Meta-Analysis of the Use of β-Adrenergic Receptor Antagonists (β-Blockers) in Sepsis/Septic Shock (Medicine-Baltimore, 2022) [MEDLINE]: n = 503 (7 randomized controlled trials(
Compared with Standard Treatment, Esmolol Significantly Decreased 28-Day Mortality (Risk Ratio 0.68, 95% CI: 0.52–0.88; P = .004), Heart Rate (Standardized Mean Difference −1.83, 95% CI: −2.95 to −0.70, P = .001), Tumor Necrosis Factor-α (Standardized Mean Difference −0.48, 95% CI: −0.94 to −0.02, P = .04), and Troponin I Level (SMD −0.59, 95% CI: −1.02 to −0.16, P = .008) 24 hrs After Treatment
No Significant Effect on Length of Intensive Care Unit Stay, Mean Arterial Pressure, Lactic Acid, Central Venous Pressure, or Central Venous Oxygen Saturation, Interleukin 6, or White Blood Cell Levels, Stroke Volume Index, or the PaO2/FiO2 Ratio
Acute Illness, Endotoxemia, and Sepsis Decrease Serum and Intracellular Ascorbic Acid (Vitamin C) Levels, Likely Due to Metabolic Consumption of Vitamin C (Pharmacol Ther, 2018) [MEDLINE]
Low Plasma Vitamin C Levels Predict the Development of Multiorgan Failure in Sepsis
Low Plasma Vitamin C Levels are Associated with Severity of Organ Failure and Mortality in Sepsis
Hydrocortisone and Ascorbic Acid Act Synergistically to Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction (Chest, 2017) [MEDLINE]
Vitamin C Reverses the Microcirculatory Injury and Organ Dysfunction in Experimental Models of Sepsis
Clinical Efficacy
Retrospective Before/After Clinical Study of Hydrocortisone, Vitamin C, and Thiamine in Sepsis (Chest, 2017) [MEDLINE]
Early Use of Intravenous Vitamin C, Hydrocortisone, and Thiamine Prevented the Progression of Organ Dysfunction (Including Acute Kidney Injury) and Decreased Mortality in Severe Sepsis and Septic Shock: additional studies are required to confirm these preliminary findings
Meta-Analysis of Vitamin C in Sepsis (Crit Care, 2018) [MEDLINE]
Despite Varying Degrees of Statistical Significance Between the 2 Studies Included, Vitamin C Appeared to Improved Mortality Rate and Decreased the Duration of Vasopressor Use in Sepsis
Further Randomized Trials are Recommended
Randomized CITRIS-ALI Trial of Vitamin C in Sepsis (JAMA, 2019) [MEDLINE]: n = 167
No Significant Differences Between the Vitamin C and Placebo Groups in Terms of the Mean Modified Sequential Organ Failure Assessment (SOFA) Score from Baseline to 96 hrs (from 9.8 to 6.8 in the Vitamin C Group [3 Points] and from 10.3 to 6.8 in the Placebo Group [3.5 Points]; Difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-Reactive Protein Levels (54.1 vs 46.1 μg/mL; Difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and Thrombomodulin Levels (14.5 vs 13.8 ng/mL; Difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hrs
Single-Blinded Randomized Controlled HYVCTTSSS Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 80
In Patients with Sepsis/Septic Shock, the Combination of Hydrocortisone/Vitamin C/Thiamine Did Not Decrease the 28-Day Mortality Rate, as Compared to Placebo
Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with a Significant Improvement of 72 hr Change in Sequential Organ Failure Assessment (SOFA) Score (P = 0.02)
Combination of Hydrocortisone/Vitamin C/Thiamine was Associated with Higher Incidence of Hypernatremia (P = 0.005)
In Prespecified Subgroup Analysis, Patients of the Combination of Hydrocortisone/Vitamin C/Thiamine Treatment Subgroup Diagnosed with Sepsis within 48 hrs Demonstrated Decreased 28-Day Mortality Rate, as Compared to Control (P = 0.02)
Randomized, Double-Blinded, Placebo-Controlled ORANGES Trial of Hydrocortisone/Vitamin C/Thiamine in Sepsis/Septic Shock (Chest, 2020) [MEDLINE]: n = 137
Combination of Hydrocortisone/Vitamin C/Thiamine Decreased the Time to Resolution of Shock (27 ± 22 vs 53 ± 38 hrs, P < 0.001)
No Statistically Significant Change in SOFA Score was Demonstrated Between Groups 3 (1 – 6) vs 2 (0 – 4), P = 0.17
No Significant Differences were Demonstrated Between Study Arms in Terms of ICU/Hospital Mortality, ICU/Hospital Length of Stay, Ventilator-Free Days, or Procalcitonin Clearance
VITAMINS Trial of Vitamin C (1.5 g q6hrs), Hydrocortisone (50 mg q6hrs), and Thiamine (200 mg q12 hrs) vs Control Group with Hydrocortisone Alone (50 mg q6hrs) in Septic Shock (JAMA, 2020) [MEDLINE]: n = 211
Patients Received Treatment Until Shock Resolution or Up to 10 Days
No Significant Difference in 90-Day Mortality Between the Groups (28.6% in Triple Therapy Treatment Group vs 24.5% in the Control Group)
No Difference in Time Alive and Vasopressor-Free Up to Day 7 Between the Groups (122.1 hrs with Interquartile Range 76.3-145.4 hrs in the Triple Therapy Treatment Group vs 124.6 hrs with Interquartile Range 82.1-147.0 hrs in the Control Group)
No Serious Adverse Events were Reported
Multicenter, Randomized, Double-Blind, Placebo-Controlled VICTAS Trial of Vitamin C, Thiamine, and Hydrocortisone in Sepsis (JAMA, 2021) [MEDLINE]: n = 501
Trial was Terminated Early for Administrative Reasons (Therefore, May Have Been Underpowered to Detect Differences)
In Critically Ill Patients with Sepsis, Treatment with Vitamin C, Thiamine, and Hydrocortisone Did Not Increase Ventilator-Free and Vasopressor-Free Days within 30 Days
Meta-Analysis of Intravenous Vitamin C in the Treatment of Sepsis/Septic Shock (Am J Emerg Med, 2021) [MEDLINE]: n = 1,400 (10 randomized controlled trials)
Intravenous Vitamin C Improved SOFA Score within 72 hrs [RR = 1.32, 95% CI (0.80,1.85), P < 0.0001]
