Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012 A Guide To The Guidelines … Nabil Abouchala, MD, FCCP, FACP Consultant, Pulmonary and Critical Care Medicine Medical Director, Med-Sug ICU-C King Faisal Hospital & Research Center Riyadh, Saudi Arabia

Surviving Sepsis Campaign: History of the guidelines… 2001 2004 2008 2012

Crit Care Med 2013; 41:580–637

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics​​

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics​​

1. Initial Resuscitation & Infection Issues A. Initial Resuscitation B. Screening for Sepsis & Performance Improvement C. Diagnosis D. Antimicrobial Therapy E. Source Control F. Infection prevention

1. Initial Resuscitation & Infection Issues Sepsis Bundle A. Initial Resuscitation RRT and Use of Sepsis Bundle Protocol B. Screening for Sepsis & Performance Improvement Use of the 1,3 beta-D-glucan assay, mannan and anti-mannan antibody assays C. Diagnosis Use of an echinocandin if candidemia is suspected Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics D. Antimicrobial Therapy E. Source Control Oral chlorhexidine gluconate (CHG) for prevention of VAP F. Infection prevention

Sepsis Bundle A. Initial Resuscitation Serum Lactate Measured Resuscitation Bundle Serum Lactate Measured Blood Culture Obtained Prior to Antibiotic Administration Broad-Spectrum Antibiotics Administered within 1 Hour of ED Admission Fluid Resuscitation (30 ML/Kg) for Hypotension or Lactate >4mmol/L Vasopressors for Ongoing Hypotension Maintain Adequate Central Venous Pressure (CVP ≥ 8) Maintain Adequate Central Venous Oxygen Saturation (ScvO2 ≥ 70%) Re-measure Serum Lactate

Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock To Examine whether Early Goal Directed Therapy (EGDT) before admission to the ICU is superior to standard hemodynamic therapy in patients with sever sepsis and septic shock #Citing articles 2469 N Engl J Med, 2001;345:1368-77

MOrtality 10-20% Sudden Death!

Results 37 Observational studies showing improved outcomes with early quantitative resuscitation between 2001 and 2011 Mortality EGT : 30.5 % Standard: 46.5 % Absolute Risk Reduction NNT = 16% 7 Multicenter trial of 314 patients with severe sepsis in eight Chinese centers (2010). This trial reported a 17.7% absolute reduction multicenter trial of 314 patients with severe sepsis in eight Chinese centers (14). This trial reported a 17.7% absolute reduction in 28-day mortality (survival rates, 75.2% vs. 57.5%) N Engl J Med, 2001;345:1368-77

fluid in septic shock, How much ?

2012: IVF recommendation Initial fluid challenge ≥ 1000 mL of crystalloids or minimum of 30 mL/kg of crystalloids in the 1st 4-6 hours (Strong recommendation; Grade 1C). Crystalloids is the initial fluid for resuscitation (Strong recommendation; Grade 1A). Adding albumin to the initial fluid resuscitation (Weak recommendation; Grade 2B). Against hydroxyethyl starches (hetastarches) with MW >200 dalton (Strong recommendation; Grade 1B).

Timing of Antibiotic Administration

Septic Shock: Timing of Antibiotics Percent 1.00 14 ICUs; n = 2,731 % Survival % Total receiving antibiotics .80 Only 50% of patients in Septic Shock received antibiotics w/in 6 hrs. .60 .40 .20 0.0 0 - .5 .5 – 1.0 1 - 2 2 - 3 3-4 4 - 5 5 - 6 6 - 9 9 - 12 12 - 24 24 - 36 > 36 Time, hrs Kumar Crit Care Med 2006

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics​​

2. Hemodynamic Support and Adjunctive Therapy G. Fluid Therapy of Severe Sepsis H. Vasopressors I. Inotropic Therapy J. Corticosteroids

