy Had a Lower Mortality Rate than Those Who Received Usual Care
The Benefit May Mainly Be Attributed to Treatments Administered within the First 6 hrs
Retrospective Cohort Study of Early Intravenous Fluid Resuscitation (30 mL/kg) for Sepsis in Patients with Congestive Heart Failure (Mayo Clin Proc Innov Qual Outcomes, 2020) [MEDLINE]: n= 211
Non-Fluid Bundle-Compliant Patients Had Higher Adjusted In-Hospital and Postdischarge Mortality Rates
Risk-Adjusted 1-Year Mortality Rate was higher for Non-Fluid Bundle-Compliant Patients (Hazard Ratio 2.18; 95% CI: 1.2 to 4.0; P = 0.01) Than for Fluid Bundle-Compliant Patients
Clinical Efficacy of Early Goal-Directed Therapy in Resource-Limited Settings
Zambian Randomized Trial of Early Resuscitation Protocol in Sepsis in Developing Countries (JAMA, 2017) [MEDLINE]
Among Adults with Sepsis and Hypotension, Most of Whom were Positive for HIV, in a Resource-Limited Setting, a Protocol for Early Resuscitation with Administration of Intravenous Fluids and Vasopressors Increased In-Hospital Mortality, as Compared to Usual Care
Clinical Efficacy of Centers for Medicare and Medicaid Services (CMS)-Mandated Hemodynamic Interventions (SEP-1) in Sepsis
Examination of Performance and Efficacy of Each of the SEP-1 Bundle Elements in Sepsis and Septic Shock in New York (N Engl J Med, 2017) [MEDLINE]: n = 49,331 (at 149 hospitals)
Only 82.5% of Patients Had the 3 hr Sepsis Bundle (Blood Cultures Drawn, Broad-Spectrum Antibiotics, and Serum Lactate Measurement) Completed within 3 hrs
Time to Completion of Bundle Elements
Median Time for 3 hr Sepsis Bundle (Blood Cultures Drawn, Broad-Spectrum Antibiotics, and Serum Lactate Measurement) Completion was 1.3 hrs (Interquartile Range, 0.65 to 2.35)
Median Time to the Administration of Antibiotics was 0.95 hrs (Interquartile Range, 0.35 to 1.95)
Median Time to Completion of the Intravenous Fluid Bolus was 2.56 hours (Interquartile Range, 1.33 to 4.20)
More Rapid Completion of the 3 hr Sepsis Bundle Early Rapid Antibiotic Administration (But Not the Rapid Completion of an Initial Bolus of Intravenous Fluids) were Associated with Decreased Risk-Adjusted In-Hospital Mortality Rate
Systematic Review of the Evidence Base Supporting the Centers for Medicare and Medicaid Services (CMS)-Mandated Hemodynamic Interventions (SEP-1) in Sepsis (Ann Intern Med, 2018) [MEDLINE]: 20 studies
No Moderate or High-Quality Evidence Indicated that SEP-1 or its Hemodynamic Interventions Decreased the Mortality Rate in Sepsis
Only One Single-Center Observational Study Reported Decreased In-Hospital Mortality with SEP-1
Sixteen Studies (2 Randomized and 14 Observational) Reported Decreased Mortality with Serial Lactate Measurements or 30 mL/kg Intravenous Fluid Infusions
None of the 17 Studies were Free of Confounders or at Low Risk of Bias
In 3 Randomized Trials, Fluid Responsiveness Testing Did Not Decrease the Mortality Rate
Clinical Efficacy-Clinical Utility of Central Venous Pressure (CVP) to Assess Volume Status and Volume Responsiveness (see Hemodynamics)
Systematic Review of the Clinical Utility of Central Venous Pressure (CVP) (Chest, 2008) [MEDLINE]
Systematic Review of 24 Studies (Which Studied Either the Relationship Between Central Venous Pressure (CVP) and Blood Volume or Reported the Associated Between Central Venous Pressure (CVP)/Delta Central Venous Pressure (CVP) 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 Central Venous Pressure (CVP), the Central Venous Pressure (CVP) Should Not Be Used to Make Clinical Decisions Regarding Fluid Management
Meta-Analysis of Central Venous Pressure to Predict Fluid Responsiveness (Crit Care Med, 2013) [MEDLINE]: n= 43 studies (healthy adult controls n = 1, intensive care unit patients n = 22, and operating room patients n = 20)
Overall 57% ± 13% of the Patients were Fluid Responders
Summary Area Under the Curve was 0.56 (95% CI: 0.54-0.58) with No Heterogenicity Between the Studies
Summary Area Under the Curve was 0.56 (95% CI: 0.52-0.60) for Those Studies Done in the Intensive Care Unit and 0.56 (95% CI: 0.54-0.58) for Those Studies Done in the Operating Room
Summary Correlation Coefficient Between the Baseline Central Venous Pressure and Change in Stroke Volume Index/Cardiac Index was 0.18 (95% CI: 0.1-0.25), Being 0.28 (95% CI: 0.16-0.40) in the Intensive Care Unit Patients and 0.11 (95% CI: 0.02-0.21) in the Operating Room Patients
There are No Data to Support the Widespread Practice of Using Central Venous Pressure to Guide Fluid Therapy
Systematic Review Examining CVP in Predicting Fluid Responsiveness in Critically Ill Patients (Intensive Care Med, 2016) [MEDLINE]: n = 1148 (51 studies)
Central Venous Pressure (CVP) was Subgrouped into Low (<8 mmHg), Intermediate (8-12 mmHg), High (>12 mmHg) Baseline Central Venous Pressure (CVP)
Although Authors Identified Some Positive and Negative Predictive Values for Fluid Responsiveness for Specific Low and High Values of Central Venous Pressure (CVP), None of the Predictive Values were >66% for Any Central Venous Pressure (CVP) from 0-20 mm Hg
Central Venous Pressure (CVP) in the Normal Range (Especially in the 8-12 mm Hg Range) Does Not Predict Fluid Responsiveness
Study of Central Venous Pressure (CVP) in Septic Shock and Its Impact on Mortality Rate and Risk of Acute Kidney Injury (AKI) (Using the AmsterdamUMCdb Database) (Am J Emerg Med, 2023) [MEDLINE]: n = 9,668
Patients Exhibited 8.2% Overall 28-Day Mortality Rate and 41.1% Incidence of Acute Kidney Injury (AKI)
Daily Time-Weighted Average Central Venous Pressure (CVP) was Strongly Associated with Increased 28-Day Mortality Rate, Primarily within 24 hrs of Intensive Care Unit Admission
Mortality Rate of Patients was Lowest When the Central Venous Pressure (CVP) was 6-12 cm H2O
When the Time of High Central Venous Pressure (CVP) (TWA-CVP >12 cm H2O) Exposure within the First 24 hrs was >5 hrs, the Risk of Death Increased by 2.69-Fold
Additionally, Patients Exposed to High Central Venous Pressure (CVP) Had a Significantly increased Risk of Developing Acute Kidney Injury (AKI)
Clinical Efficacy of Lactate-Guided Therapy
Trial of Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy (JAMA, 2010) [MEDLINE]
In Septic Shock Treated to Normalize Central Venous Pressure and Mean Arterial Pressure, Additional Management to Normalize Lactate Clearance, as Compared with Management to Normalize ScvO2 Did Not Significantly Decrease In-Hospital Mortality
LACTATE Study Examining Lactate-Guided Therapy in Critically Ill Patients (Am J Respir Crit Care Med, 2010) [MEDLINE]: multi-center
Early, Aggressive Resuscitation is Associated with Improved Outcome in Sepsis
In Patients with Hyperlactatemia on ICU Admission, Lactate-Guided Therapy Decreased the Hospital Mortality Rate When Adjusting for Predefined Risk Factors
Analysis of Serum Lactate in Sepsis-Associated Hypoperfusion from the Surviving Sepsis Campaign Database (Crit Care Med, 2015) [MEDLINE]
Increased Lactate Levels were Associated with Increased In-Hospital Mortality in Sepsis
However, Only Patients Who Presented with Serum Lactate >4 mmol/L (with and without Hypotension) were at Significantly Higher Risk for In-Hospital Mortality, as Compared to Serum Lactate at Lower Levels (2-3 and 3-4 mmol/L)
Meta-Analysis and Systematic Review of Early Goal-Directed Therapy (J Crit Care, 2016) [MEDLINE]
Early Goal-Directed Therapy Did Not Decrease the Mortality Rate
Benefit of Early Goal-Directed Therapy was Confined to Patients with a >35% Control Group Mortality Rate
Lactate-Guided Therapy Improved Outcome, as Compared to Usual Care or a ScvO2 Normalization Strategy
Latin American Prospective, Multicenter, Parallel-Group, Randomized Controlled ANDROMEDA-SHOCK Trial Targeting Peripheral Perfusion Status vs Serum Lactate Levels in Septic Shock (JAMA, 2019) [MEDLINE]: n = 424 (from 5 Latin American countries)
In Patients with Septic Shock, a Resuscitation Strategy Targeting Normalization of Capillary Refill Time, as Compared with a Strategy Targeting Normalization of Serum Lactate, Did Not Decrease the All-Cause 28-Day Mortality Rate
Secondary Analysis of ANDROMEDA-SHOCK Trial Data for Systematic Assessment of Fluid Responsiveness During Early Septic Shock Resuscitation (Crit Care, 2020) [MEDLINE]
Systematic Assessment Allowed Determination of Fluid Responsiveness Status in >80% of Patients with Early Septic Shock
Fluid Boluses Could Be Stopped in Non-Fluid Responsive Patients without Any Negative Impact on Clinically Relevant Outcomes
Clinical Efficacy-Urine Output Monitoring
Retrospective Cohort Study of Impact of Intensive Urine Output Monitoring in Critically Ill Patients on Development of Acute Kidney Injury (Chest, 2017) [MEDLINE]: 15,724 adults admitted to ICUs from 2000-2008
Intensive Urine Output Monitoring: hourly urine output recordings and no gaps of >3 hrs for the initial 48 hrs after ICU admission
Intensive Urine Output Monitoring was Associated with Improved Detection of Acute Kidney Injury and Decreased 30-Day Mortality in Patients Experiencing Acute Kidney Injury
Intensive Urine Output Monitoring was Associated with Less Cumulative Fluid Volume and Less Fluid Overload for All Patients During the First 72 hrs of ICU Stay
Trial of Two Fluid Management Strategies in Acute Lung Injury (NEJM, 2006) [MEDLINE]
Although There was No Significant Difference in the Primary Outcome of 60-Day Mortality, the Conservative Fluid Management Strategy Improved Lung Function and Shortened the Duration of Mechanical Ventilation and intensive Care without Increasing Nonpulmonary Organ Failures
These Results Support the Use of a Conservative Fluid Management Strategy in Patients with Acute Lung Injury
Systematic Review of Fluid Overload and Re-Resuscitation in Sepsis (Anaesthesiol Intensive Ther, 2014) [MEDLINE]
Positive Cumulative Fluid Balance is Associated with Intra-Abdominal Hypertension and Worse Outcome
Interventions to Limit the Development of Positive Fluid Balance are Associated with Improved Outcome
Late Conservative Fluid Management and De-Resuscitation Should Be Considered
Study of the Association Between Fluid Balance and Survival in Critical Illness (J Intern Med, 2015) [MEDLINE]
Positive Fluid Balance at the Time of ICU Discharge is Associated with Increased 90-Day Mortality, Especially in Patients with Underlying Heart/Kidney Disease
Pilot Study of Targeted Fluid Minimization After Initial Resuscitation (Chest, 2015) [MEDLINE]: pilot study (n= 82) conducted at Barnes-Jewish Hospital
Targeted Fluid Minimization Strategy Resulted in Non-Significant Decreases in Positive Fluid Balance at Days 3/5, as Compared to Usual Care
Targeted Fluid Minimization Strategy Did Not Impact Mortality Rate, Ventilator Days, Need for Renal Replacement Therapy, or Vasopressor Days
Prospective Study of Fluid Balance in Sepsis (Crit Care, 2015) [MEDLINE]: n = 173 (single-center trial)
Persistent Daily Positive Fluid Balance Over Time was Strongly Associated with Higher Mortality Rate in Sepsis
Retrospective Review of Fluid Management in Septic Shock (Ann Am Thorac Soc, 2015) [MEDLINE]
Volume Overload Was Independently Associated with Impaired Mobility and Discharge to a Healthcare Facility in Survivors of Septic Shock
Retrospective Study of Fluid Balance and Risk for Acute Kidney Injury and Mortality in Severe Sepsis/Septic Shock (J Crit Care, 2015) [MEDLINE]
Late Positive Fluid Balance is an Independent Risk Factor for Mortality in Severe Sepsis
Positive Fluid Balance Has No Impact on the Risk for Acute Kidney Injury