There were No Differences in Short-Term Mortality Rate (28-30 Days) [RR = 0.83,95% CI (0.65,1.05), P = 0.11], Long-Term Mortality Rate (90 Days) [RR = 1.16, 95% CI (0.82,1.66), P = 0.40], Hospital Length of Stay [RR = 0.15, 95% CI (-0.73,1.03), P = 0.55], ICU Length of Stay [RR = 0.22, 95% CI (-0.13,0.57), P = 0.22], or Ventilator-Free Days [RR = 0.09, 95% CI (-0.24,0.42), P = 0.60]
Subgroup Analysis Demonstrated that Intravenous Vitamin C Alone Can Reduce the Short-Term Mortality Rate (28-30 Days) [RR = 0.61, 95% CI (0.47,0.79), P = 0.0002]
Results Need to Be Verified in Large, Randomized Trials
LOVIT Trial of Vitamin C in Adults with Sepsis in the Intensive Care Unit (NEJM, 2022) [MEDLINE]: n = 872
Intravenous Vitamin C Increased the Mortality Rate and Risk of Persistent Organ Dysfunction at Day 28, as Compared to Placebo
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
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Sepsis/Septic Shock, Vitamin C Therapy is Not Recommended (Weak Recommendation, Low Quality of Evidence)
Retrospective Before/After Clinical Study of Hydrocortisone, Vitamin C, and Thiamine in Sepsis (Chest, 2017) [MEDLINE]
Early Use of Intravenous Vitamin C, Hydrocortisone, and Thiamine Prevented the Progression of Organ Dysfunction (Including Acute Kidney Injury) and Decreased Mortality in Severe Sepsis and Septic Shock: additional studies are required to confirm these preliminary findings
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
Post-Hoc Analysis of Two Randomized Trials of Thiamine in Septic Shock (Thiamine in Septic Shock Trial, NCT01070810 and the Thiamine for Renal Protection in Septic Shock Trial, NCT03550794) (Crit Care, 2024) [MEDLINE]: n = 158
Thiamine Administration was Associated with Increased Odds of Being Alive and Renal Replacement Therapy-Free (Adjusted Odds Ratio 2.05; 95% CI: 1.08-3.90) and Not Needing Renal Replacement Therapy (Adjusted Odds Ratio: 2.59; 95% CI: 1.01-6.62)
In the Thiamine-Deficient Group, Thiamine Administration was Associated with Increased Odds of Being Alive and and Renal Replacement Therapy-Free (Adjusted Odds Ratio 8.17; 95% CI: 1.79-37.22) and Surviving to Hospital Discharge (Adjusted Odds Ratio 6.84; 95% CI: 1.54-30.36)
There was a Significant Effect Modification by Baseline Thiamine Deficiency for Alive and Renal Replacement Therapy-Free (Interaction, p = 0.016) and Surviving to Hospital Discharge (p = 0.019)
Glycemic Control
Clinical Efficacy
Belgian Leuven Medical Trial Examining Intensive Insulin Therapy (NEJM, 2006) [MEDLINE]
Mean Blood Glucose was Lower in the Intensive Insulin Therapy Group, as Compared to the Conventional Group
Intensive Insulin Therapy Decreased ICU Length of Stay, Hospital Length of Stay, Duration of Mechanical Ventilation, and Acute Kidney Injury
Intensive Insulin Therapy Significantly Decreased Morbidity, But Not Mortality in the Medical ICU
Hypoglycemia was More Common in the Intensive Insulin Therapy Group
Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) Trial of Intensive Insulin Therapy and Pentastarch in Severe Sepsis (NEJM, 2008) [MEDLINE]
Mean Morning Blood Glucose was Lower in the Intensive Insulin Therapy Group
Hypoglycemia was More Frequent in the Intensive Insulin Therapy Group
Intensive Insulin Therapy Did Not Improve the 28-Day Mortality Rate, 90-Day Mortality Rate, Morbidity, or Risk of Organ Failure
Glucontrol Trial of Intensive Insulin Therapy in Critically Ill Medical/Surgical ICU Patients (Intensive Care Med, 2009) [MEDLINE]
Trial was Terminated Early Due to High Frequency of Unintended Protocol Violations
Intensive Insulin Therapy Increased the Rate of Hypoglycemia
Intensive Insulin Therapy Did Not Improve the Mortality Rate: there was a non-significant trend toward increased 28-day mortality rare and hospital mortality rate
Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation (NICE-SUGAR) Trial Examining Intensive Insulin Therapy in Critically Ill Medical/Surgical ICU Patients (NEJM, 2009) [MEDLINE]
Intensive insulin Therapy Group Had Lower Time-Weighted Blood Glucose
Intensive insulin Therapy Group Had an Increased 90-Day Mortality Rate
Intensive insulin Therapy Group Had a Higher Incidence of Hypoglycemia
In the Subgroup of Operative Patients, Intensive insulin Therapy Increased Mortality Rate
Meta-Analysis of Intensive Insulin Therapy in Medical/Surgical ICU Patients (CMAJ, 2009) [MEDLINE]
Intensive Insulin Therapy Had No Mortality Benefit: although patients in surgical ICU’s appeared to benefit more from intensive insulin therapy
Intensive Insulin Therapy Significantly Increased the Risk of Hypoglycemia
Corticosteroid Treatment and Intensive insulin Therapy for Septic Shock (COIITSS) (JAMA, 2010) [MEDLINE]
Intensive insulin Therapy Did Not Improve Mortality in Patients Treated with Hydrocortisone for Septic Shock
No Difference in ICU Length of Stay, Ventilator-Free Days, or Vasopressor-Free Days
Systematic Review Examining the Effect of Intensive Insulin Therapy on Outcome in Hospitalized Patients (Ann Intern Med. 2011) [MEDLINE]
Trials Differed with Regard to Target Glucose Levels, Achieved Glucose Levels, Intensive Insulin Therapy Protocols, and Medical Settings: however, there was no statistical heterogeneity across the trials
No Short-Term (28-Day Hospital or ICU), 90-Day, or 180-Day Mortality Benefit with Intensive Insulin Therapy (Glucose 80-180 mg/dL)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Sepsis/Septic Shock, Initiating Insulin Therapy at a Glucose Level of ≥ 180mg/dL is Recommended (10 mmol/L) (Strong Recommendation, Moderate Quality of Evidence)
Following Initiation of Insulin Therapy, Typical Target Blood Glucose Range is 144−180 mg/dL
Blood Glucose Should Be Monitored Every 1-2 hrs Until Insulin Infusions Rates and Glucose Values are Stable, Then Every 4 hrs Thereafter