Which Inotropes to use? Norepinephrine as the first choice ( Grade 1B) Adding or substituting epinephrine when an additional drug is needed (Strong recommendation; Grade 1B). Vasopressin 0.03 units/min may be added (Weak recommendation; Grade 2A) Dopamine only in highly selected patients at very low risk of arrhythmias or low heart rate (Weak recommendation; Grade 2C). Dobutamine infusion be started or added with low cardiac output) or ongoing signs of hypoperfusion, even after adequate intravascular volume (Strong recommendation; Grade 1C)

Norepinephrine Compared With Dopamine in Severe Sepsis Summary of Evidence Epinephrine Although some human and animal studies suggest epinephrine has deleterious effects on splanchnic circulation and produces hyperlactatemia, no clinical evidence shows that epinephrine results in worse outcomes, and it should be the first alternative to norepinephrine. Indeed, information from 4 randomized trials (n = 540) comparing norepinephrine to epinephrine found no evidence for differences in the risk of dying (RR, 0.96; CI, 0.77−1.21; fixed effect; I2 = 0%) (142, 147, 154, 155). Epinephrine may increase aerobic lactate production via stimulation of skeletal muscles’ β2-adrenergic receptors and thus may prevent the use of lactate clearance to guide resuscitation

Crit Care Med 2012; 40:725–730

Sepsis induced vasodilatation NE Lower amount of fluid required to fill the tank

Early NE + Fluids Late NE + Fluids Fluids NE LPS Crit Care Med 2007; 35:1736–1740 Early NE + Fluids Late NE + Fluids Fluids NE LPS

Adequate fluid resuscitation …

Early administration of norepinephrine aimed at rapidly achieving a sufficient perfusion pressure in severely hypotensive septic-shock (DBP < 40) patients is able to increase cardiac output through an increase in cardiac preload and cardiac contractility

Individual values (open circles) and mean + SD (closed circles) of pre-infusion central venous pressure (CVP) (both expressed in mmHg) in responders (R) and nonresponders (NR). Design: Retrospective study. Setting: A 24-bed medical intensive care unit. Patients: All consecutive septic patients monitored with a pulmonary artery catheter who underwent a volume challenge between 2001 and 2004. Intervention: None. The decision to give fluid was based on the presence of at least one clinical sign of acute circulatory failure or associated signs of hypoperfusion. In all patients, the volume challenge consisted of the infusion of 500 mL of 6% hydroxyethyl starch in a period 20 mins. Patients exhibiting an increase in cardiac index induced by the volume challenge of 15% and 15% were classified as responders and nonresponders, respectively. Measurements and Main Results: A total of 150 volume challenges in 96 patients were reviewed. In 65 instances, the volume challenge resulted in an increase in cardiac index of >15% (responders). The pre-infusion central venous pressure was similar in responders and nonresponders (8 4 vs. 9 4 mm Hg). The pre-infusion pulmonary artery occlusion pressure was slightly lower in responders (10 4 vs. 11 4 mm Hg, p < .05). Crit Care Med 2007; 35:64–68

Individual values (open circles) and mean + SD (closed circles) of pre-infusion central venous pressure (CVP) (both expressed in mmHg) in responders (R) and nonresponders (NR). Crit Care Med 2007; 35:64–68

PLR mimics fluid challenge Passive Leg raising PLR mimics fluid challenge Unlike fluid challenge, no fluid is infused and the effects are reversible and transient PLR may be considered a reversible “autotransfusion” = 150-mL fluid challenge In should be noted that intra-abdominal hypertension (intra-abdominal pressure > 16 mmHg) impairs venous return and reduces the ability of PLR to detect fluid responsiveness

Hemodynamic monitoring and management has greatly improved during the past decade. Technologies have evolved from very invasive to non-invasive, and the philosophy has shifted from a static approach to a functional approach. However, despite these major changes, the critical care community still has potential to improve its ability to adopt the most modern standards of research methodology in order to more effectively evaluate new monitoring systems and their impact on patient outcome. Today, despite the huge enthusiasm raised by new hemodynamic monitoring systems, there is still a big gap between clinical research studies evaluating these monitors and clinical practice. A few studies, especially in the perioperative period, have shown that hemodynamic monitoring systems coupled with treatment protocols can improve patient outcome. These trials are small and, overall, the corpus of science related to this topic does not yet fit the standard of clinical research methodology encountered in other specialties such as cardiology and oncology. Larger randomized trials or quality improvement processes will probably answer questions related to the real impact of these systems.