Retrospective Analysis of the Impact Early Goal-Directed Therapy on Fluid Overload in Severe Sepsis and Septic Shock (Shock, 2015) [MEDLINE]
When Adjusted for Baseline Severity of Illness, Fluid Overload was Associated with Increased Use of Fluid-Related Medical Interventions (Thoracentesis and Diuretics) and Hospital Mortality (Odds Ratio, 1.92; Confidence Interval, 1.16-3.22)
Single-Center Retrospective Study of Fluid Balance in Severe Sepsis/Septic Shock (Am J Emerg Med, 2016) [MEDLINE]
Positive Fluid Balance Increased Both the ICU and In-Hospital Mortality Rate
Systematic Review and Meta-Analysis of Conservative Fluid Management or Deresuscitation in Sepsis or ARDS Following the Resuscitation Phase of Critical Illness (Intensive Care Med, 2017) [MEDLINE]
Conservative or Deresuscitative Fluid Strategy Resulted in an Increased Number of Ventilator-Free Days and a Decreased ICU Length of Stay, as Compared to Liberal Strategy or Standard Care
The Effect on Mortality Remains Uncertain
International (European) Open-Label, Randomized Conservative vs Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trial of Intravenous Fluid Restriction in Intensive Care Unit Adult Patients with Septic Shock (NEJM, 2022) [MEDLINE]: n = 1,554
Patients Received a Median of 3 Liters of Intravenous Fluid Before They were Randomized and They were Enrolled within 3 Hours After ICU Admission
Intravenous Fluid Given After Randomization
Restrictive-fluid Group Received a Median of 1,798 mL of Intravenous Fluid (Interquartile Range: 500-4,366 mL)
Standard-Fluid Group Received a Median of 3,811 mL (Interquartile Range: 1,861-6,762 mL)
Restrictive Fluid Group Had 90-Day Death Rate was 42.3%, While the Standard Fluid Group was 42.1% (Adjusted Absolute Difference, 0.1 Percentage Points; 95% CI: -4.7 to 4.9; P = 0.96)
At 90 Days After Randomization, Number of Days Alive without Life Support and Days Alive and Out of the Hospital were Similar in Both Groups
Serious Adverse Events were Similar in Both Groups
Critique: patients received median of 3 liters of fluid prior to randomization, which could have influenced the results
Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) Multicenter Unblinded Superiority Trial of Early Restrictive (Prioritizing Vasopressors and Lower Intravenous Fluid Volumes) or Liberal Fluid (Prioritizing Higher Volumes of Intravenous Fluids Before Vasopressor Use) Management for Sepsis-Induced Hypotension (NEJM, 2023) [MEDLINE]: n = 1,563 (at 60 centers)
Less Intravenous Fluid was Administered in the Restrictive Fluid Group than in the Liberal Fluid Group (Difference of Medians -2134 ml; 95% CI: -2318 to -1949), Whereas the Restrictive Fluid Group Had Earlier, More Prevalent, and Longer Duration of Vasopressor Use
Death from Any Cause Before Discharge Home by Day 90 Occurred in 14.0% of Patients in the Restrictive Fluid Group and in 14.9% of the Patients in the Liberal Fluid Group (Estimated Difference -0.9 Percentage Points; 95% CI: -4.4 to 2.6; P = 0.61)
Five Patients in the Restrictive Fluid Group and 4 Patients in the Liberal Fluid Group Had Their Data Censored (Lost to Follow-Up)
Number of Reported Serious Adverse Events was Similar in the Two Groups
Meta-Analysis and Trial Sequential Analysis of Lower vs Higher Fluid Volume in Patients with Sepsis (Chest, 2023) [MEDLINE]: n = 4,006 (13 trials)
Meta-Analysis of All-Cause Mortality in 8 Trials with Low Risk of Bias Demonstrated Relative Risk of 0.99 (97% CI: 0.89-1.10; Moderate Certainty Evidence)
Six Trials with Predefined Definitions of Serious Adverse Events Demonstrated Relative Risk of 0.95 (97% CI, 0.83-1.07; Low Certainty Evidence)
Health-Related Quality of Life was Not Reported
In Adult Patients with Sepsis, Lower Intravenous Fluid Volumes Probably Result in Little to No Difference in All-Cause Mortality, as Compared to Higher Intravenous Fluid Volumes
However, the Interpretation is Limited by Imprecision in the Estimate, Which Does Not Exclude Potential Benefit or Harm
Evidence Suggests Lower Intravenous Fluid Volumes Result in Little to No Difference in Serious Adverse Events
Clinical Efficacy-Passive Leg Raise (PLR)
Systematic Review and Meta-Analysis of Passive Leg Raise in Predicting Fluid Responsiveness (Intensive Care Med, 2016) [MEDLINE]: n = 991 (21 studies)
Cardiac Output was Measured by Echocardiogram (6 Studies), Calibrated Pulse Contour Analysis (6 Studies), Bioreactance (4 Studies), Esophageal Doppler (3 Studies), Transpulmonary Thermodilution or Pulmonary Artery Catheter (1 Study(, and Suprasternal Doppler (1 Study)
Pooled Correlation Between the Passive Leg Raise-Induced and the Fluid-Induced Changes in CO was 0.76 (0.73-0.80)
For the Passive Leg Raise-Induced Changes in CO, Pooled Sensitivity was 85% (0.81-0.88) and Pooled Specificity was 91% (0.88-0.93)
The Best Threshold was a Passive Leg Raise-Induced Increase in Cardiac Output ≥10 ± 2 %
For the Passive Leg Raise-Induced Changes in Pulse Pressure, Pooled Sensitivity was 56% and Pooled Specificity was 83%
Passive Leg Raise-Induced Changes in Cardiac Output Very Reliably Predicted the Response of CO to Fluid Challenge in Adults with Acute Circulatory Failure
When Passive Leg Raise Effects are Assessed by Changes in Pulse Pressure, the Specificity of the Passive Leg Raise Test Remained Acceptable, But its Sensitivity was Poor
Systematic Review and Meta-Analysis of Dynamic Assessments of Fluid Responsiveness in Goal-Directed Therapy in Septic Shock (Crit Care Med, 2017) [MEDLINE]: n = 1,652 (13 trials)
Assessments Included Stroke Volume Variation (9 Trials), Pulse Pressure Variation (1 Trial), and Stroke Volume Change with Passive Leg Raise/Fluid Challenge (3 Trials)
In 12 Trials Reporting Mortality Rate, the Risk Ratio for Death Associated with Dynamic Assessment of Fluid Responsiveness was 0.59 (95% CI: 0.42-0.83; I = 0%; n = 1,586)
The Absolute Risk Reduction in Mortality Associated with Dynamic Assessment of Fluid Responsiveness was -2.9% (95% CI, -5.6% to -0.2%)
Dynamic Assessment of Fluid Responsiveness was Associated with Decreased ICU Length of Stay (Weighted Mean Difference -1.16 Days [95% CI: -1.97 to -0.36]; I = 74%; n = 394, 6 Trials) and Decreased Duration of Mechanical Ventilation (Weighted Mean Difference -2.98 hr [95% CI: -5.08 to -0.89]; I = 34%; n = 334, 5 Trials)
Prospective, Multicenter, Randomized Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) Trial of the Effect of Passive Leg Raise on Stroke Volume in US and UK (Chest, 2020) [MEDLINE]
Fluid Balance at 72 hrs or ICU Discharge was Significantly Lower (-1.37 L Favoring Intervention Arm, 0.65 ± 2.85 L Intervention Arm vs. 2.02 ± 3.44 L Usual Care Arm, p = 0.021)
Fewer Patients Required Renal Replacement Therapy (5.1% vs 17.5%, p = 0.04) or Mechanical Ventilation (17.7% vs 34.1%, p=0.04) in the Intervention Arm, a Compared to Usual Care
Clinical Efficacy-Pulse Pressure Variation
Study of Pulse Pressure Variation (Respiratory Changes in Arterial Pressure) in Mechanically-Ventilated Patients with Sepsis (Am J Respir Crit Care Med. 2000) [MEDLINE]
DeltaPp (Respiratory Change in Pulse Pressure) = Pp(max) – Pp(min), Divided by the Mean of the Two Values and Expressed as a Percentage
DeltaPs (Respiratory Change in Systolic Pressure) was Calculated Similarly
In Mechanically-Ventilated Patients with Sepsis, DeltaPp Predicted Fluid Responsiveness Better than DeltaPs
Systematic Review and Meta-Analysis of Pulse Pressure Variation in Predicting Fluid Responsiveness in the ICU (Crit Care, 2014) [MEDLINE]: n = 22 studies (n = 807 patients)
Pulse Pressure Variation Predicts Fluid Responsiveness Accurately in Mechanically-Ventilated Patients with Relatively Large Tidal Volumes (VT ≥8 mL/kg) (without Spontaneous Breathing or Arrhythmia)
Using Pulse Pressure Variation Cutoff of >12%
Sensitivity = 88%
Specificity = 89%
In General, Pulse Pressure Variation >13% Implied Fluid Responsiveness, While Pulse Pressure Variation <10% Indicated Fluid Unresponsiveness
Pulse Pressure Variation May Be of Limited Value in Patient on Tidal Volumes <8 mL/kg, Due to the Fact that Cyclic Changes in Intrathoracic Pressures Were Not Significant Enough to Induce Preload Variations (Although When Using Higher Levels of PEEP, this May Enhance the Cyclic Changes in Pleural Pressure): for this reason, tidal volume can be temporarily adjusted to allow measurement of the pulse pressure variation
Systematic Review and Meta-Analysis of Dynamic Assessments of Fluid Responsiveness in Goal-Directed Therapy in Septic Shock (Crit Care Med, 2017) [MEDLINE]: n = 1,652 (13 trials)
Assessments Included Stroke Volume Variation (9 Trials), Pulse Pressure Variation (1 Trial), and Stroke Volume Change with Passive Leg Raise/Fluid Challenge (3 Trials)
In 12 Trials Reporting Mortality Rate, the Risk Ratio for Death Associated with Dynamic Assessment of Fluid Responsiveness was 0.59 (95% CI: 0.42-0.83; I = 0%; n = 1,586)
The Absolute Risk Reduction in Mortality Associated with Dynamic Assessment of Fluid Responsiveness was -2.9% (95% CI, -5.6% to -0.2%)
Dynamic Assessment of Fluid Responsiveness was Associated with Decreased ICU Length of Stay (Weighted Mean Difference -1.16 Days [95% CI: -1.97 to -0.36]; I = 74%; n = 394, 6 Trials) and Decreased Duration of Mechanical Ventilation (Weighted Mean Difference -2.98 hr [95% CI: -5.08 to -0.89]; I = 34%; n = 334, 5 Trials)
Clinical Efficacy-Manipulation of the Level PEEP in a Patient on Mechanical Ventilation to Determine Volume Responsiveness
Prospective PEEP-Test Study of the Manipulation of PEEP Level in Mechanically Ventilated Patients (without Spontaneous Breathing) to Determine Volume Responsiveness (Crit Care, 2023) [MEDLINE]: n = 64
Protocol
Volume Responsiveness was Assessed by a Positive Passive Leg Raise Test, Defined as an Increase in Pulse-Contour-Derived Cardiac Index During Passive Leg Raise ≥10%
PEEP-Test Consisted of Reducing the PEEP from the High Level to 5 cmH 2O for 1 min
Pulse-Contour-Derived Cardiac Index (PiCCO2) was Monitored During Passive Leg Raise and the PEEP-Test
In Volume Responsive Patients, the PEEP-Test Induced a Significant Increase in Cardiac Index of 16% (12-20%) (From 2.4 ± 0.7 to 2.9 ± 0.9 L/min/m2, p < 0.0001), in Comparison with Volume Unresponsive Patients
In Volume Unresponsive Patients, Passive Leg Raise and the PEEP-Test Increased Cardiac Index by 2% (1-5%) and 6% (3-8%), Respectively
Volume Responsiveness was Predicted by an Increase in Cardiac Index >8.6% During the PEEP-Test with a Sensitivity of 96.8% (95%CI: 83.3-99.9%) and a Specificity of 84.9% (95% CI: 68.1-94.9%)
Area Under the Receiver Operating Characteristic Curve of the PEEP-test for Detecting Volume Responsiveness was 0.94 (95% CI: 0.85-0.98) (p < 0.0001 vs 0.5)
Spearman’s Correlation Coefficient Between the Changes in Cardiac Induced by Passive Leg Raise and the PEEP-Test was 0.76 (95% CI: 0.63-0.85, p < 0.0001)
In Mechanically Ventilated Patients on a PEEP ≥ +10, Upon Decreasing the PEEP to +5, an Increase in Cardiac Index >8.6% Reliably Detected Volume Responsiveness
Clinical Efficacy-Rate of Fluid Resuscitation
Brazilian Randomized BaSICS Trial Studying the Rate of Fluid Resuscitation in Sepsis in the Intensive Care Unit (JAMA, 2021) [MEDLINE]: n = 10, 520 (in 75 ICU’s)
Slow Rate of Intravenous Fluid Resuscitation Did Not Impact the 90-Day Mortality Rate, as Compared to Fast Rate of Fluid Resuscitation (26.6% vs 27.0%)
There was No Significant Interaction Between the Fluid Type and the Fluid Infusion Rate
Clinical Efficacy-Deresuscitation
Single Academic Center Pilot Study of Protocolized Deresuscitation in the Intensive Care Unit (Crit Care, 2020)[MEDLINE]: n = 364