Blood Glucose Values Obtained with Point-of-Care Testing Should Be Interpreted with Caution as These Values May Not Reflect Arterial Blood or Plasma Glucose Values
While Both the US FDA and Centers for Medicare and Medicaid Services (CMS) Have Advocated Prohibiting Using Point-of-Care Glucose Testing in Critically Ill Patients, Experts Have Suggested that This Recommendation Be Postponed (Due to the Potential Harm Which Could Result from Utilizing Laboratory Blood Glucose Testing with Slower Processing Times)
Arterial Blood Glucose Values are Suggested Over Point-of-Care Glucose Values in Patients with Arterial Lines
Increased Plasma Viscosity: doubling the Hct (from 20 to 40%) will double plasma viscosity -> increases oxygen delivery to coronary arteries but increases myocardial work
Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Erythropoietin in Critical Illness (Crit Care Med 1999) [MEDLINE]
Erythropoietin Did Not Impact the Mortality Rate
Erythropoietin Increased the Hematocrit and Decreased the Number of Units of Packed Red Blood Cells Required
Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Erythropoietin in Critical Illness (JAMA 2002) [MEDLINE]
Weekly Erythropoietin Did Not Impact the Mortality Rate
Weekly Erythropoietin Increased the Hematocrit and Decreased the Number of Units of Red Blood Cells Required
Meta-Analysis of the Effect of Erythropoietin on Acute Kidney Injury in the Setting of Critical Illness (J Cardiovasc Pharmacol, 2015) [MEDLINE]
Prophylactic Erythropoietin Did Not Prevent Acute Kidney Injury, Decrease the Requirement for Hemodialysis, or Impact the Mortality Rate in Critical Illness or in the Setting of Perioperative Care
Canadian Critical Care Trials Group Transfusion Requirements in Critical Care (TRICC) Trial (NEJM, 1999) [MEDLINE]: trial comparing transfusion cut-offs of Hb 7g/dL vs 10 g/dL (trial excluded: acute myocardial infarction and unstable angina)
No Overall Difference in 30-Day Mortality: however, less acutely ill (APACHE score of ≤20) and <55 y/o groups had lower mortality rates with the restrictive transfusion strategy
Restrictive Transfusion Strategy Utilizing a Threshold Hemoglobin of 7 g/dL Decreased the Hospital Mortality Rate
Rivers Early Goal-Directed Therapy Trial (NEJM, 2001) [MEDLINE]
Resuscitation Protocol Used in the Trial Maintained Hematocrit ≥30%
Early Goal-Directed Therapy (Used for First 6 hrs of ED Care) Decreased 28-Day Mortality in Severe Sepsis and Septic Shock
Transfusion Requirements in Septic Shock (TRISS) Trial (NEJM, 2014) [MEDLINE]: Danish multi-center RCT (n = 998) comparing hemoglobin of 7 g/dL vs 9 g/dL in septic shock (trial excluded: acute myocardial ischemia, acute burn injury, previous PRBC transfusion, and acute life-threatening bleeding) -> primary outcome: 90-day mortality
No Difference in Mortality (and Rates of Ischemic Events, Transfusion Reactions, and Use of Life Support) Between the 7 g/dL and 9 g/dL Hemoglobin Groups: however, the 7 g/dL hemoglobin group had lower PRBC utilization
Protocolized Care for Early Septic Shock (PROCESS) Trial (NEJM, 2014) [MEDLINE]: tertiary care, multi-center trial (n = 1,341) from 2008-2013 -> 439 were randomly assigned to protocol-based early goal-directed therapy (transfusion threshold hematocrit >10 g/dL when the ScvO2 was <70% after the initial resuscitation), 446 to protocol-based standard therapy (transfusion threshold hemoglobin >7.5 g/dL when the ScvO2 was <70% after the initial resuscitation), and 456 to usual care
With Diagnosis of Sepsis in the ED, Protocol-Based Resuscitation Did Not Improve In-Hospital Mortality to 60-days or 1-Year Mortality Rate: importantly, the PROCESS trial was designed more to directly assess protocolized resuscitation, rather than tranfusion thresholds, but the use of a threshold for packed red blood cell transfusion does not support a higher transfusion threshold of 10 g/dL
Australasian Resuscitation in Sepsis Evaluation (ARISE) Trial (NEJM, 2014) [MEDLINE]: multi-center RCT in Australia/New Zealand (n = 1600)
Resuscitation Protocol Used in the Trial Targeted a Hematocrit ≥30% (Similar to the 2001 Rivers Trial)
With Diagnosis of Septic Shock in the ED, Early Goal-Directed Therapy Had No Impact on 90-day Mortality (18.6% mortality), as Compared to Usual Care (18.8% Mortality)
No Significant Differences in Survival Time, In-Hospital Mortality, Duration of Organ Support, or Length of Hospital Stay Between the Groups
International Prospective Cohort Study of Packed Red Blood Cell Tranfusion Practices in Intensive Care Unit Patients (JAMA, 2023) [MEDLINE]: n = 3,643 (233 ICU’s in 30 countries)
Approximately 25% of Patients Received ≥1 Units of Packed Red Blood Cells During Their ICU Stay, with a Median Total of 2 Units Per Patient (IQR: 1-4)
Among Patients Who Received a Transfusion, the Most Common Clinical Indications were Low Hemoglobin Value (81.8%; Mean +/- SD Lowest Hemoglobin Before Transfusion was 7.4 +/- 1.2 g/dL), Active Bleeding (27.7%), and Hemodynamic Instability (23.5%)
Among the Events with a Stated Physiological Trigger, the Most Frequently Stated Triggers were Hypotension (42.2%), Tachycardia (27.4%), and Increased Lactate Level (17.8%)
Median Lowest Hemoglobin Level on Days with an Red Blood Cell Transfusion Ranged from 5.2-13.1 g/dL Across Centers, from 5.3-9.1 g/dL Across Countries, and from 7.2-8.7 g/dL Across Continents
Approximately 84% of ICU’s Administered Transfusions to Patients at a Median Hemoglobin Level >7 g/dL
Recommendations in Hemodynamically Stable Adults and Children (American Association of Blood Banks, AABB) (Ann Intern Med, 2012)[MEDLINE]
