Update in Sepsis. Conflicts of Interest: None. Bill Janssen, M.D.

Update in Sepsis Bill Janssen, M.D. Associate Professor of Medicine National Jewish Health University of Colorado Denver Conflicts of Interest: None A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. T 102, HR 130, RR 24, BP 100/50, SaO 2 = 94% on 6L. CXR shows right lower lobe consolidation. Wbc 14, Creatinine 2.1, Lactate 2.1

A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. T 102, HR 130, RR 24, BP 100/50, SaO 2 = 94% on 6L. CXR shows right lower lobe consolidation. Wbc 14, Creatinine 2.1, Lactate 2.1 What is the patient s diagnosis? A. SIRS B. Sepsis C. Severe sepsis D. Septic shock E. I used to think I knew what sepsis was, but I don t anymore. Didn t they change the definition? Sepsis Definitions Centers for Medicare and Medicaid Services (CMS) Federal reporting requirements for hospitalized patients In effect October 2015 SEPSIS BUNDLE PROJECT (SEP) v 5.0a.

Sepsis Definitions - Old SIRS Severe Sepsis Sepsis Septic Shock Sepsis Definitions - Old SIRS Severe Sepsis Sepsis Septic Shock Systemic Inflammatory Response Syndrome 2 or more of: Temperature >38 0 or <36 0 Heart rate >90 beats/min Respiratory rate >20 or PaCO2 < 32 mmhg wbc >12,000, <4,000, or left-shift (>10%) * Can result from a variety of insults (infection, trauma, pancreatitis, etc) Sepsis Definitions - Old SIRS Severe Sepsis Sepsis Septic Shock SIRS + Suspected Infection Possible in your note is enough for the coders to code sepsis.

Sepsis Definitions - Old SIRS Severe Sepsis Sepsis Septic Shock All 3 criteria met within 6 hrs of each other 1.Documentation of suspected source of infection ( possible ) 2.SIRS 3.Organ dysfunction (need only one) SBP < 90 or MAP < 65 mm Hg within 1 st hr Creatinine > 2 or urine output <.5 ml/kg/hr for > 2hr Bilirubin > 2 mg/dl Platelets < 100,000 Coagulopathy (INR > 1.5 or PTT > 60 sec) Lactate > 2 mmol/l Sepsis Definitions - Old SIRS Severe Sepsis Sepsis Septic Shock Severe Sepsis with: Hypoperfusion despite adequate fluid resuscitation (SBP < 90 or MAP < 65 mm Hg or 40% reduction from baseline) OR Lactate > 4.0 mmol/l

JAMA 2016;; 315 (8) 801 The current use of 2 or more SIRS criteria to identify sepsis was unanimously considered by the task force to be unhelpful. Changes in the white blood cell count, temperature, and heart rate reflect inflammation, the host response to danger in the form of infection or other insults. The SIRS criteria do not necessarily indicate a dysregulated, life-threatening response. The Original Sepsis Paradigm It is our response... that makes the disease 1972 -Lewis Thomas, NEJM,

The problem has not been the therapies tested, but the underlying hypothesis that massive, uncontrolled inflammation is the dominant cause of sepsis. - Roger Bone, JAMA 1996 Sepsis, A Tale of 2 States Systemic Inflammatory Response Syndrome (SIRS) Compensatory Anti-inflammatory Response Syndrome (CARS) Leukocyte Activation Sepsis-Induced Tissue Injury Leukocyte Deactivation Sepsis-Induced Immunosuppression Systemic Inflammatory Response Syndrome (SIRS) Compensatory Anti-Inflammatory Response Syndrome (CARS) Cytokine/mediator Levels TNF, IL-1b Chemokines IL-6 Leukotrienes Anti-inflammatory cytokines (e.g. IL-10, IL-1ra) Prostaglandins Inhibitors of TLRs Time Post Insult

JAMA. 2016;315(8):762-774. JAMA. 2016;315(8):762-774.

From: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. T 102, HR 130, RR 24, BP 100/50, SaO 2 = 94% on 6L. CXR shows right lower lobe consolidation. Wbc 14, Creatinine 2.1, Lactate 2.1 What is the patient s diagnosis? A. SIRS B. Sepsis C. Severe sepsis D. Septic shock E. I used to think I knew what sepsis was, but I don t anymore. Didn t they change the definition?