Protocolized Diuresis was Associated with a Significant Decrease in 72 hrs Post-Shock Cumulative Fluid Balance (Median Interquartile Range – 2257 (- 5676-920) mL vs 265 (- 2283-3025) mL; p < 0.0001]
In-Hospital Mortality in the Intervention Group was Lower, as Compared to the Historical Group (5.5% vs 16.1%; p = 0.008) and Higher Intensive Care Unit-Free Days (p = 0.03)
No Statistically Significant Difference was Demonstrated in Terms of Ventilator-Free Days
Increased Rates of Hypernatremia and Hypokalemia were Demonstrated in the Intervention Group
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Assessment of Cardiac Function is Recommended if Clinical Examination Does Not Indicate a Clear Diagnosis (Best Practice Statement)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
Sepsis/Septic Shock are Medical Emergencies and Treatment/Resuscitation Should Begin Immediately (Best Practice Statement)
For Patients with Sepsis-Induced Hypoperfusion or Septic Shock, ≥30 mL/kg of Intravenous Crystalloid Fluid Should Be Given within the First 3 hrs of Resuscitation (Weak Recommendation, Low Quality of Evidence)
For Adults with Sepsis/Septic Shock, Use of Dynamic Hemodynamic Variables are Recommended to Guide Intravenous Fluid Resuscitation Over Physical Examination or Static Parameters (CVP, ScvO2 Obtained from Central Venous Catheter, SvO2 Obtained from Swan-Ganz Catheter, etc) Alone (Weak Recommendation, Very Low Quality of Evidence)
Dynamic Hemodynamic Variables
Passive Leg Raise/Fluid Challenge Against Stroke Volume
Variation in Systolic Blood Pressure in Response to Changes in Intrathoracic Pressure Associated with Mechanical Ventilation
Variation in Pulse Pressure in Response to Changes in Intrathoracic Pressure Associated with Mechanical Ventilation
Variation in Stroke Volume in Response to Changes in Intrathoracic Pressure Associated with Mechanical Ventilation
ScvO2 ≥70% (Obtained from Central Venous Catheter)
SvO2 ≥65% (Obtained from Swan-Ganz Catheter)
For Adults with Sepsis/Septic Shock, Guiding Resuscitation to Decrease the Serum Lactate in Patients with Elevated Serum Lactate Level is Recommended Over Not Using the Serum Lactate (Weak Recommendation, Low Quality of Evidence)
During Acute Intravenous Fluid Resuscitation, Serum Lactate Level Should Be Interpreted Considering the Clinical Context and Other Etiologies of Elevated Serum Lactate
For Adults with Septic Shock, Use of Capillary Refill Time to Guide Resuscitation as an Adjunct to Other Measures of Perfusion is Recommended (Weak Recommendation, Low Quality of Evidence)
Insufficient Evidence to Make a Recommendation on the Use of Restrictive vs Liberal Fluid Strategies in the First 24 hrs of Resuscitation in Patients with Sepsis/Septic Shock Who Still Have Signs of Hypoperfusion and Volume Depletion After the Initial Resuscitation (No Recommendation)
Intravenous Fluid Resuscitation Should Be Given Only in Patients Have Signs of Hypoperfusion
Choice of Resuscitation Fluid
Clinical Efficacy
SAFE Trial: Comparing Crystalloid (Normal Saline) vs Colloid (4% Albumin) in Heterogenous Population of ICU Patients (NEJM, 2004) [MEDLINE]
No Difference in 28-Day Mortality or Need for Hemodialysis
Traumatic Brain Injury (TIB) Subgroup: Colloid Use Increased the Mortality Rate (see Traumatic Brain Injury)
Colloid Use in Septic Shock Subgroup Demonstrated a Trend Toward Lower Mortality Rate
German VISEP Trial of Pentastarch and Intensive Insulin Therapy in Severe Sepsis (NEJM, 2008) [MEDLINE]
Intensive Insulin Therapy Placed Critically Ill Patients with Sepsis at Increased Risk for Serious Adverse Events Related to Hypoglycemia
Hydroxyethyl Starch was Harmful, and its Toxicity Increased with Accumulating Doses
ATS/ERS/ESICM/SCCM/SRLF Statement: Prevention and Management of Acute Renal Failure in the ICU Patient (Am J Respir Crit care Med, 2010) [MEDLINE]
Hyper-Oncotic Fluids (Hydroxyethyl Starch, Dextrans, 20-25% Albumin) are Not Recommended, Due to Their Risk of Renal Dysfunction
Hypo-Oncotic Colloids (5% Albumin) are as Effective as Crystalloids
Systematic Review/Meta-Analysis of Albumin in Sepsis (Crit Care Med, 2011) [MEDLINE]
Albumin-Containing Solutions Were Associated with Lower Mortality Than Other Fluid Resuscitation Regimens in Sepsis
Australian/New Zealand Crystalloid vs Hydroxyethyl Starch Trial (CHEST): Comparing Hydroxyethyl Starch vs Normal Saline Resuscitation in ICU Patients (NEJM, 2012) [MEDLINE]
No Difference in 90-Day Mortality Between 6% Hydroxyethyl Starch vs Normal Saline
However, Hydroxyethyl Starch Group Had Higher Need for Hemodialysis
Danish 6S Trial of Hydroxyethyl Starch vs Ringer’s Acetate in Severe Sepsis (NEJM, 2012) [MEDLINE]
Hydroxyethyl Starch Increased the 90-Day Mortality Rate and were More Likely to Require Renal Replacement Therapy
Study of Chloride-Restrictive Intravenous Fluid Resuscitation Strategy in Critically Ill Patients (JAMA, 2012) [MEDLINE]: study is based on the observation that hyperchloremia may induce renal vasoconstriction
Chloride-Restrictive IV Fluid Resuscitation Strategy Decreased Incidence of Acute Kidney Injury and Use of Hemodialysis
Chloride-Restrictive IV Fluid Resuscitation Strategy Demonstrated No Difference in Hospital Mortality, Hospital or ICU Length of Stay, or Need for Hemodialysis After Hospital Discharge
CRISTAL Trial Examining Crystalloid vs Colloid Intravenous Fluid Resuscitation in Critically Ill Patients with Hypovolemic Shock (JAMA, 2013) [MEDLINE]
28-Day Mortality: no difference between use of crystalloid vs colloid in septic shock
90-Day Mortality: improved with use of colloids (although authors note that these findings need to be confirmed in future trials)
Fluids in Sepsis and Septic Shock Group Study (Ann Intern Med, 2014) [MEDLINE]: systematic review and network meta-analysis (14 studies, n = 18,916 patients)
Network Meta-Analysis at the 4-Node Level: higher mortality with starches than with crystalloids (high confidence)
Network Meta-Analysis at the 4-Node Level: lower mortality with albumin than with crystalloids (moderate confidence) or starches (moderate confidence)
Network Meta-Analysis at the 6-Node Level: lower mortality with albumin than with saline (moderate confidence) and low-molecular-weight starch (low confidence) and with balanced crystalloids than with saline (low confidence) and low and high-molecular-weight starches (moderate confidence)
Conclusions: resuscitation with balanced crystalloids (lactated ringers, etc) or albumin was associated with decreased mortality, as compared to other fluids
Italian ALBIOS Study of Albumin Fluid Resuscitation in Severe Sepsis (NEJM, 2014) [MEDLINE]
Albumin in Addition to Crystalloids Did Not Improve the 28-Day and 90-Day Survival, as Compared to Crystalloid Alone
Subgroup Analysis Suggested that Albumin Decreased the 90-Day Mortality Rate in Subgroup of Patients with Septic Shock
Meta-Analysis of Impact of Albumin and Crystalloid on Mortality in Adult Patients with Severe Sepsis and Septic Shock (Crit Care, 2014) [MEDLINE]
A Trend Toward Decreased 90-Day Mortality was Observed in Severe Sepsis Patients Resuscitated with Albumin, as Compared Crystalloid and Saline
Moreover, the 90-Day Mortality of Patients with Septic Shock Decreased Significantly
Meta-Analysis of Impact of Albumin vs Other Fluids on Mortality in Sepsis (PLoS One, 2014) [MEDLINE]
No Significant Advantage of Albumin Over Any Other Fluids in Sepsis of Any Severity
Study of Effect of Hyperchloremia of Hospital Mortality in Critically Ill Sepsis Patients (Crit Care Med, 2015) [MEDLINE]
In Critically Ill Sepsis Patients, Hyperchloremia (Serum Cl ≥110 mEq/L) on ICU Admission, as Well as Higher Serum Chloride and within Subject Worsening of Hyperchloremia at 72 hrs of the ICU Stay were Associated with Increased All-Cause Hospital Mortality
The Associations were Independent of Base Deficit, Cumulative Fluid Balance, Acute Kidney Injury, and Other Critical Illness Parameters
French HYPERS2S Trial of Hyperoxia and Hypertonic Saline in Septic Shock (Lancet Respir Med, 2017) [MEDLINE]
Trial Stopped Prematurely for Safety Reasons
Setting FiO2 to 100% to Induce Arterial Hyperoxia Might Increase the Mortality Rate in Septic Shock
Hypertonic (3%) Saline Resuscitation Did Not Decrease the Mortality Rate in Septic Shock
Retrospective Review of Resuscitative Fluids in Sepsis in the Emergency Department (Am J Emerg Med, 2018) [MEDLINE]
Use of Balanced Resuscitative Fluids (Lactated Ringer’s or Isolyte) was Associated with Decreased Mortality Rate, as Compared to Normal Saline
Cluster-Randomized, Multiple-Crossover SMART-MED and SMART-SURG Trial of Balanced Crystalloids (Lactated Ringers or Plasma-Lyte) vs Normal Saline in Critically Ill Adults (NEJM, 2018) [MEDLINE]: n = 7,942 (5 ICU’s)
In-Hospital 30-Day All-Cause Mortality Rate was 10.3% in the Balanced Crystalloid Group and 11.1% in the Saline Group (P = 0.06)
Incidence of New Renal Replacement Therapy was 2.5% in the Balanced Crystalloid Group and 2.9% in the Saline Group (P = 0.08)
Incidence of Persistent Renal Dysfunction was 6.4% in the Balanced Crystalloid Group and 6.6% in the Saline Group (P = 0.60)
Brazilian Randomized BaSICS Trial of Fluid Resuscitation in Sepsis in the Intensive Care Unit (JAMA, 2021) [MEDLINE]: n = 10,520 (in 75 ICU’s)
Among Critically Ill Patients Requiring Intravenous Fluid Challenge, the Use of a Balanced Solution (as Compared with Normal Saline) Did Not Significantly Decrease the 90-Day Mortality Rate
Australian/New Zealand Double-Blind, Randomized Controlled PLUS Trial Comparing Saline vs Balanced Multiple Electrolyte Solution in the Resuscitation of Critically Ill Adults (NEJM, 2022) [MEDLINE]: n = 5,037
90-Day Mortality Rate was Comparable for Balanced Multiple Electrolyte Solution Group (21.8%) vs Saline Group (22.0%) (Difference of -0.15 Percentage Points; 95% CI: -3.60 to 3.30; P = 0.90)
Need for New Renal Replacement Therapy was Comparable for the Balanced Multiple Electrolyte Solution Group (12.7%) vs the Saline Group (12.9%) (Difference of -0.20 Percentage Points; 95% CI: -2.96 to 2.56)
Mean (± SD) Maximum Increase in Serum Creatinine Level was 0.41 ± 1.06 mg Per Deciliter (36.6 ± 94.0 μmol Per Liter) in the Balanced Multiple Electrolyte Solution Group and 0.4 1± 1.02 mg Per Deciliter (36.1 ± 90.0 μmol Per Liter) in the Saline group, for a Difference of 0.01 mg Per Deciliter (95% CI: -0.05 to 0.06) (0.5 μmol Per Liter; 95% CI: -4.7 to 5.7)
Number of Adverse and Serious Adverse Events Did Not Differ Meaningfully Between the Groups
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Hyperchloremia Should Be Avoided (Regardless of Which Fluid is Used)
Due to Concern that Hyperchloremia May Induce Renal Vasoconstriction
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Sepsis/Septic Shock, Crystalloids are Recommended as the First-Line Intravenous Fluid for Resuscitation (Strong Recommendation, Moderate Quality Evidence)
For Adults with Sepsis/Septic Shock, Balanced Crystalloids are Recommended for Resuscitation Instead of Normal Saline (Weak Recommendation, Low Quality Evidence)
For Adults with Sepsis/Septic Shock, Albumin is Recommended in Patients Who Have Received Large Volumes of Crystalloids (Weak Recommendation, Moderate Quality Evidence)
For Adults with Sepsis/Septic Shock, Hydroxyethyl Starches are Not Recommended for Resuscitation (Strong Recommendation, High Quality Evidence)
Due to Concerns Related to an Increased Mortality Rate and Increased Risk for Hemodialysis