Restrictive Transfusion Strategy (Hemoglobin 7-8 g/dL) is Recommended in Hospitalized, Stable Patients (Grade: Strong Recommendation, High-Quality Evidence)
Restrictive Transfusion Strategy (Hemoglobin 7-8 g/dL) is Recommended in Hospitalized Patients with Preexisting Cardiovascular Disease (Grade: Weak Recommendation, Moderate-Quality Evidence)
Consider Transfusion for Patients with Symptoms or a Hemoglobin ≤8 g/dL (Grade: Weak Recommendation, Moderate-Quality Evidence)
No Recommendation for or Against a Liberal or Restrictive Transfusion Threshold for Hospitalized, Hemodynamically Stable Patients with Acute Coronary Syndrome (Grade: Uncertain Recommendation, Very Low-Quality Evidence)
Transfusion Decisions Should Be Influenced by Symptoms as Well as Hemoglobin Concentration (Grade: Weak Recommendation. Low-Quality Evidence)
Recommendations in Critically Ill Adults (British Journal of Hematology Guidelines) (Br J Haematol, 2013) [MEDLINE]
Transfusion Triggers
A Transfusion Threshold of ≤7 g/dL, with a target Hemoglobin Range of 7-9 g/dL, Should Be the Default for All Critically Ill Patients, Unless Specific Comorbidities or Acute Illness-Related Factors Modify Clinical Decision-Making (Grade 1B)
Transfusion Triggers Should Not Exceed 9 g/dL in Most Critically Ill Patients (Grade 1B)
Alternatives to Red Blood Cell Transfusion
Erythropoietin Should Not Be Used to Treat Anemia in Critically Ill Patients Until Further Safety and Efficacy Data are Available (Grade 1B)
In the Absence of Clear Evidence of Iron Deficiency, Routine Iron Supplementation is Not Recommended During Critical Illness (Grade 2D)
Blood Sampling Techniques to Decrease Iatrogenic Blood Loss
The Introduction of Blood Conservation Sampling Devices Should Be Considered to Decrease Phlebotomy-Associated Blood Loss (Grade 1C)
Pediatric Blood Sampling Tubes Should Be Considered for Decreasing Iatrogenic Blood Loss (Grade 2C)
Pre-Transfusion Clinical Assessment Should Be Undertaken Including Assessment of Concomitant Medical Conditions Which Increase the Risk of TACO (Congestive Heart Failure, Kidney Disease, Hypoalbuminemia, Fluid Overload) (Grade 1D)
Attention to the Rate of Transfusion Together with Careful Fluid Balance and Appropriate Use of Diuretics Can Decrease the Risk of TACO (Grade 1D)
Patients Developing Acute Dyspnoea with Hypoxemia and Bilateral Pulmonary Infiltrates During or within 6 hrs of Transfusion Should Be Carefully Assessed for the Probability of TRALI and Patients Should Be Admitted to a Critical Care Area for Supportive Care (Grade 1D)
Any Adverse Events or Reactions Related to Transfusion Should Be Appropriately Investigated and Reported Via Systems for Local Risk Management, and Also to National Hemovigilance Schemes (Grade 1D)
Red Blood Cell Storage Duration
The Evidence Base is Insufficient to Support the Routine Administration of “Fresher Blood” to Critically Ill Patients (Grade 2B)
Critically Ill Patients with Sepsis
In the Early Resuscitation Phase in Patients with Severe Sepsis, if There is Clear Evidence of Inadequate Oxygen Delivery, Transfusion of Red Blood Cells to a Target Hemoglobin of 9-10 g/dL Should Be Considered (Grade 2C)
During the Later Stages of Severe Sepsis, a Conservative Approach to Transfusion Should Be Followed with a Target Hemoglobin of 7-9 g/ldL(Grade 1B)
Anaemic Critically Ill Patients with Stable Angina Should Have a Hemoglobin Maintained >7 g/dL, But Transfusion to a Hemoglobin >10 g/dL has Uncertain Benefit (Grade 2B)
In Patients Suffering from Acute Coronary Syndrome the Hemoglobin Should Be Maintained at >8–9 g/dL (Grade 2C)
In Patients with SAH, the Target Hemoglobin Should Be 8-10 g/dL (Grade 2D)
Recommendations (2016 Surviving Sepsis Guidelines) (Intensive Care Med, 2017) [MEDLINE]
Erythropoietin is Not Recommended to Treat Anemia Associated with Sepsis (Strong Recommendation, Moderate Quality of Evidence)
Erythropoietin May Increase the Risk of a Hypercoagulable State
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Sepsis/Septic Shock Use of Restrictive Red Blood Cell Transfusion Strategy is Recommended Over a Liberal Red Blood Cell Transfusion Strategy (Strong Recommendation, Moderate Quality of Evidence)
Restrictive Packed Red Blood Cell Transfusion Strategy Typically Includes a Hemoglobin Transfusion Trigger of 7.0 mg/dL
However, Red Blood Cell Transfusion Should Be Guided by the Hemoglobin Concentration, as Well the Patient’s Overall Clinical Status (Including Acute Myocardial Ischemia, Severe Hypoxemia, Acute Hemorrhage, etc)
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Fresh Frozen Plasma is Not Recommended to Correct Coagulopathy in the Absence of Bleeding or Planned Invasive Procedures (Weak Recommendation, Very Low Quality of Evidence)
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Platelet Transfusion Threshold of 10k/mm3 is Recommended in the Absence of Bleeding (Weak Recommendation, Very Low Quality of Evidence
Platelet Transfusion Threshold of 20k/mm3 is Recommended if the Patient Has Significant Risk of Bleeding (Weak Recommendation, Very Low Quality of Evidence
Platelet Transfusion Threshold of <50k/mm3 is Recommended in the Presence of Active Bleeding or Prior to Surgery/Invasive Procedures (Weak Recommendation, Very Low Quality of Evidence
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
When Pharmacologic Deep Venous Thrombosis Prophylaxis is Contraindicated, Mechanical Prophylaxis is Recommended (Weak Recommendation, Low Quality of Evidence)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Sepsis/Septic Shock, Pharmacologic Deep Venous Thrombosis Prophylaxis is Recommended (Unless a Contraindication Exists) (Strong Recommendation, Moderate Quality of Evidence)