Stroke volume variation SVV = SV max – SV min / SV mean

Higher PVI = More likely to respond to fluid administration Pleth Variability index (PVI) to Help Clinicians Optimize Preload / Cardiac Output Stroke Volume 10 % Lower PVI = Less likely to respond to fluid administration 24 % Higher PVI = More likely to respond to fluid administration Preload Maxime Cannesson, MD, PhD

2. Hemodynamic Support and Adjunctive Therapy Crystalloids = Albumin Against the use of hydroxyethyl starches Hemodynamic response based on Dynamic assessment G. Fluid Therapy of Severe Sepsis Norepinephrine is 1st choice Epinephrine 2nd Dopamine only in highly selected cases Phenylephrine is not recommended Low-dose dopamine should not be used for renal protection H. Vasopressors I. Inotropic Therapy Not using IV hydrocortisone to treat adult septic shock unless … Use Hydrocortisone at 200 mg/day, preferably as IV infusion, to be tapered off J. Corticosteroids Target MAP ≥ 65 … Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day (grade 2C).

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics​​

3. Other Supportive Therapy of Severe Sepsis K. Blood Product Administration Target Hemoglobin (7-9 g/dl) unless … L. Immunoglobulins: Not recommended M. Selenium: Not recommended N. History of Recommendations Regarding Use of Recombinant Activated Protein C O. Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS) P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Q. Glucose Control R. Renal Replacement Therapy S. Bicarbonate Therapy T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer V. Nutrition W. Setting Goals of Care

3. Other Supportive Therapy of Severe Sepsis K. Blood Product Administration Target Hemoglobin (7-9 g/dl) unless … L. Immunoglobulins: Not recommended M. Selenium: Not recommended N. History of Recommendations Regarding Use of Recombinant Activated Protein C R. Renal Replacement Therapy S. Bicarbonate Therapy

The Rise and Fall of xigris! -6.5% +1.2%

3. Other Supportive Therapy of Severe Sepsis K. Blood Product Administration Target Hemoglobin (7-9 g/dl) unless … L. Immunoglobulins: Not recommended M. Selenium: Not recommended N. History of Recommendations Regarding Use of Recombinant Activated Protein C O. Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS) P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Q. Glucose Control R. Renal Replacement Therapy S. Bicarbonate Therapy T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer V. Nutrition W. Setting Goals of Care

3. Other Supportive Therapy of Severe Sepsis O. Mechanical Ventilation of Sepsis-Induced (ARDS) 1. Target a TV of 6 mL/kg predicted body weight (grade 1A vs. 12 mL/kg) 2. Plateau pressures be measured in patients with ARDS be ≤30 cm H2O (grade 1B) 3. (PEEP) be applied (grade 1B) 4. Higher rather than lower levels of PEEP for moderate or severe ARDS (grade 2C) 5. Recruitment maneuvers be used with severe refractory hypoxemia (grade 2C) 6. Prone positioning be used Pao2/Fio2 ratio ≤ 100 mm (grade 2B) 7. HOB elevated to 30-45 (grade 1B) 8. (NIV) be used in minority of patients in whom the benefits of NIV (grade 2B) 9. Weaning protocol be in place 10. Against the routine use of the pulmonary artery catheter (grade 1A) 11. A conservative rather than liberal fluid strategy (grade 1C) 12. not using beta 2-agonists for treatment of sepsis-induced ARDS (grade 1B)

Reducing from 12 to 6 ml/kg VT saved lives ARMA Trial Reducing from 12 to 6 ml/kg VT saved lives NNT 12 14000 Lives Saved/Year Intervention Control TV (4-6 ml/Kg) PEEP 8.5 TV (10-12 ml/Kg) PEEP 8.6