For Adults with Sepsis/Septic Shock, Gelatin is Not Recommended for Resuscitation (Weak Recommendation, Moderate Quality Evidence)
Methylene Blue Selectively Inhibits the Action of Nitric Oxide on Guanylate Cyclase, Decreasing Endotoxin-Mediated Vasodilation, and Resulting in Increased Systemic Blood Pressure
Administration
Single Intravenous Bolus Dose of 1-2 mg/kg Over 20-60 min
Improvement in Shock (i.e. Increased Systemic Vascular Resistance, Decreased Vasopressor Dosage, etc) May Be Observed within 1-2 hrs After Dose
May Subsequently Continue Dosing with Infusion of 0.5-1 mg/kg/hr
Indicated for Septic Shock and Hypotension Refractory to Multiple Vasopressors without Evidence of Acute Respiratory Distress Syndrome (ARDS)
At This Low Dose, Vasopressin Causes Systemic Vasoconstriction, with Increased Mean Arterial Pressure (and Decreased Cardiac Output): however, splanchnic blood flow is usually increased or unchanged
This Low Dose Can May Also Modestly Increase Pulmonary Pressures
Clinical Efficacy-Vasopressors
Vasopressin and Septic Shock Trial (VASST) of Vasopressin Add-On Therapy (to Norepinephrine) in Septic Shock (NEJM, 2008) [MEDLINE]
Low-Dose Vasopressin (0.01-0-03 U/min) Add-On Therapy to Norepinephrine Did Not Decrease Mortality, as Compared to Norepinephrine Alone in Septic Shock
Lower Mortality Rates were Observed in the Stratum of Patients Randomized to Receive Vasopressin with Norepinephrine-Equivalent Doses <15 μg/min at the Time of Randomization (90-Day Mortality 35.8% vs 46.1%; Absolute Risk Reduction, –10.4% [95% CI, –20.3% to –0.4%]), as Compared with Those Who Received Norepinephrine Alone (Stratum Interaction p = 0.10)
Sepsis Occurrence in Acutely Ill Patients (SOAP) II Trial Comparing Dopamine with Norepinephrine in Shock of Various Etiologies (NEJM, 2010) [MEDLINE]
No Mortality Difference Between Dopamine and Norepinephrine in Shock
However, Dopamine Was Associated with More Arrhythmic Adverse Events
Use of Additional Vasopressin and Epinephrine for Unresponsive Shock was Similar in Both Groups
In Subgroup with Cardiogenic Shock, Dopamine Increased 28-Day Mortality, as Compared to Norepinephrine: this increase in mortality was not observed in septic and hypovolemic shock
Small Randomized Trial Comparing Phenylephrine with Norepinephrine in Septic Shock Unresponsive to Dopamine Therapy (Indian J Crit Care Med, 2010) [MEDLINE]: n = 54
Phenylephrine was Comparable to Norepinephrine in Reversing the Hemodynamic and Metabolic Abnormalities in Septic Shock
Phenylephrine Had the Additional Benefit of Decreasing the Heart Rate and Improving the SVI
Meta-Analysis Comparing Dopamine with Norepinenephrine in Septic Shock (Crit Care Med, 2012) [MEDLINE]
In Septic Shock, Dopamine Increased Arrhythmias and Mortality Rate, as Compared to Norepinephrine
Comparison of the Cardiopulmonary Effects Vasopressin and Norepinephrine in Septic Shock (Chest, 2012) [MEDLINE]: data from VASST trial patients
Vasopressin Decreased the Norepinephrine Requirement
Vasopressin Decreased the Heart Rate, But Did Not Decrease Cardiac Output
However, There was an Increased Use of Inotropic Drugs (Mostly Dobutamine) in the Vasopressin Group (Especially in the Most Severe Subset of Patients)
No Difference Between Vasopressin and Norepinephrine with Regard to Pulmonary Artery Pressures, Oxygenation, and Cardiac Filling Pressures
Prospective Substudy (of a Randomized Trial) of Myocardial Ischemia in Septic Shock (Crit Care, 2013) [MEDLINE]
Troponin Elevation is Common in Adults with Septic Shock
No Differences in Troponin Elevation, CK Elevation, or EKG Changes in Patients Treated with Vasopressin vs Epinephrine
Bayesian Network Meta-Analysis of Vasopressors Effect on Mortality Rate in Septic Shock (J Crit Care, 2014) [MEDLINE]
Norepinephrine (with/without Vasopressin) is the Preferred First Choice Pressor in Septic Shock in Terms of Mortality Benefit
No Evidence Exists that Epinephrine vs Dopamine as the Second-Line Agent Decreases the Mortality Rate
No Evidence that the Addition of an Inotropic Agent (Such as Dobutamine) Decreases the Mortality Rate
Pilot Study Examining the Effect of Corticosteroids on Vasopressor Requirement in Septic Shock (Crit Care Med, 2014) [MEDLINE]
Hydrocortisone Decreased Vasopressin Duration and Dose Requirements in Septic Shock: although hydrocortisone did not alter the plasma vasopressin level
Systematic Review and Meta-Analysis Examining Various Vasopressors in Septic Shock (Ther Clin Risk Mgmt, 2015) [MEDLINE]
Norepinephrine May Be Superior to Dopamine in Terms of Mortality Rate
There is Insufficient Evidence to Suggest Superiority of Any Other Pressor Over Another
Systematic Review and Meta-Analysis Examining Various Vasopressors in Septic Shock (PLoS One, 2015) [MEDLINE]
Norepinephrine is Superior to Dopamine in Terms of Hemodynamic Profile and Adverse Events: authors recommend norepinephrine as the first choice vasopressor
Meta-Analysis Examining the Effect of Inotropes/Vasopressors on the Mortality Rate in Critically Ill Patients (Br J Anaesth, 2015) [MEDLINE]: included n = 28,280 patients from 177 trials
Inotropes/Vasopressors Did Not Improve Mortality in Critically Ill Patients
Inotropes/Vasopressors Did Improve Mortality in the Subsets of Patients with Sepsis, Vasoplegic Syndrome, and Cardiac Surgery
Systematic Review and Meta-Analysis of Vasopressors in Septic Shock (PloS One, 2015) [MEDLINE]: n = 32 trials
Evidence Suggests a Survival Benefit, Better Hemodynamic Profile, and Decreased Adverse Events for Norepinephrine Over Dopamine
VANISH Trial (JAMA, 2016) [MEDLINE]: randomized trial (n = 409) of patients in septic shock (enrolled within 6 hrs) conducted in the UK
Early Use of Vasopressin Did Not Decrease the Incidence of Acute Kidney Injury, as Compared to Norepinephrine: although vasopressin group had less use of renal replacement therapy (25.4% vs 35.3%)
No Difference in Mortality Between the Early Use of Vasopressin Compared with Norepinephrine
Network Meta-Analysis of Vasopressors in Septic Shock ( J Intensive Care Soc, 2016) [MEDLINE]
Vasopressin was Superior to Dopamine for in Terms of 28-Day Mortality in Septic Shock
Existing Pairwise Information Supports the Use of Norepinephrine Over Dopamine
Cochrane Database Systematic Review of Vasopressors for Septic Shock (Cochrane Database Syst Rev, 2016)
No Evidence of Substantial Differences in Total Mortality Between Several Vasopressors
Dopamine Increases the Risk of Arrhythmia (as Compared to Norepinephrine) and Might Increase Mortality Rate
Otherwise, Evidence of Any Other Differences Between Any of the 6 Vasopressors Examined is Insufficient
Authors Identified Low Risk of Bias and High-Quality Evidence for the Comparison of Norepinephrine vs Dopamine and Moderate to Very Low-Quality Evidence for All Other Comparisons (Mainly Because Single Comparisons Occasionally were Based on Only a Few Participants)
Increasing Evidence Indicates that the Treatment Goals Most Often Employed are of Limited Clinical Value
Authors’ Findings Suggest that Major Changes in Clinical Practice are Not Required, But that Selection of Vasopressors Could Be Better Individualized and Could Be Based on Clinical Variables Reflecting Hypoperfusion
Systematic Review and Meta-Analysis of Efficacy of Vasopressin with Catecholamines vs Catecholamines Alone in Septic Shock (JAMA, 2018) [MEDLINE]
The Addition of Vasopressin to Catecholamine Vasopressors (as Compared with Catecholamines Alone) was Associated with a Lower Risk of Atrial Fibrillation
Single Center Phase II Randomized Thailand CENSER Trial of Early Norepinephrine Use in Septic Shock (Am J Respir Crit Care Med, 2019) [MEDLINE]: n= 310
Primary Endpoint: shock control rate (defined as achievement of mean arterial blood pressure >65 mm Hg, with urine flow >0.5 mL/kg/hr for 2 consecutive hrs, or decreased serum lactate >10% from baseline) by 6 hrs after diagnosis
Median Time from Emergency Department Arrival to Norepinephrine Administration was Significantly Shorter in the Early Norepinephrine Group (93 v 192 min; p<0.001)
Early Norepinephrine Use was Associated with Increased Shock Control by 6 hrs
Early Norepinephrine Use was Associated with Decreased Incidence of Pulmonary Edema (22/155 [14.4%] vs. 43/155 [27.7%]; P=0.004) and New Onset Arrhythmia (17/155 [11%] vs. 31/155 [20%]; P=0.03)
Early Norepinephrine Did Not Impact the 28-Day Mortality Rate
Systematic Review and Meta-Analysis of Timing of Norepinephrine Initiation in Septic Shock (Crit Care, 2020) [MEDLINE]: n = 929 (5 studies)
Early Norepinephrine Initiation Group Had Lower Short-Term Mortality Rate than Late Norepinephrine Initiation Group (Odds Ratio 0.45; 95% CI: 0.34-0.61; P < 0.00001; χ2 = 3.74; I2 = 0%)
Early Norepinephrine Initiation Group Had Shorter Time to Achieve Target Mean Arterial Pressure than Late Norepinephrine Initiation Group (Mean Difference – 1.39; 95% CI: – 1.81 to – 0.96; P < 0.00001; χ2 = 1.03; I2 = 0%)
Volume of Intravenous Fluids within 6 hrs of the Early Norepinephrine Initiation Group was Less than that of the Late Norepinephrine Initiation Group (Mean Difference – 0.50; 95% CI: – 0.68 to – 0.32; P < 0.00001; χ2 = 33.76; I2 = 94%)
No Statistically Significant Difference in the Intensive Care Unit Length of Stay Between the Two Group (Mean Difference – 0.11; 95% CI: – 1.27 to 1.05; P = 0.86; χ2 = 0.85; I2 = 0%)
Cleveland Clinic Health System Retrospective, Observational Study of Timing of Initiation of Add-On Vasopressin in Septic Shock (Crit Care Med, 2022) [MEDLINE]: n = 1,610
At Vasopressin Initiation, Median Serum Lactate was 3.9 mmol/L (Interquartile Range: 2.3–7.2 mmol/L), Median Norepinephrine-Equivalent Dose was 25 μg/min (Interquartile Range: 18–40 μg/min), and Median 5.3 hrs (Interquartile Range: 2.1–12.2 hrs) Had Elapsed Since Shock Onset
Odds of In-Hospital Mortality Increased 20.7% for Every 10 μg/min Increase in Norepinephrine-Equivalent Dose Up to 60 μg/min at the Time of Vasopressin Initiation (Adjusted Odds Ratio 1.21 (95% CI: 1.09–1.34), But There was No Association When the Norepinephrine-Equivalent Dose Exceeded 60 μg/min (Adjusted Odds Ratio: 0.96 (95% CI: 0.84–1.10)
There was a Significant Interaction Between the Timing of Vasopressin Initiation and Lactate Concentration (p = 0.02) for the Association with In-Hospital Mortality
A Linear Association Between Increasing In-Hospital Mortality was Detected for Increasing Lactate Concentration at the Time of Vasopressin Initiation, But No Association was Detected for Time Elapsed from Shock Onset
Conclusions
There was a Lower Mortality Rate When Vasopressin was Initiated at a Lower (vs a Higher) Norepinephrine Dose
There was a Lower Mortality Rate When Vasopressin was Initiated at a Lower (vs a Higher) Serum Lactate Level
Further Prospective Studies Should Explore This Association
Clinical Efficacy-Weaning of Vasopressors
Retrospective Cohort Study Examining the Order of Vasopressor Weaning in Septic Shock (J Crit Care, 2010) [MEDLINE]
Tapering of Vasopressin Before Norepinephrine Resulted in a Greater Incidence of Clinically Significant Hypotension than Did the Reverse Order
Small Single-Center DOVSS Trial Examining the Order of Vasopressor Withdrawal in Septic Shock (Crit Care, 2018) [MEDLINE]: n = 78
In Patients on Concomitant Norepinephrine and Vasopressin, Tapering Norepinephrine Rather than Vasopressin May Be Associated with a Higher Incidence of Hypotension in Patients Recovering from Septic Shock
Study Examining the Order of Vasopressor Weaning in Septic Shock (J Intensive Care Med, 2017) [MEDLINE]: n = 62 (vasopressin weaned first) and 92 (vasopressin weaned last)