For Adults with Sepsis/Septic Shock, Low Molecular Weight Heparin is Recommended Over Unfractionated Heparin for Deep Venous Thrombosis Prophylaxis (Strong Recommendation, Moderate Quality of Evidence)
For Adults with Sepsis/Septic Shock, Mechanical Deep Venous Thrombosis Prophylaxis is Not Recommended in Addition to Pharmacological Prophylaxis (Strong Recommendation, Low Quality of Evidence)
Nutritional Support
Clinical Efficacy
Meta-Analysis and Systematic Review of Prokinetic Agents in Critically Ill Patients Receiving Enteral Nutrition (Crit Care, 2016) [MEDLINE]
Prokinetic Agents Decrease Feeding Intolerance in Critically Ill Patients, as Compared to Placebo or No Intervention
However, the Impact of Prokinetic Agents on Other Outcomes (Such as Pneumonia, Mortality, and ICU Length of Stay is Unclear
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Early Initiation of Enteral Feeding (Rather than Fasting or Glucose-Containing Intravenous Fluids) is Recommended in Critically ill Patients with Sepsis/Septic Shock Who Can Be Fed Enterally (Weak Recommendation, Low Quality of Evidence)
At Least Early Trophic Enteral Feeding is Recommended in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Moderate Quality of Evidence): enteral feeding should then be advanced, as tolerated
Early Total Parenteral Nutrition (TPN) (Alone or in Combination with Enteral Nutrition) is Not Recommended in Patients with Sepsis/Septic Shock Who Can Be Fed Enterally (Strong Recommendation, Moderate Quality of Evidence)
TPN is Not Recommended (Alone or in Combination with Enteral Nutrition) Over the First 7 Days in Patients with Sepsis/Septic Shock in Whom Enteral Feeding is Not Feasible (Strong Recommendation, Moderate Quality of Evidence): alternatively, glucose-containing intravenous fluids with attempts to advance the enteral feeding are instead recommended
Mechanical Aspects of Enteral Nutrition
Placement of Post-Pyloric Feeding Tube is Recommended in Critically ill Patients with Sepsis/Septic Shock Who at High Risk for Aspiration (Weak Recommendation, Low Quality of Evidence)
Prokinetic Agents (Metoclopramide, Erythromycin, Domperidone) are Recommended in Critically ill Patients with Sepsis/Septic Shock and Feeding Intolerance (Weak Recommendation, Low Quality of Evidence): feeding intolerance is defined as vomiting, aspiration of gastric contents, or high gastric residual volumes
Routine Monitoring of Gastric Residual Volumes are Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence): this recommendation is in accord with that of the Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN) (J Parenter Enteral Nutr, 2016) [MEDLINE]
However, Gastric Residual Volumes are Suggested in Patients Who are at High Risk for Aspiration (Weak Recommendation, Very Low Quality of Evidence): this recommendation is in accord with that of the Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN) (J Parenter Enteral Nutr, 2016) [MEDLINE]
Supplements
Omega-3 Fatty Acids are Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Strong Recommendation, Low Quality of Evidence)
Intravenous Selenium is Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Strong Recommendation, Moderate Quality of Evidence)
Arginine is Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence)
Glutamine is Not Recommended in Critically ill Patients with Sepsis/Septic Shock (Strng Recommendation, Moderate Quality of Evidence)
No Recommendation is Made Regarding the Use of Carnitine in Critically ill Patients with Sepsis/Septic Shock (Weak Recommendation, Low Quality of Evidence)
Recommendations for Enteral Nutrition in the Setting of Hemodynamic Instability (Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN, 2016 Guidelines) [MEDLINE]
Tube Feedings Should Be Withheld Until the Patient is Fully Resuscitated and/or Stable (Quality of Evidence: Expert Consensus)
Recommendations for Enteral Nutrition in the Setting of Sepsis (Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN, 2016 Guidelines) [MEDLINE]
Use of Exclusive/Supplemental Parenteral Nutrition are Not Recommended in the Acute Phase of Sepsis, Regardless of Degree of Nutrition Risk (Quality of Evidence: Very Low)
Benefits of Use of Selenium, Zinc, and Antioxidants in Sepsis are Unclear (Quality of Evidence: Moderate)
Immune Modulating Formulations are Not Recommended in Sepsis (Quality of Evidence: Moderate)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adult Patients with Sepsis/Septic Shock Who Can Be Fed Enterally, Early Initiation of Enteral Nutrition (within 72 hrs) is Recommended (Weak Recommendation, Very Low Quality of Evidence)
Renal Support
Clinical Efficacy
Systematic Review of Continuous vs Intermittent Renal Hemodialysis in the Intensive Care Unit (Am J Kidney Dis, 2002) [MEDLINE]
In Comparison to Intermittent Renal Replacement Therapy, Continuous Renal Replacement Therapy Does Not Improve Survival or Renal Recovery in Unselected Critically Ill Patients with Acute Kidney Injury
Meta-Analysis of Intermittent vs Continuous Renal Replacement Therapy in Critically Ill Patients (Intensive Care Med, 2002) [MEDLINE]
Overall, There was No Difference in Mortality Between Intermittent and Continuous Renal Replacement Therapy in Critically Ill Patients
However, After Adjusting for Study Quality and Severity of Illness, Continuous Renal Replacement Therapy Had a Lower Mortality Rate (Relative Risk 0.72)
French IDEAL-ICU Trial of Timing of Renal Replacement Therapy in Patients with Acute Kidney Injury Associated with Septic Shock (NEJM, 2018) [MEDLINE]