Wet First –Dry later Approach that combines both adequate initial fluid resuscitation followed by conservative late-fluid management was associated with improved survival CHEST 2009; 136:102–109

Wet First –Dry later CHEST 2009; 136:102–109 A retrospective analysis was performed at Barnes-Jewish Hospital (St. Louis, MO) and in the medical ICU of Mayo Medical Center (Rochester, MN). Patients hospitalized with septic shock were enrolled into the study if they met the American-European Consensus definition of ALI within 72 h of septic shock onset. Adequate initial fluid resuscitation (AIFR) was defined as the administration of an initial fluid bolus of > 20 mL/kg prior to and achievement of a central venous pressure of > 8 mm Hg within 6 h after the onset of therapy with vasopressors. Conservative late fluid management (CLFM) was defined as even-tonegative fluid balance measured on at least 2 consecutive days during the first 7 days after septic shock onset. CHEST 2009; 136:102–109

JAMA. 2010;303(9):865-873

Higher PEEP is better in Moderate to Severe ARDS (PO2/FiO2 ≤ 200 mmHg) The potentially lower hospital mortality and the absence of increased serious adverse events associated with Higher PEEP levels in patients with ARDS support the safety of higher PEEP in these patients. For this purpose, clinicians could titrate PEEP as described in the 3 major trials in this review (eAppendix) JAMA. 2010;303(9):865-873

Higher PEEP is better in Moderate to Severe ARDS (PO2/FiO2 ≤ 200 mmHg) The potentially lower hospital mortality and the absence of increased serious adverse events associated with Higher PEEP levels in patients with ARDS support the safety of higher PEEP in these patients. For this purpose, clinicians could titrate PEEP as described in the 3 major trials in this review (eAppendix) Death in ICU  6.3 % NNT 16 Days off the MV -5 days JAMA. 2010;303(9):865-873

3. Other Supportive Therapy of Severe Sepsis (NMBAs) be avoided if possible without ARDS Short course of NMBA (<48 hours) for early ARDS + Pao2/Fio2<150 mm Hg P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Q. Glucose Control PPIs rather than H2RA (grade 2D) T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer V. Nutrition

Glucose control in ICU -10% +1.5% ITT- 2001 NICE-SUGAR- 2009

3. Other Supportive Therapy of Severe Sepsis P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis (NMBAs) be avoided if possible without ARDS Short course of NMBA (<48 hours) for early ARDS + Pao2/Fio2<150 mm Hg Q. Glucose Control T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer PPIs rather than H2RA (grade 2D) V. Nutrition

Omega/EDEN* studies Objective: dietary supplementation of Omega-3 FA increase ventilator –free days in patients with ALI/ARDS Intervention: BID bolus supplementation of omega-3 FA vs isocaloric control The study was stopped by the steering committee for futility at the first interim analysis Rice at al. for the NHLBI ARDS Clinical Trials Network JAMA. 2011;306(14):1574-1581

Daily energy intake Rice at al. for the NHLBI ARDS Clinical Trials Network . JAMA. 2012

Survival and hospital Discharge Rice at al. for the NHLBI ARDS Clinical Trials Network . JAMA. 2012

3. Other Supportive Therapy of Severe Sepsis (NMBAs) be avoided if possible without ARDS Short course of NMBA (<48 hours) for early ARDS + Pao2/Fio2<150 mm Hg P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Target an upper BG 140-180 mg/dL rather than ≤ 110 mg/dL (grade 1A) Q. Glucose Control PPIs rather than H2RA (grade 2D) T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day) No specific immunomodulating supplementation V. Nutrition

Take home message BE Goal Directed: Antimicrobials: ARDS: More and faster fluid No hetastarch Earlier Inotropes Use norepineprine and epinephrine over dopamine Lactic acid clearance Dynamic SVV is better than CVP Antimicrobials: Fast <1 hr, consider early antifungals, use biomarkers to deescalate or stop ARDS: Wet first, dry later Higher PEEP Glucose control Not so tight (140-180 mg/dl = 8-10 mmol/l) Nutrition Underfeed first week No supplement