Adult Patients Receiving Norepinephrine and Vasopressin in the Resolving Phase of Septic Shock May Be Less Likely to Develop Clinically Significant Hypotension if Vasopressin is the Final Vasopressor Discontinued
Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Trial ( NEJM, 2017) [MEDLINE]; n = 344
Angiotensin II Effectively Increased Blood Pressure in Patients with Vasodilatory Shock Who Did Not Respond to High Doses of Conventional Vasopressors
Post-Hoc Analysis of the Effect of Angiotensin II on Renal Outcomes in Vasodilatory Shock in the ATHOS-3 Trial (Crit Care Med, 2018) [MEDLINE]
In Patients with Acute Kidney Injury Requiring Renal Replacement Therapy at Study Initiation, 28-Day Survival in the Angiotensin II Group, as Compared to the Placebo Group
In Patients with Acute Kidney Injury Requiring Renal Replacement Therapy at Study Initiation, Mean Arterial Pressure was Higher and Rate of Liberation from Renal Replacement Therapy was Greater in the Angiotensin II Group, as Compared to the Placebo Group
Case Report of Hydroxocobalamin in Septic Shock (Cureus, 2021) [MEDLINE]
Single Center, Retrospective Case Series of Hydroxocobalamin in Refractory Septic Shock (Crit Care Explor, 2021) [MEDLINE]: n = 26
Hydroxocobalamin Increase in Mean Arterial Pressure at 1, 6, and 24 hrs (+16.3, +14.3, and +16.3 mm Hg, Respectively; p < 0.001)
Increase in Mean Arterial Pressure from Baseline Remained Statistically Significant When Controlling for Age/Sex/Comorbid Conditions
There was No Change in the Norepinephrine Equivalents Patients Required 1 hr Following Hydroxocobalamin, But a Statistically Significant Decrease in Norepinephrine Equivalent was Observed at 6 and 24 hrs (p < 0.001)
Phase 2 Single Center, Double-Blinded Study of Hydroxycobolamin in the Treatment of Septic Shock (Intravenous Hydroxocobalamin in Septic Shock Trial) (Chest, 2023) [MEDLINE]: n = 20
In the High-Dose Intravenous Hydroxocobalamin Group, as Compared to Placebo, There was a Greater Reduction in Vasopressor Dose Between Randomization and Postinfusion (-36% vs 4%, P < o.001) and Randomization and 3 hrs Postinfusion (-28% vs 10%, P = 0.019)
In the High-Dose Intravenous Hydroxocobalamin Group, the Plasma Hydrogen Sulfide Level was Reduced Over 45 mins by -0.80 ± 1.73 μM, as Compared with -0.21 ± 0.64 μM in the Placebo Group (P = 0.3)
Clinical Efficacy-Inotropes
Trial of Dobutamine to Increase Cardiac Output and Oxygen Delivery in Critically Ill Patients (NEJM, 1994) [MEDLINE]: intervention increased the mortality rate
Trial of Achieving Supranormal Cardiac Output or Normal SvO2 in Critically Ill Patients (NEJM, 1995) [MEDLINE]: no mortality benefit
Study of Effects of Dobutamine on Physiologic Parameters in Septic Shock (Intensive Care Med, 2013) [MEDLINE]
Dobutamine Had No Effect on Sublingual Microcirculatory, Metabolic, Hepatosplanchnic, or Peripheral Perfusion Parameters Despite an Increase in Systemic Hemodynamic Variables in Septic Shock Patients with Persistent Hypoperfusion, But Without Low Cardiac Output
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
General Recommendations
Vasopressor Dosing Should Be Titrated to an Endpoint Reflecting Perfusion (and Decreased/Stopped in the Face of Worsening Hypotension or Arrhythmias)
Dopamine (Low Dose) is Not Recommended for Renal Protection (Strong Recommendation, High Quality of Evidence)
Phenylephrine Use Should Be Limited in Sepsis Until Further Data are Available
However, the 2012 Surviving Sepsis Guidelines Stated that Phenylephrine was Not Recommended, Except When Norepinephrine is Associated with Arrhythmias, Cardiac Output is High with Low Mean Arterial Pressure, or as Salvage Therapy When Combined Inotropes/Vasopressors Fail to Achieve Mean Arterial Pressure Targets (Grade 1C Recommendation) (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Septic Shock, Norepinephrine is Recommended as the First-Line Vasopressor (Strong Recommendation)
vs Dopamine (High Quality Evidence)
vs Vasopressin (Moderate Quality Evidence)
vs Epinephrine (Low Quality of Evidence)
vs Selepressin (Low Quality of Evidence)
vs Angiotensin II (Very Low Quality Evidence)
General Comments
If Norepinephrine is Not Available, Dopamine or Epinephrine May Be Used as an Alternative (with Caution Regarding the Potential for Development of Arrhythmias)
For Adults with Septic Shock on Norepinephrine with Inadequate Mean Arterial Pressure, Addition of Vasopressin (Up to 0.03-0.04 U/min) is Recommended Instead of Escalating the Norepinephrine Dose (Weak Recommendation, Moderate Quality of Evidence)
For Adults with Septic Shock and Inadequate Mean Arterial Pressure Despite Norepinephrine and Vasopressin, Addition of Epinephrine is Recommended (Weak Recommendation, Low Quality of Evidence)
For Adults with Septic Shock, Terlipressin is Not Recommended (Weak Recommendation, Low Quality of Evidence)
For Adults with Septic Shock and Cardiac Dysfunction with Persistent Hypoperfusion Despite Adequate Volume Status and Arterial Blood Pressure, Addition of Dobutamine to Norepinephrine or Using Epinephrine Alone is Recommended (Weak Recommendation, Low Quality of Evidence)
Dobutamine Should Not Be Used Target a Supranormal Cardiac Output
Monitoring Response in Indices of Perfusion to a Measured Dobutamine-Induced Increase in Cardiac Output is Recommended
For Adults with Septic Shock and Cardiac Dysfunction with Persistent Hypoperfusion Despite Adequate Volume Status and Arterial Blood Pressure, Levosimendan is Not Recommended (Weak Recommendation, Low Quality of Evidence)
For Adults with Septic Shock, Invasive Arterial Blood Pressure Monitoring is Recommended Over Noninvasive Arterial Blood Pressure Monitoring, as Soon as Practical and if Resources are Available (Weak Recommendation, Very Low Quality of Evidence)
For Adults with Septic Shock, Starting Vasopressors Peripherally is Recommended to Restore Mean Arterial Pressure, Rather than Delaying Vasopressor Initiation Until a Central Venous Line is Placed (Weak Recommendation, Very Low Quality of Evidence)
When Using Vasopressors Peripherally, They Should Be Administered Only for a Short Period of Time and in a Vein in or Proximal to the Antecubital Fossa
Prospective Observational Study of Midodrine in Septic Shock in the Surgical Intensive Care Unit (ICU) (J Crit Care, 2013) [MEDLINE]: n = 20 patients who met ICU discharge criteria except for an intravenous vasopressor requirement
Midodrine Treatment was Associated with an Increase in the Magnitude of Decline of the Intravenous Vasopressor Rate
Single Center Retrospective Cohort Study of Midodrine During the Recovery Phase in Septic Shock (Chest, 2016) [MEDLINE]: n = 275 patients hospitalized with septic shock requiring ≥24 hrs of intravenous vasopressors (who demonstrated a period of clinical stability)
Midodrine Decreased the Intravenous Vasopressor Duration (2.9 Days vs 3.8 Days) (p <0.001)
Midodrine Decreased the Intensive Care Unit Length of Stay (7.5 Days vs 9.4 Days) (p = 0.017)
An Intravenous Vasopressor was Restarted After Discontinuation in 5.2% of Patients in the Midodrine Group, as Compared to 15% of the Patients in the Control Group (P = 0.007)
The Only Complication of Midodrine Use was Transient Bradycardia in One Patient (Which Resolved Upon Discontinuation of Midodrine)
US/Australian MIDAS Randomized, Double-Blind, Placebo-Controlled Trial of Midodrine in Septic Shock (Intensive Care Med, 2020) [MEDLINE]: n = 132 patients on a single vasopressor for ≥24 hrs
No Difference in Time to Intravenous Vasopressor Discontinuation (23.5 vs 22.5, P = 0.62)
No Differences in Secondary Endpoints (Time to Intensive Care Unit Discharge Readiness, Intensive Care Unit and Hospital Lengths of Stay, and Intensive Care Unit Readmission Rate)
Bradycardia Occurred More Often After Midodrine Administration (7.6% vs 0%, p = 0.02)
Cleveland Clinic-Abu Dhabi/Mayo Clinic-Rochester Pilot, Double-Blind, Placebo-Controlled Randomized Trial of Midodrine During the First 24 hrs of Septic Shock (with Mean Arterial Pressure <70 mm Hg Despite Sepsis Treatment) in Adults (Crit Care Explor, 2021) [MEDLINE]: n = 32
Methods
Only 3 Doses of Midodrine 10 mg were Administered vs Placebo
Decreased Median Duration of Intravenous Vasopressors in the Midodrine Group (14.5 ± 8.1 hrs), as Compared to the Placebo Group (18.8 ± 7.1 hrs) (p = 0.19)
Decreased Total Intravenous Vasopressor Requirement in the Midodrine Group, as Compared to the Placebo Group (P = 0.59)
Decreased Intensive Care Unit Length of Stay in the Midodrine Group (2.29 Days; Interquartile Range: 1.65-3.9 Days), as Compared to the Placebo Group (2.45 Days; Interquartile Range: 1.6-3.2 Days) (p = 0.36)
Similar Hospital Length of Stay in Both Groups (P = 0.41)
A Future Phase II Trial Powered for Clinical Outcomes is Justified
Single Center Prospective Randomized Controlled Trial of Midodrine (in Addition to Norepinephrine) in Septic Shock (Ir J Med Sci, 2022) [MEDLINE]: n = 60 patients on vasopressors for ≥24 hrs
Median Duration of Norepinephrine Administration in the Midodrine and Norepinephrine Groups was 4 and 6 Days, Respectively (p = 0.001)
Use of Midodrine Significantly Decreased the Duration of Norepinephrine Administration, Weaning Period During the Septic Shock Recovery Phase, and Mortality Rate
Mean Length of Stay was Comparable Between the Groups
Midodrine Group Demonstrated Cost-Saving Results vs the Norepinephrine Group
Arrhythmia Management
Clinical Efficacy
Retrospective Cohort Study of Practice Patterns in the Management of Atrial Fibrillation During Sepsis (Chest, 2016) [MEDLINE]: n = 39,693
While Calcium Channel Blockers were the Frequently Used Intravenous Medications for Atrial Fibrillation During Sepsis, β-Blockers were Associated with Superior Clinical Outcomes (In-Hospital Mortality Rate) in the Subgroups Analyzed: results were similar among subgroups with new-onset vs pre-existing AF, heart failure, vasopressin-dependent shock, or hypertension
Multicenter Retrospective Cohort Study of the Treatment of Sepsis-Associated Atrial Fibrillation with Rapid Ventricular Response (with Heart Rate > 110 beats/min) (Chest, 2020) [MEDLINE]: n = 666
In the Study, 50.6% Initially Received Amiodarone, 33.8% Received a Calcium Channel Blocker, 10.1% Received a β-Blocker, and 5.6% Received Digoxin
Adjusted Hazard Ratio for Heart Rate of <110 beats/min by 1 hr
Amiodarone vs β-Blocker: 0.50 (95% CI: 0.34-0.74)
Digoxin vs β-Blocker: 0.37 (95% CI: 0.18-0.77)
Calcium Channel Blocker vs β-Blocker: 0.75 (95% CI: 0.51-1.11)
Adjusted Hazard Ratio for Heart Rate of <110 beats/min by 6 hrs
Amiodarone vs β-Blocker: : 0.67 (95% CI: 0.47-0.97)
Digoxin vs β-Blocker: 0.60 (95% CI: 0.36-1.004)
Calcium Channel Blocker vs β-Blocker: 1.03 (95% CI: 0.71-1.49)
Conclusions
β-Blocker Treatment Strategy Improved Heart Rate Control at 1 hr
With All of the Strategies, There was Generally Similar Heart Rate Control at 6 hrs
Corticosteroids Have Unclear Benefit in Septic Shock
Clinical Efficacy
CORTICUS Trial of Hydrocortisone Therapy for Septic Shock (NEJM, 2008) [MEDLINE]” n = 499 patients
Hydrocortisone Did Not Decrease the Mortality Rate or Enhance the Reversal of Shock in Patients with Septic Shock (Either Overall or in Patients Who Did Not Have a Response to Corticotropin): however, hydrocortisone hastened the reversal of shock in the subset of patients in whom shock was reversed
Subanalysis of CORTICUS Septic Shock Trial Data Examining the Effects of Etomidate (Intensive Care Med, 2009) [MEDLINE]