Early Renal Replacement Therapy Strategy Did Not Decrease the 90-Day Mortality Rate, as Compared to Delayed Strategy
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
In Adults with Sepsis/Septic Shock and Acute Kidney Injury, Renal Replacement Therapy Should Not Be Used in the Absence of Indications for Hemodialysis (Weak Recommendation, Moderate Quality of Evidence)
In Adults with Sepsis/Septic Shock and Acute Kidney Injury, Either Continuous Renal Replacement Therapy (CRRT) or Intermittent Renal Replacement Therapy are Recommended (Weak Recommendation, Low Quality of Evidence)
Continuous Renal Replacement Therapy is Suggested to Facilitate Management of Fluid Balance in Hemodynamically Unstable Patients
Italian Oxygen-ICU Trial of Conventional Oxygen Strategy (pO2 Up to 150 mm Hg or SaO2 97-100%) vs Conservative Oxygen Strategy (pO70-100 or SaO2 94-98%) in a General ICU Population (Stay of ≥72 hrs) (JAMA, 2016) [MEDLINE]: trial had unplanned, early termination
Conservative Oxygen Strategy Decreased the Mortality Rate in a General ICU Population, as Compared to the Conventional Oxygen Strategy
Improving Oxygen Therapy in Acute-illness (IOTA) Systematic Review and Meta-Analysis of Conservative vs Liberal Oxygen Strategy in Critically Ill Patients (Lancet, 2018) [MEDLINE]: n = 25 trials (in patients with sepsis, critical illness, stroke, trauma, myocardial infarction, cardiac arrest, and emergency surgery)
In Acutely Ill Adults, Liberal Oxygen Therapy Strategy (Median SaO2 96%, Range 94-99%) Increases the 30-Day (and Longest Follow-Up) Mortality Rate, as Compared to a Conservative Oxygen Therapy Strategy (Relative Risk at 30 Days was 1.21, 95% CI 1.03-1.43)
Supplemental Oxygen Might Become Unfavorable with SaO2 >94-96%
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
In the Absence of Bronchospasm, β2-Agonists are Not Recommended in Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, Moderate Quality of Evidence)
Conservative Fluid Management Strategy is Recommended in Established Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) in the Absence of Tissue Hypoperfusion (Strong Recommendation, Moderate Quality of Evidence)
Head of the Bed Elevation
Elevation of the Head of the Bed to 30-45 Degrees is Recommended to Limit the Aspiration Risk and to Prevent the Development of Ventilator-Associated Pneumonia (VAP) During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation, Low Quality of Evidence)
Respiratory Rate Should Be ≤35 Breaths/min: recognizing that some patients may experience hypercapnia (hypercapnia is generally well-tolerated in the absence of contraindications, such as increased intracranial pressure, sickle cell crisis, etc)
Invasive Mechanical Ventilation Mode
No Ventilator Mode is Recommended Over Another
However, High-Frequency Oscillation Ventilation is Not Recommended in Adult Patients with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, Moderate Quality of Evidence) (see High-Frequency Ventilation)
Continuous or Intermittent Sedation Should Be Minimized (with Specific Sedation Endpoints) in Sepsis-Associated Mechanically-Ventilated Respiratory Failure (Best Practice Statement)
Spontaneous Breathing Trials (When Specific Criteria are Met) are Recommended in Sepsis-Associated Respiratory Failure (Strong Recommendation, High Quality of Evidence)
Weaning Protocol is Recommended for Appropriate Patients During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation)
Swan-Ganz Catheter is Not Routinely Recommended in the Management of Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, High Quality of Evidence)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
*In Adults with Sepsis-Induced Hypoxemic Respiratory Failure, There is Insufficient Evidence to Make a Recommendation Regarding the Use of Conservative Oxygen Targets (No Recommendation)
In Adults with Sepsis-Induced Hypoxemic Respiratory failure, High-Flow Nasal Cannula (HFNC) Oxygen is Recommended Over Noninvasive Positive-Pressure Ventilation (Weak Recommendation, Low Quality of Evidence)
In Adults with Sepsis-Induced Hypoxemic Respiratory Failure, There is Insufficient Evidence to Make a Recommendation Regarding the Use of Noninvasive Positive-Pressure Ventilation in Comparison to Invasive Mechanical Ventilation (No Recommendation)
For Adults with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Low Tidal Volume Ventilation (6 mL/kg) is Recommended Over a High Tidal Volume Ventilation (> 10 mL/kg) (Strong Recommendation, High Quality Evidence)
For Adults with Sepsis-Associated Respiratory Failure without Acute Respiratory Distress Syndrome (ARDS), Low Tidal Volume Ventilation (6 mL/kg) is Recommended Over a High Tidal Volume Ventilation (> 10 mL/kg) (Weak Recommendation, Low Quality Evidence)
Plateau Pressure
For Adults with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Maintenance of the Plateau Pressure <30 cm H2O is Recommended (Strong Recommendation, Moderate Quality Evidence)
Positive End-Expiratory Pressure (PEEP)
For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Higher PEEP is Recommended Over Use of Lower PEEP (Weak Recommendation, Moderate Quality Evidence)
The Optimal Method for Selecting PEEP is Unclear (Titrating PEEP Upward on a Tidal Volume of 6 mL/kg Until Plateau Pressure is 28 cm H20, Titrating PEEP to Optimize Thoracoabdominal Compliance with the Lowest Driving Pressure, Titrating PEEP Based on Decreasing the FIO2 to Maintain Oxygenation, etc)
Recruitment Maneuvers
For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Recruitment Maneuvers is Recommended (Weak Recommendation, Moderate Quality Evidence)