Use of Bolus Dose Etomidate in the 72 h Before Study Inclusion was Associated with an Increased Incidence of Inadequate Response to Corticotropin, But was Also Likely Associated with an Increase in the Mortality Rate
Review of Corticosteroid Use in Septic Shock (Am J Respir Crit Care Med, 2012) [MEDLINE]
Low-Dose Corticosteroids Improve Blood Pressure and Result in Shorter Duration of Vasopressor Use in Septic Shock
However, the Mortality Benefit is Unclear
Fludocortisone is Not a Beneficial Component of This Regimen and Might Increase the Infection Risk
Early High-Dose Corticosteroids are Potentially Harmful in the Treatment of Septic Shock
Analysis of Low-Dose Corticosteroids in Adult Septic Shock (Intensive Care Med, 2012) [MEDLINE]
Corticosteroids Increased the Adjusted Hospital Mortality Rate
Pilot Study Examining the Effect of Corticosteroids on Vasopressor Requirement in Septic Shock (Crit Care Med, 2014) [MEDLINE]
Hydrocortisone Decreased Vasopressin Duration and Dose Requirements in Septic Shock: although hydrocortisone did not alter the plasma vasopressin level
Cochrane Database Systematic Review of Corticosteroid Treatment in Sepsis (Cochrane Database Syst Rev, 2015) [MEDLINE]
Low-Quality Evidence Indicates that Corticosteroids Decreased Mortality in Sepsis
Moderate Quality Evidence Suggests that a Long Course of lLow-Dose Corticosteroids Decreased 28-day Mortality without Inducing Major Complications and Led to an Increase in Metabolic Disorders (Hyperglycemia, Hypernatremia)
German HYPRESS Trial of Hydrocortisone in Severe Sepsis without Shock (JAMA, 2016) [MEDLINE]: intention to treat analysis (n = 353)
Hydrocortisone Did Not Decrease the Development of Shock within 14 Days or the 28-Day Mortality Rate
Hydrocortisone Group Had Higher Incidence of Hyperglycemia (90.9% vs 81.5%), Secondary Infection (21.5% vs 16.9% ), and Muscle Weakness (30.7% vs 23.8% ), But No Difference in Weaning Failure (8.6% vs 8.5%), as Compared to Placebo Group
Australian-New Zealand Randomized, Placebo-Controlled ADRENAL Trial of Adjunctive Corticosteroids in Mechanically Ventilated Patients with Septic Shock (NEJM, 2018) [MEDLINE]: n = 3800
Hydrocortisone Regimen: 200 mg/day, continuous intravenous infusion over 24 hrs for a maximum of 7 days or until ICU discharge or death
Continuous Hydrocortisone Infusion Resulted in Faster Time to Shock Resolution (3 Days vs 4 Days), as Compared to Placebo
Continuous Hydrocortisone Infusion Resulted in Shorter Duration of Initial Mechanical Ventilation (6 Days vs 7 Days), as Compared to Placebo
However, There Were No Differences in (Alive) Ventilator-Free Days
Continuous Hydrocortisone Infusion Resulted in Less Blood Transfusions, as Compared to Placebo
Continuous Hydrocortisone Infusion Did Not Impact Rate of Recurrence of Septic Shock, Number of Days Alive and Out of the ICU, Number of Days Alive and Out of the Hospital, Recurrence of Mechanical Ventilation, Rate of Renal Replacement Therapy, and Incidence of Bacteremia/Fungemia
Continuous Hydrocortisone Infusion Did Not Decrease 28-Day or 90-Day Mortality, as Compared to Placebo
French APROCCHSS Trial of Hydrocortisone and Fludrocortisone for Adults with Septic Shock (NEJM, 2018) [MEDLINE]: n = 1241
Hydrocortisone and Fludrocortisone Decreased the 90-Day All-Cause Mortality Rate, as Compared to Placebo
Hydrocortisone and Fludrocortisone Increased the Number of Vasopressors-Free Days and Organ Failure-Free Days
There was No Difference in Ventilator-Free Days
Hyperglycemia was More Common in the Hydrocortisone and Fludrocortisone Group
Systematic Review and Meta-Analysis of Corticosteroids in Adult Patients with Septic Shock (Intensive Care Med, 2018) [MEDLINE]: n = 7297 (22 trials)
Low-Dose Corticosteroids Did Not Impact Short or Long-Term Mortality Rates
Low-Dose Corticosteroids Decreased the Duration of Shock, Duration of Mechanical Ventilation, and Decreased the ICU Length of Stay
Low-Dose Corticosteroids Increased Adverse Events
Systematic Review and Meta-Analysis of Corticosteroids in Sepsis (Crit Care Med, 2018) [MEDLINE]: n = 10,194 (42 trials)
Based on Low Certainty, Corticosteroids Possibly Resulted in a Small Decrease in the Short-Term (28-Day/30-Day) Mortality Rate (Relative Risk, 0.93; 95% CI, 0.84-1.03; 1.8% Absolute Risk Reduction; 95% CI, 4.1% Reduction to 0.8% Increase
Based on Moderate Certainty, Corticosteroids Possibly Possibly Resulted in a Small Decrease in the Long-Term (60-Day/1-Year) Mortality (60 d to 1 yr) (Relative Risk, 0.94; 95% CI, 0.89-1.00; 2.2% Absolute Risk Reduction; 95% CI, 4.1% Reduction to No Effect)
Based on Moderate Certainty, Corticosteroids Probably Resulted in a Small Decrease in ICU Length (Mean Difference, -0.73 d; 95% CI, -1.78 to 0.31) and Hospital Length of Stay (Mean Difference, -0.73 d; 95% CI, -2.06 to 0.60)
Based on High Certainty, Corticosteroids Resulted in Higher Rates of Shock Reversal at Day 7 (Relative Risk, 1.26; 95% CI, 1.12-1.42) and Lower Sequential Organ Failure Assessment Scores at Day 7 (Mean Difference, -1.39; 95% CI, -1.88 to -0.89)
Based on Moderate Certainty, Corticosteroids Likely Increased the Risk of Hypernatremia (Relative Risk, 1.64; 95% CI, 1.32-2.03) and Hyperglycemia (Relative Risk, 1.16; 95% CI, 1.08-1.24)
Based on Low Certainty, Corticosteroids, Possibly Increased the Risk of Neuromuscular Weakness (Relative Risk, 1.21; 95% CI, 1.01-1.52)
Subgroup Analysis Did Not Demonstrate a Credible Subgroup Effect on Any of the Outcomes of Interest
Single-Blinded Randomized Controlled HYVCTTSSS Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 80
In Patients with Sepsis/Septic Shock, the Combination of Hydrocortisone/Vitamin C/Thiamine Did Not Decrease the 28-Day Mortality Rate, as Compared to Placebo
Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with a Significant Improvement of 72 hr Change in Sequential Organ Failure Assessment (SOFA) Score (P = 0.02)
Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with Higher Incidence of Hypernatremia (P = 0.005)
In Prespecified Subgroup Analysis, Patients of the Combination of Hydrocortisone/Vitamin C/Thiamine Treatment Subgroup Diagnosed with Sepsis within 48 hrs Demonstrated Decreased 28-Day Mortality Rate, as Compared to Control (P = 0.02)
Randomized, Double-Blinded, Placebo-Controlled ORANGES Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 137
Combination of Hydrocortisone/Vitamin C/Thiamine Decreased the Time to Resolution of Shock (27 ± 22 vs 53 ± 38 hrs, P < 0.001)
No Statistically Significant Change in SOFA Score was Demonstrated Between Groups 3 (1 – 6) vs 2 (0 – 4), P = 0.17
No Significant Differences were Demonstrated Between Study Arms in Terms of ICU/Hospital Mortality, ICU/Hospital Length of Stay, Ventilator-Free Days, or Procalcitonin Clearance
VITAMINS Trial of Vitamin C (1.5 g q6hrs), Hydrocortisone (50 mg q6hrs), and Thiamine (200 mg q12 hrs) vs Control Group with Hydrocortisone Alone (50 mg q6hrs) in Septic Shock (JAMA, 2020) [MEDLINE]: n = 211
Patients Received Treatment Until Shock Resolution or Up to 10 Days
No Significant Difference in 90-Day Mortality Between the Groups (28.6% in Triple Therapy Treatment Group vs 24.5% in the Control Group)
No Difference in Time Alive and Vasopressor-Free Up to Day 7 Between the Groups (122.1 hrs with Interquartile Range 76.3-145.4 hrs in the Triple Therapy Treatment Group vs 124.6 hrs with Interquartile Range 82.1-147.0 hrs in the Control Group)
No Serious Adverse Events were Reported
Multicenter, Randomized, Double-Blind, Placebo-Controlled VICTAS Trial of Vitamin C, Thiamine, and Hydrocortisone in Sepsis (JAMA, 2021) [MEDLINE]: n = 501
Trial was Terminated Early for Administrative Reasons (Therefore, May Have Been Underpowered to Detect Differences)
In Critically Ill Patients with Sepsis, Treatment with Vitamin C, Thiamine, and Hydrocortisone Did Not Increase Ventilator-Free and Vasopressor-Free Days within 30 Days
Prespecified Secondary Analysis of the VICTAS Trial of Vitamin C, Thiamine, and Hydrocortisone in Sepsis (JAMA Netw Open, 2023) [MEDLINE]
In Sepsis Survivors, Treatment with Vitamin C, Thiamine, and Hydrocortisone Did Not Improve or Had Worse Cognitive, Psychological, and Functional Outcomes at 6 mos, as Compared to Patients Who Received Placebo
Single Center, Retrospective Trial Comparing Hydrocortisone vs Hydrocortisone with Fludrocortisone in Septic Shock Refractory to Intravenous Fluids and Vasopressors (Ann Pharmacother, 2023) [MEDLINE]: n = 251
No Difference in Time to Shock Reversal (65.2 vs 71 hrs; P = 0.24)
Cox Proportional Hazards Model Showed Time to First Corticosteroid Dose, Full-Dose Hydrocortisone Duration, and Use of Hydrocortisone + Fludrocortisone were Associated with Shorter Shock Duration, While Time to Vasopressor Therapy was Not
However, in 2 Multivariable Models Controlling for Covariates, Use of Hydrocortisone + Fludrocortisone was Not an Independent Predictor of Shock Reversal at >72 hrs and In-Hospital Mortality
No Differences were Observed in Hospital Length of Stay or Mortality
Hyperglycemia Occurred More Frequently with Hydrocortisone + Fludrocortisone (62.3% vs 45.6%; P = 0.01)
Retrospective Cohort Study (from 2016-2020) Comparing Hydrocortisone vs Hydrocortisone with Fludrocortisone in Septic Shock Refractory to Intravenous Fluids and Vasopressors in Adults Using Premier Healthcare Database (Accounting for 25% of US Hospitalizations) (JAMA Intern Med, 2023) [MEDLINE]: n = 88,275
Primary Composite Outcome of Death in Hospital or Discharge to Hospice Occurred Among 47.2% of Patients Treated with Hydrocortisone-Fludrocortisone vs 50.8% Treated with Hydrocortisone Alone (Adjusted Absolute Risk Difference, -3.7%; 95% CI, -4.2% to -3.1%; P < 0.001)
In this Comparative Effectiveness Cohort Study in Adult Patients with Septic Shock Who Began Hydrocortisone Treatment, the Addition of Fludrocortisone was Superior to Hydrocortisone Alone
Systematic Review With Bayesian Network Meta-Analysis of Randomized Controlled Trials of Fludrocortisone in Addition to Hydrocortisone in Adult Patients With Septic Shock (Crit Care Med, 2023) [MEDLINE]: n = 95,841 (from 19 studies)
Hydrocortisone Plus Fludrocortisone Demonstrated the Lowest Short-Term Mortality vs Placebo (Odds Ratio 0.79; 95% Credible Interval: 0.64-0.99; Number Needed to Treat 21, Range: 12-500; Low Certainty of Evidence) in Terms of Informative Priors
Surface Under the Cumulative Ranking Curve Values for Hydrocortisone Plus Fludrocortisone, Hydrocortisone Alone, and Placebo were 0.9469, 0.4542, and 0.0989, Respectively
Consistent Results were Observed in Randomized Controlled Trials Alone and Those Using a Daily Hydrocortisone 200 mg Dose
Although Gastroduodenal Bleeding or Superinfection Demonstrated No Clear Increase, Hyperglycemia Risk Increased
The Odds Ratios were 0.53 for Placebo vs Hydrocortisone Plus Fludrocortisone and 0.64 for Placebo vs Hydrocortisone Alone, with Very Low Certainty of Evidence
Recommendations (American College of Critical Care Medicine Consensus Statement on the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients, Crit Care Med, 2008) [MEDLINE]
General Comments: involved a multi-disciplinary, multi-specialty group from the membership of the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and international experts in endocrinology
Use of Adrenocorticotrophic Hormone (ACTH) Stimulation Test
Adrenocorticotrophic Hormone (ACTH) Stimulation Test Should Not Be Used to Identify Those Patients with Septic Shock/ARDS Who Should Receive Glucocorticoids
Agents
Hydrocortisone (50 mg q6hrs IV for ≥7 Days) is Recommended for Septic Shock
Dexamethasone is Not Recommended to Treat Critical Illness-Related Corticosteroid Insufficiency
Methylprednisolone (1 mg/kg/day for ≥14 Days) is Recommended in Patients with Severe Early Acute Respiratory Distress Syndrome
Administration
Glucocorticoids Should be Weaned and Not Stopped Abruptly
Reinstitution of Treatment Should Be Considered with Recurrence of Signs of Sepsis, Hypotension, or Worsening Oxygenation
Glucocorticoids in the Management of Patients with Community-Acquired Pneumonia, Liver Failure, Pancreatitis, Those Undergoing Cardiac Surgery, and Other Groups of Critically Ill Patients Requires Further Investigation
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Septic Shock and Ongoing Vasopressor Requirement, Intravenous Corticosteroids are Recommended (Weak Recommendation, Moderate Quality Evidence)
It is Suggested that Intravenous Corticosteroids Should Be Initiated at a Dose of Norepinephrine or Epinephrine ≥0.25 μg/kg/min at Least 4 hrs After Initiation
Recommended Hydrocortisone Dosing: 50 mg q6hrs IV (Weak Recommendation, Low Quality of Evidence)
The 2012 Surviving Sepsis Guidelines Recommended that if Hydrocortisone is Used, it Should Be Tapered When Vasopressors are No Longer Required (Grade 2D Recommendation) (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]
The 2012 Surviving Sepsis Guidelines Recommended that ACTH Stimulation Testing Should Not Be Used to Identify Adults with Septic Shock Who Should Receive Hydrocortisone (Grade 2B Recommendation) (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]
Recommendations (2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia) (Crit Care Med, 2024) [MEDLINE]
Administration of Corticosteroids is Suggested for Adult patients with Septic Shock (Conditional Recommendation, Low Certainty Evidence)
In Prior 2017 Recommendations
Administering Corticosteroids were Not Suggested in Adult Patients with Sepsis without Shock (Conditional Recommendation, Moderate Quality of Evidence)
Administration of High Dose/Short Duration Corticosteroids (>400 mg/d Hydrocortisone Equivalent for <3 Days) is Not Recommended for Adult Patients with Septic Shock (Strong Recommendation, Low Certainty) (Strong Recommendation, Moderate Certainty Evidence)
In Prior 2017 Recommendations
We Suggest Using Corticosteroids in Patients with Septic Shock that is Not Responsive to Fluid and Moderate-High Dose Vasopressor Therapy (Conditional Recommendation, Low Quality of Evidence)
References
Treatment
General
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Bicarbonate Therapy
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Blood Pressure Target
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Intravenous Fluid Resuscitation Strategy (Including Early Goal-Directed Therapy)
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Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564 [MEDLINE]
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PROMISE Trial: Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. doi: 10.1056/NEJMoa1500896. Epub 2015 Mar 17. [MEDLINE]
A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015 Sep;41(9):1549-60 [MEDLINE]
Association between fluid balance and survival in critically ill patients. J Intern Med. 2015;277:468–477 [MEDLINE]
Targeted Fluid Minimization Following Initial Resuscitation in Septic Shock: A Pilot Study. Chest. 2015 Dec;148(6):1462-9. doi: 10.1378/chest.15-1525 [MEDLINE]
A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care 2015: 19:251 [MEDLINE]
Volume overload: prevalence, risk factors, and functional outcome in survivors of septic shock. Ann Am Thorac Soc 2015: 12(12):1837–1844 [MEDLINE]
Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5‐year study. Crit Care Med 2015: 43 (1):3–12 [MEDLINE]
Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock. 2015;43(1):68 [MEDLINE]
Positive fluid balance as a prognostic factor for mortality and acute kidney injury in severe sepsis and septic shock. J Crit Care 2015: 30(1):97–101 [MEDLINE]
Positive fluid balance as a major predictor of clinical outcome of patients with sepsis/septic shock after ICU discharge. Am J Emerg Med 2016: 34(11):2122–2126 [MEDLINE]
A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016;116:339-49 [MEDLINE]
Early goal‐directed therapy for severe sepsis and septic shock: a living systematic review. J Crit Care 2016; 36:43–48 [MEDLINE]
Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017; 376:2235–2244 [MEDLINE]
Early, Goal-Directed Therapy for Septic Shock – A Patient-Level Meta-Analysis. N Engl J Med. 2017 Jun 8;376(23):2223-2234. doi: 10.1056/NEJMoa1701380 [MEDLINE]
Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA. 2017;318(13):1233 [MEDLINE]
Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155-170 [MEDLINE]
Intensive Monitoring of Urine Output Is Associated With Increased Detection of Acute Kidney Injury and Improved Outcomes. Chest. 2017 Nov;152(5):972-979. doi: 10.1016/j.chest.2017.05.011 [MEDLINE]
Incorporating Dynamic Assessment of Fluid Responsiveness Into Goal-Directed Therapy: A Systematic Review and Meta-Analysis. Crit Care Med. 2017 Sep;45(9):1538-1545. doi: 10.1097/CCM.0000000000002554 [MEDLINE]
Evidence Underpinning the U.S. Government-Mandated Hemodynamic Interventions for Sepsis: A Systematic Review. Ann Intern Med. 2018 Feb 20. doi: 10.7326/M17-2947 [MEDLINE]
Treating Sepsis Is Complicated: Are Governmental Regulations for Sepsis Care Too Simplistic? Ann Intern Med. 2018 Feb 20. doi: 10.7326/M18-0290 [MEDLINE]
Early Goal-Directed Therapy in Severe Sepsis and Septic Shock: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. J Intensive Care Med. 2018;33(5):296 [MEDLINE]
FRESH Trial. Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. Chest. 2020 Apr 27;S0012-3692(20)30768-6. doi: 10.1016/j.chest.2020.04.025 [MEDLINE]
Improvement in Mortality With Early Fluid Bolus in Sepsis Patients With a History of Congestive Heart Failure. Mayo Clin Proc Innov Qual Outcomes. 2020 Aug 19;4(5):537-541. doi: 10.1016/j.mayocpiqo.2020.05.008. eCollection 2020 Oct [MEDLINE]
Fluid resuscitation: history, physiology, and modern fluid resuscitation strategies. Emerg Med Clin North Am. 2020;38 (4):783–793. doi:10.1016/j.emc.2020.06.004 [MEDLINE]
Effect of Slower vs Faster Intravenous Fluid Bolus Rates on Mortality in Critically Ill Patients. The BaSICS Randomized Clinical Trial. JAMA. 2021;326(9):830-838. doi:10.1001/jama.2021.11444 [MEDLINE]
CLASSIC Trial. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707 [MEDLINE]
Fluid Resuscitation in Patients Presenting with Sepsis: Current Insights. Open Access Emerg Med. 2022 Nov 29;14:633-638. doi: 10.2147/OAEM.S363520. eCollection 2022 [MEDLINE]
Impact of protocolized diuresis for de- resuscitation in the intensive care unit. Crit Care. 2020 Feb 28;24(1):70. doi: 10.1186/s13054-020-2795-9 [MEDLINE]
The increase in cardiac output induced by a decrease in positive end-expiratory pressure reliably detects volume responsiveness: the PEEP-test study. Crit Care. 2023 Apr 9;27(1):136. doi: 10.1186/s13054-023-04424-7 [MEDLINE]
Fluid Therapy for Critically Ill Adults With Sepsis: A Review. JAMA. 2023 Jun 13;329(22):1967-1980. doi: 10.1001/jama.2023.7560 [MEDLINE]
CLOVERS Trial. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Feb 9;388(6):499-510. doi: 10.1056/NEJMoa2212663 [MEDLINE]
Lower vs Higher Fluid Volumes in Adult Patients With Sepsis: An Updated Systematic Review With Meta-Analysis and Trial Sequential Analysis. Chest. 2023 Oct;164(4):892-912. doi: 10.1016/j.chest.2023.04.036 [MEDLINE]
Lactate-Guided Therapy
Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32(8):1637-1642
Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009; 32(1):35-39
LACTATE Study. Early lactate-guided therapy in intensive care unit patients. Am J Respir Crit Care Med 2010; 182:752-761 [MEDLINE]
Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303(8):739–746 [MEDLINE]
The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2012; 24(1):42–45 [MEDLINE]
Comparison of the effect of fluid resuscitation as guided either by lactate clearance rate or by central venous oxygen saturation in patients with sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2013; 25(10):578–583 [MEDLINE]
Efficacies of fluid resuscitation as guided by lactate clearance rate and central venous oxygen saturation in patients with septic shock. Zhonghua Yi Xue Za Zhi 2015; 95(7):496–500 [MEDLINE]
Early lactate clearance‐guided therapy in patients with sepsis: a meta‐analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med 2015; 41(10):1862–1863 [MEDLINE]
Early goal‐directed therapy for severe sepsis and septic shock: a living systematic review. J Crit Care 2016: 36:43–48 [MEDLINE]
SEP-1: The Lactate Myth and Other Fairytales. Crit Care Med. 2018 Oct;46(10):1689-1690. doi: 10.1097/CCM.0000000000003313 [MEDLINE]
Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):654-664. doi: 10.1001/jama.2019.0071 [MEDLINE]
Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial. Crit Care. 2020 Jan 23;24(1):23. doi: 10.1186/s13054-020-2732-y [MEDLINE]
Choice of Resuscitation Fluid
SAFE Trial: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247–2256 [MEDLINE]
VISEP Trial. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125 [MEDLINE]
An Official ATS/ERS/ESICM/SCCM/SRLF Statement: Prevention and Management of Acute Renal Failure in the ICU Patient: an international consensus conference in intensive care medicine. Am J Respir Crit Care Med 2010; 181:1128-1155. DOI: 10.1164/rccm.200711-1664ST [MEDLINE]
The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011 Feb;39(2):386-91. doi: 10.1097/CCM.0b013e3181ffe217 [MEDLINE]
Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev. Nov 9 2011;CD001208 [MEDLINE]
Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72. doi: 10.1001/jama.2012.13356 [MEDLINE]
6S Trial. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124 [MEDLINE]
CHEST Trial. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med Nov 15, 2012; 367(20):1901-1911. DOI: 10.1056/NEJMoa1209759. Epub Oct 17, 2012 [MEDLINE]
Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013 Nov 6;310(17):1809-17. doi: 10.1001/jama.2013.280502 [MEDLINE]
Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care. 2014;18(6):702 [MEDLINE]
Albumin versus other fluids for fluid resuscitation in patients with sepsis: a meta-analysis. PLoS One. 2014;9(12):e114666 [MEDLINE]
Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis. Ann Intern Med. 2014 Jul 22. doi: 10.7326/M14-0178 [MEDLINE]
ALBIOS Study. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727. Epub 2014 Mar 18 [MEDLINE]
Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med. 2017;5(3):180 [MEDLINE]
Choice of resuscitative fluids and mortality in emergency department patients with sepsis. Am J Emerg Med. 2018;36(4):625 [MEDLINE]
Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):819-828. doi: 10.1056/NEJMoa1711586 [MEDLINE]
Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584 [MEDLINE]
Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021 Aug 10;326(9):1-12. doi: 10.1001/jama.2021.11684 [MEDLINE]
Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. 2022 Mar 3;386(9):815-826. doi: 10.1056/NEJMoa2114464 [MEDLINE]
Albumin versus saline infusion for sepsis-related peripheral tissue hypoperfusion: a proof-of-concept prospective study. Crit Care. 2024 Feb 7;28(1):43. doi: 10.1186/s13054-024-04827-0 [MEDLINE]
Balanced crystalloids versus saline for critically ill patients (BEST-Living): a systematic review and individual patient data meta-analysis. Lancet Respir Med. 2024 Mar;12(3):237-246. doi: 10.1016/S2213-2600(23)00417-4 [MEDLINE]