When Using Recruitment Maneuvers, Use of Incremental PEEP Titration/Strategy is Not Recommended (Strong Recommendation, Moderate Quality Evidence)
Prone Ventilation
For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS) and pO2/FIO2 Ratio <150, Use of Prone Ventilation for >12 hrs Daily is Recommended (Strong Recommendation, Moderate Quality Evidence)
For Adults with Moderate-Severe Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Intermittent Neuromuscular Junction Antagonist Boluses is Recommended Over Neuromuscular Junction Antagonist Continuous Infusion (Weak Recommendation, Moderate Quality Evidence)
For Adults with Sepsis-Associated Acute Respiratory Distress Syndrome (ARDS), Use of Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) When Conventional Invasive Mechanical Ventilation Fails is Recommended for Use in Experienced Centers with Adequate Infrastructure (Weak Recommendation, Low Quality Evidence)
Systematic Review and Meta-Analysis of Stress Ulcer Prophylaxis in Critically Ill Patients (Intensive Care Med, 2014) [MEDLINE]
Both the Quality and the Quantity of Evidence Supporting the Use of Stress Ulcer Prophylaxis in Adult ICU Patients is Low
Moderate Quality Evidence Indicated that Stress Ulcer Prophylaxis (with Either PPI or H2-Blockers) Significantly Decreased the Risk of Gastrointestinal Bleeding in Critically Ill Patients (Relative Risk 0.44)
Low Quality Evidence Suggested that Stress Ulcer Prophylaxis Non-Significantly Increased the Risk of Pneumonia (Relative Risk 1.23)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Sepsis/Septic Shock and Risk Factors for Gastrointestinal Hemorrhage, Stress Ulcer Prophylaxis is Recommended (Weak Recommendation, Moderate Quality Evidence
Antithrombin is the Most Abundant Anticoagulant Circulating in the Plasma
An Observed Decrease in Antithrombin Activity Early in the Course of Sepsis and is Correlated with the Occurrence of Disseminated Intravascular Coagulation (DIC) and Poor Outcome
Clinical Efficacy
Systematic Review of Antithrombin III in Critical Illness (Cochrane Database Syst Rev, 2016) [MEDLINE]
Antithrombin III Had No Impact on the Mortality Rate in Sepsis, But Increased the Risk of Bleeding
Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Antithrombin is Not Recommended in Sepsis/Septic Shock (Strong Recommendation, Moderate Quality of Evidence)
Blood Purification
Techniques
High-Volume Hemofiltration or Hemoadsorption (Hemoperfusion): sorbents remove either endotoxin or cytokines
Plasma Exchange or Plasma Filtration: plasma is separated from whole blood, removed, and replaced wth either normal saline, albumin, or fresh frozen plasma
Hybrid System: coupled plasma filtration adsorption (CPFA), which combines plasma filtration and adsorption (by a resin cartridge which removes cytokines)
Recommendations (Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021) (Crit Care Med, 2021) [MEDLINE]
For Adults with Sepsis/Septic Shock, Polymyxin B Hemoperfusion is Not Recommended (Weak Recommendation, Low Quality of Evidence)
There is Insufficient Evidence to Make a Recommendation Regarding the Use of Other Blood Purification Techniques (No Recommendation)
Drotecogin Alfa (Activated Protein C) Had No Impact on 28-Day or 90-Day Mortality (or Difference in Bleeding Risk) in Septic Shock: Drotecogin Alfa was pulled from the worldwide market on 10/25/11
ACCESS Trial of Eritoran in Sepsis (JAMA, 2013) [MEDLINE]
Eritoran (a Synthetic Lipid A Antagonist Which Blocks Lipopolysaccharide from Binding at the Cell Surface MD2-TLR4 receptor) Had No Impact on 28-Day Mortality in Sepsis
Foreword. The future of sepsis performance improvement. Crit Care Med 2015; 43(9):1787–1789 [MEDLINE]
Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015 Jan;43(1):3-12. doi: 10.1097/CCM.0000000000000723 [MEDLINE]
Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. PLoS One. 2015 May 6;10(5):e0125827. doi: 10.1371/journal.pone.0125827. eCollection 2015 [MEDLINE]
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Jan 18. doi: 10.1007/s00134-017-4683-6 [MEDLINE]
Surviving Sepsis Guidelines: A Continuous Move Toward Better Care of Patients With Sepsis. JAMA. 2017 Feb 28;317(8):807-808. doi: 10.1001/jama.2017.0059 [MEDLINE]
Implementation of the Surviving Sepsis Campaign guidelines. Curr Opin Crit Care. 2017 Oct;23(5):412-416. doi: 10.1097/MCC.0000000000000438 [MEDLINE]
SOMANZ guidelines for the investigation and management sepsis in pregnancy. Aust N Z J Obstet Gynaecol. 2017;57(5):540 [MEDLINE] Crit Care Med
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021 Nov 1;49(11):e1063-e1143. doi: 10.1097/CCM.0000000000005337.2021 Nov 1;49(11):e1063-e1143. doi: 10.1097/CCM.0000000000005337 [MEDLINE]
Benefits of esmolol in adults with sepsis and septic shock: An updated meta-analysis of randomized controlled trials. Medicine (Baltimore). 2022 Jul 8; 101(27): e29820. Published online 2022 Jul 8. doi: 10.1097/MD.0000000000029820 [MEDLINE]
Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036 [MEDLINE]
Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest. 2017 Nov;152(5):954-962. doi: 10.1016/j.chest.2017.07.014 [MEDLINE]
Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Ther. 2018 Sep;189:63-70. doi: 10.1016/j.pharmthera.2018.04.007 [MEDLINE]
Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis. Crit Care. 2018 Oct 11;22(1):258. doi: 10.1186/s13054-018-2191-x [MEDLINE]
Bet 2: Does intravenous vitamin C improve mortality in patients with severe sepsis? Emerg Med J. 2018 Apr;35(4):272-274. doi: 10.1136/emermed-2018-207608.3 [MEDLINE]
Vitamin C: The next step in sepsis management? J Crit Care. 2018 Feb;43:230-234. doi: 10.1016/j.jcrc.2017.09.031 [MEDLINE]
Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270. doi: 10.1001/jama.2019.11825 [MEDLINE]
HYVCTTSSS Trial. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. Chest 2020 Jul;158(1):174-182. doi: 10.1016/j.chest.2020.02.065 [MEDLINE]
Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049 [MEDLINE]
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]
Efficacy of intravenous vitamin C intervention for septic patients: A systematic review and meta-analysis based on randomized controlled trials. Am J Emerg Med. 2021 Aug 12;50:242-250. doi: 10.1016/j.ajem.2021.08.012 [MEDLINE]
LOVIT Trial. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022 Jun 23;386(25):2387-2398. doi: 10.1056/NEJMoa2200644 [MEDLINE]
Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230380. doi: 10.1001/jamanetworkopen.2023.0380 [MEDLINE]
Thiamine administration in septic shock: a post hoc analysis of two randomized trials. Crit Care. 2024 Feb 6;28(1):41. doi: 10.1186/s13054-024-04818-1 [MEDLINE]
Glycemic Control
Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367
Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461 [MEDLINE]
German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139
VISEP Trial. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125 [MEDLINE]
NICE-SUGAR Trial. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283 [MEDLINE]
A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009;35(10):1738 [MEDLINE]
Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009;180(8):821 [MEDLINE]
Corticosteroid treatment and intensive insulin therapy for septic shock (COIITSS) in adults: a randomized controlled trial. JAMA. 2010;303(4):341 [MEDLINE]
Systematic review: intensive insulin therapy in hospitalized patients. Ann Intern Med. 2011;154: 268 [MEDLINE]
Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260 [MEDLINE]
Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double‐blind, placebo‐controlled trial. Crit Care Med 1999, 27(11):2346–2350 [MEDLINE]
A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-417 [MEDLINE]
Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001; 345:1368-1377 [MEDLINE]
Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002, 288(22):2827–2835 [MEDLINE]
Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009 Apr;7(2):132-50. doi: 10.2450/2009.0005-09 [MEDLINE]
Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012;157(1):49 [MEDLINE]
Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol. 2013 Feb;160(4):445-64. doi: 10.1111/bjh.12143. Epub 2012 Dec 27 [MEDLINE]
ARISE Trial: Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1 [MEDLINE]
Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617. Epub 2014 Oct 1 [MEDLINE]
An official American Thoracic Society/American Association of Critical-Care Nurses/American College of Chest Physicians/Society of Critical Care Medicine policy statement: the Choosing Wisely® Top 5 list in Critical Care Medicine. Am J Respir Crit Care Med. 2014 Oct 1;190(7):818-26. doi: 10.1164/rccm.201407-1317ST [MEDLINE]
Efficacy and Safety of Erythropoietin to Prevent Acute Kidney Injury in Patients With Critical Illness or Perioperative Care: A Systematic Review and Meta-analysis of Randomized Controlled Trials. J Cardiovasc Pharmacol. 2015 Jun;65(6):593-600. doi: 10.1097/FJC.0000000000000229 [MEDLINE]
Red Blood Cell Transfusion in the Intensive Care Unit. JAMA. 2023 Oct 12:e2320737. doi: 10.1001/jama.2023.20737 [MEDLINE]
Nutritional Support
Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863 [MEDLINE]
The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta‐analysis of randomized trials. Crit Care 2016, 20(1):259 [MEDLINE]
Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863 [MEDLINE]
Renal Support
Continuous versus intermittent renal replacement therapy: a meta‐analysis. Intensive Care Med 2002, 28(1):29–37 [MEDLINE]
Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002, 40(5):875–885 [MEDLINE]
IDEAL-ICU Trial. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018;379(15):1431 [MEDLINE]
Respiratory Support
Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016;316(15):1583 [MEDLINE]
Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018 Apr 28;391(10131):1693-1705. doi: 10.1016/S0140-6736(18)30479-3 [MEDLINE]
Stress Ulcer Prophylaxis
Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta‐ analysis and trial sequential analysis. Intensive Care Med 2014, 40(1):11–22 [MEDLINE]
Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286:1869-1878
KyberSept Trial: High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med. 2006 Feb;34(2):285-92 [MEDLINE]
Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD005370 [MEDLINE]
Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2016 Feb 8;2:CD005370. doi: 10.1002/14651858.CD005370.pub3 [MEDLINE]
The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med. 2015 Mar;43(3):511-8. doi: 10.1097/CCM.0000000000000763 [MEDLINE]
Efficacy and safety of recombinant activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003;31:12-19
PROWESS Trial: The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results. Crit Care Med 2003;31:2291-2301
ADDRESS Trial: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005 Sep 29;353(13):1332-41 [MEDLINE]
PROWESS Shock Trial: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31;366(22):2055-64 [MEDLINE]
Efficacy and Safety of Vilobelimab (IFX-1), a Novel Monoclonal Anti-C5a Antibody, in Patients With Early Severe Sepsis or Septic Shock-A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase IIa Trial (SCIENS Study). Crit Care Explor. 2021 Nov 17;3(11):e0577. doi: 10.1097/CCE.0000000000000577. eCollection 2021 Nov [MEDLINE]