Choice of Vasopressor
Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103:1826-1831
The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994; 272:1354-1357
Methylene blue increases myocardial function in septic shock. Crit Care Med 1995;23:1363–70
Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock. Intensive Care Med 1995;21: 1027–31
Methylene blue administration in septic shock: a clinical trial. Crit Care Med 1995;23:259–64
Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122-1125
Use of methylene blue in patients with refractory septic shock: impact on hemodynamics and gas exchange. J Crit Care 1998;13:164–8
Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue. Braz J Med Biol Res 1999;32:1505–13
Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors. Circulation 1999; 100 (suppl II):II-244-II-246
Low-dose vasopressin (VP) in the treatment of vasodilatory septic shock. J Trauma 1999; 47:699-703
The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 2001; 93:7-13
Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med 2001;29:1860–7 [MEDLINE]
Does methylene blue administration to septic shock patients affect vascular permeability and blood volume? Crit Care Med 2002;30: 2271–7
The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care 2002;30:755–62
Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 2002 Mar;96(3):576-82 [MEDLINE]
The effects of methylene blue on hemodynamic parameters and cytokine levels in refractory septic shock. Korean J Intern Med 2005;20:123–8
Use of methylene blue in sepsis: a systematic review. J Intensive Care Med. 2006 Nov-Dec;21(6):359-63 [MEDLINE]
VASST Trial. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373 [MEDLINE]
Short-term beneficial effects of methylene blue on kidney damage in septic shock patients. Intensive Care Med 2008;34:350–4
The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010 May;51(3):194-200 [MEDLINE]
SOAP II Trial. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779-789 [MEDLINE]
Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock. Indian J Crit Care Med. 2010 Jan;14(1):29-34. doi: 10.4103/0972-5229.63033 [MEDLINE]
Discontinuation of vasopressin before norepinephrine increases the incidence of hypotension in patients recovering from septic shock: a retrospective cohort study. J Crit Care. 2010;25:362 e367–11 [MEDLINE]
Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis. Crit Care Med 2012;40:725-730 [MEDLINE]
The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock. Chest. 2012 Sep;142(3):593-605 [MEDLINE]
Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine. Crit Care. 2013 Jun 20;17(3):R117. doi: 10.1186/cc12789 [MEDLINE]
Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study. Intensive Care Med. 2013 Aug;39(8):1435-43. doi: 10.1007/s00134-013-2982-0 [MEDLINE]
Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol. 2013 Sep;9(3):242-9. doi: 10.1007/s13181-013-0298-7 [MEDLINE]
A review of methylene blue treatment for cardiovascular collapse. J Emerg Med. 2014 May;46(5):670-9 [MEDLINE]
Mortality benefit of vasopressor and inotropic agents in septic shock: a Bayesian network meta-analysis of randomized controlled trials. J Crit Care. 2014 Oct;29(5):706-10. doi: 10.1016/j.jcrc.2014.04.011. Epub 2014 Apr 26 [MEDLINE]
The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial. Crit Care Med. 2014 Jun;42(6):1325-33. doi: 10.1097/CCM.0000000000000212 [MEDLINE]
Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014 Oct 6;18(5):534. doi: 10.1186/s13054-014-0534-9 [MEDLINE]
Vasopressors in septic shock: a systematic review and network meta-analysis. Ther Clin Risk Manag. 2015 Jul 14;11:1047-59. doi: 10.2147/TCRM.S80060. eCollection 2015 [MEDLINE]
Angiotensin II in septic shock. Crit Care. 2015 Mar 16;19:98. doi: 10.1186/s13054-015-0802-3 [MEDLINE]
Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis. PLoS One. 2015 Aug 3;10(8):e0129305. doi: 10.1371/journal.pone.0129305. eCollection 2015 [MEDLINE]
The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. Br J Anaesth. 2015 Nov;115(5):656-75. doi: 10.1093/bja/aev284 [MEDLINE]
Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther. 2015 May;20(3):249-60. doi: 10.1177/1074248414559838. Epub 2014 Nov 28 [MEDLINE]
Vasopressors for the treatment of septic shock: systematic review and meta-analysis. PloS One. 2015;10(8):e0129305 [MEDLINE]
Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485 [MEDLINE]
Comparative safety and efficacy of vasopressors for mortality in septic shock: A network meta-analysis. J Intensive Care Soc. 2016;17(2):136 [MEDLINE]
Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016;2:CD003709 [MEDLINE]
ATHOS-3 trial. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154 [MEDLINE]
Severe Undifferentiated Vasoplegic Shock Refractory to Vasoactive Agents Treated with Methylene Blue. Case Rep Crit Care. 2017;2017:8747326. doi: 10.1155/2017/8747326 [MEDLINE]
Angiotensin II in Refractory Septic Shock. Shock. 2017 May;47(5):560-566. doi: 10.1097/SHK.0000000000000807 [MEDLINE]
A systematic analysis of methylene blue for drug-induced shock in humans. Clin Toxicol (Phila). 2017 Mar;55(3):228. doi: 10.1080/15563650.2016.1271885 [MEDLINE]
Intraoperative vasoplegia: methylene blue to the rescue! Curr Opin Anaesthesiol. 2018;31(1):43 [MEDLINE]
Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Crit Care Med. 2018 Jun;46(6):949-957. doi: 10.1097/CCM.0000000000003092 [MEDLINE]
Intraoperative vasoplegia: methylene blue to the rescue! Curr Opin Anaesthesiol. 2018;31(1):43 [MEDLINE]
Angiotensin in Critical Care. Crit Care. 2018 Mar 20;22(1):69. doi: 10.1186/s13054-018-1995-z [MEDLINE]
Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA. 2018 May 8;319(18):1889-1900. doi: 10.1001/jama.2018.4528 [MEDLINE]
Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial (DOVSS). Crit Care. 2018 May 21;22(1):131. doi: 10.1186/s13054-018-2034-9 [MEDLINE]
Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med. 2019 Feb 1. doi: 10.1164/rccm.201806-1034OC [MEDLINE]
Discontinuation of vasopressin before norepinephrine in the recovery phase of septic shock. J Intensive Care Med. 2019 Oct;34(10):805-810. doi: 10.1177/0885066617714209 [MEDLINE]
Timing of norepinephrine initiation in patients with septic shock: a systematic review and meta-analysis. Crit Care. 2020;24 (1):488. doi:10.1186/s13054-020-03204-x [MEDLINE]
Hydroxocobalamin in Refractory Septic Shock: A Retrospective Case Series. Crit Care Explor, 2021 Apr; 3(4): e0408. Published online 2021 Apr 26. doi: 10.1097/CCE.0000000000000408 [MEDLINE]
Extended Duration Infusion of Hydroxocobalamin for Vasoplegic Rescue in Septic Shock. Cureus. 2021 Feb; 13(2): e13388 [MEDLINE]
Association of Catecholamine Dose, Lactate, and Shock Duration at Vasopressin Initiation With Mortality in Patients With Septic Shock. Crit Care Med. 2022 Apr 1;50(4):614-623. doi: 10.1097/CCM.0000000000005317 [MEDLINE]
High-Dose IV Hydroxocobalamin (Vitamin B12) in Septic Shock: A Double-Blind, Allocation-Concealed, Placebo-Controlled Single-Center Pilot Randomized Controlled Trial (The Intravenous Hydroxocobalamin in Septic Shock Trial. Chest. 2023 Feb;163(2):303-312. doi: 10.1016/j.chest.2022.09.021 [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]
Oral midodrine treatment accelerates the liberation of intensive care unit patients from intravenous vasopressor infusions. J Crit Care 2013; 28(5):756–762. doi:10.1016/j.jcrc.2013.05.021 [MEDLINE]
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]
Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial. Intensive Care Med 2020; 46(10):1884–1893. doi:10.1007/s00134-020-06216-x [MEDLINE]
Oral midodrine administration during the first 24 hours of sepsis to reduce the need of vasoactive agents: placebo-controlled feasibility clinical trial. Crit Care Explor 2021; 3(5):e0382. doi:10.1097/CCE.0000000000000382 [MEDLINE]
Midodrine improves clinical and economic outcomes in patients with septic shock: a randomized controlled clinical trial. Ir J Med Sci 2022; 191(6):2785–2795. doi:10.1007/s11845-021-02903-w [MEDLINE]
Should midodrine be used as an intravenous vasopressor-sparing agent in septic shock?. Cleve Clin J Med. 2023 Oct 2;90(10):603-605. doi: 10.3949/ccjm.90a.23040 [MEDLINE]
Arrhythmia Management
Practice Patterns and Outcomes of Treatments for Atrial Fibrillation During Sepsis: A Propensity-Matched Cohort Study. Chest. 2016 Jan;149(1):74-83. doi: 10.1378/chest.15-0959. Epub 2016 Jan 6 [MEDLINE]
Comparative Effectiveness of Heart Rate Control Medications for the Treatment of Sepsis-Associated Atrial Fibrillation. Chest. 2020 Oct 24;159(4):1452-1459. doi: 10.1016/j.chest.2020.10.049 [MEDLINE]
Steroids in the treatment of clinical septic shock. Ann Surg 1976; 184:333-41 [MEDLINE]
The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984;311:1137-43 [MEDLINE]
A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317:653-8 [MEDLINE]
A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317:653-658 [MEDLINE]
Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71 [MEDLINE]
Steroids for septic shock: back from the dead? (Con). Chest 2003; 123:482S-489S
Cortisol response to critical illness: effect of intensive insulin therapy. J Clin Endocrinol Metab 2006;91:3803-13 [MEDLINE]
CORTICUS Trial. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366 [MEDLINE]
Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008 Jun;36(6):1937-49 [MEDLINE]
The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med. 2009 Nov;35(11):1868-76. doi: 10.1007/s00134-009-1603-4. Epub 2009 Aug 4 [MEDLINE]
Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009 Jun 10;301(22):2362-75 [MEDLINE]
Global utilization of low-dose corticosteroids in severe sepsis and septic shock: a report from the PROGRESS registry. Crit Care 2010;14:R102 [MEDLINE]
Systemic steroids in severe sepsis and septic shock. Am J Respir Crit Care Med. 2012 Jan 15;185(2):133-9 [MEDLINE]
Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign. Intensive Care Med. 2012 Dec;38(12):1946-54 [MEDLINE]
Reduced cortisol metabolism during critical illness. N Engl J Med. 2013 Apr 18;368(16):1477-88. doi: 10.1056/NEJMoa1214969. Epub 2013 Mar 19 [MEDLINE]
Adrenal dysfunction in critically ill patients. N Engl J Med 2013;368(16):1547-1548 [MEDLINE]
Corticosteroids for treating sepsis. Cochrane Database Syst Rev 2015;12:CD002243 [MEDLINE]
Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 2015;41: 1220-34 [MEDLINE]
Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016;316(17):1775 [MEDLINE]
ADRENAL trial. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/NEJMoa1705835. Epub 2018 Jan 19 [MEDLINE]
APROCCHSS Trial. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716 [MEDLINE]
Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2018;44(7):1003 [MEDLINE]
Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis. Crit Care Med. 2018 Sep;46(9):1411-1420. doi: 10.1097/CCM.0000000000003262 [MEDLINE]
HYVCTTSSS Trial. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. Chest 2020 Jul;158(1):174-182. doi: 10.1016/j.chest.2020.02.065 [MEDLINE]
Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049 [MEDLINE]
Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020 Feb 4;323(5):423-431. doi: 10.1001/jama.2019.22176 [MEDLINE]
Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021 Feb 23;325(8):742-750. doi: 10.1001/jama.2020.24505 [MEDLINE]
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