A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. T 102, HR 130, RR 24, BP 100/50, SaO 2 = 94% on 6L. CXR shows right lower lobe consolidation. Wbc 14, Creatinine 2.1, Lactate 2.1 What is the patient s diagnosis? A. SIRS B. Sepsis C. Severe sepsis D. Septic shock E. I used to think I knew what sepsis was, but I don t anymore. Didn t they change the definition? If I Ruled the World SIRS + evidence of infection = sepsis (screen) If Sepsis, evaluate for organ dysfunction with qsofa If + qsofa, check SOFA and lactate an move to unit trained in sepsis care If + SOFA = severe sepsis (mortality prediction) If vasopressors and elevated lactate = septic shock (mortality prediction) A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. CXR shows right lower lobe consolidation. Wbc 14, Creatinine 2.1, Lactate 2.1 The patient s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 75 kg) What are the next best steps? A. Get blood cultures B. Give broad spectrum C. Place a central line to measure CVP D. A and B E. All the above

CMS - Severe Sepsis Bundle 0 3 hr 6 hr Severe Sepsis - All 3 criteria met within 6 hrs of each other 1.Documentation of suspected source of infection ( possible ) 2.SIRS 3.Organ dysfunction (need only one) CMS - Severe Sepsis Bundle 0 3 hr 6 hr A. measure lactate level B. obtain blood cultures prior to C. administer broad spectrum Severe Sepsis - All 3 criteria met within 6 hrs of each other 1.Documentation of suspected source of infection ( possible ) 2.SIRS 3.Organ dysfunction (need only one) CMS - Severe Sepsis Bundle 0 3 hr 6 hr A. measure lactate level B. obtain blood cultures prior to C. administer broad spectrum D. administer 30 ml/kg crystalloid Severe Sepsis - All 3 criteria met within 6 hrs of each other 1.Documentation of suspected source of infection ( possible ) 2.SIRS 3.Organ dysfunction (need only one)

CMS - Septic Shock Bundle 0 3 hr 6 hr Septic Shock - Severe Sepsis with: Hypoperfusion despite adequate fluid resuscitation OR Lactate > 4.0 mmol/l CMS - Septic Shock Bundle 0 3 hr 6 hr A. measure lactate level B. obtain blood cultures prior to C. administer broad spectrum D. administer 30 ml/kg crystalloid Septic Shock - Severe Sepsis with: Hypoperfusion despite adequate fluid resuscitation OR Lactate > 4.0 mmol/l CMS - Septic Shock Bundle 0 3 hr 6 hr A. measure lactate level B. obtain blood cultures prior to C. administer broad spectrum D. administer 30 ml/kg crystalloid E. apply vasopressors for hypotension that does not respond to initial fluid resuscitation (MAP 65) F. re-assess volume status and tissue perfusion and document findings.* G. Re-measure lactate if initial level was elevated

CMS - Septic Shock Bundle Reassessment of volume status and tissue perfusion To meet the requirements, a focused exam by a licensed independent practitioner (LIP) or any 2 other items are required: 1. Measure CVP 2. Measure ScVO 2 3. Bedside cardiovascular ultrasound 4. Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge Focused exam including vital signs, cardiopulmonary, capillary refill, pulse and skin findings. CMS - Septic Shock Bundle 0 3 hr 6 hr A. measure lactate level B. obtain blood cultures prior to C. administer broad spectrum CVP ScVO2 Echo Dynamic assessment D. administer 30 ml/kg crystalloid E. apply vasopressors for hypotension that does not respond to initial fluid resuscitation (MAP 65) F. re-assess volume status and tissue perfusion and document findings.* G. Re-measure lactate if initial level was elevated Physical exam Prompt Administration of Antibiotics Saves Lives 100 80 N = 2731 patients 10 hospitals, 14 ICUs % Surviving 60 40 20 0 Time to Antibiotic Administration (hrs) Kumar. Crit Care Med 2006

established in 1812 may 1, 2014 vol. 370 no. 18 Prompt Administration of Antibiotics Saves Lives 100 80 Each hour of delay is associated with an 8% decrease in survival % Surviving 60 40 20 0 Time to Antibiotic Administration (hrs) Kumar. Crit Care Med 2006 Severe Sepsis or Septic Shock Early Goal Directed Therapy CVP < 8 mm Hg IV Fluids 8-12 mm Hg MAP < 65 mm Hg Vasopressors > 65 mm Hg > 70% SvO2 < 70% Transfuse blood until Hct > 30% < 70% No > 70% Goals Met? Dobutamine Yes ICU Admission Rivers. NEJM 345:1368-1377,2001 The new england journal of medicine A Randomized Trial of Protocol-Based Care for Early Septic Shock The ProCESS Investigators* The new england journal of medicine original article Goal-Directed Resuscitation for Patients with Early Septic Shock The ARISE Investigators and the ANZICS Clinical Trials Group* The new england journal of medicine original article Trial of Early, Goal-Directed Resuscitation for Septic Shock Paul R. Mouncey, M.Sc., Tiffany M. Osborn, M.D., G. Sarah Power, M.Sc., David A. Harrison, Ph.D., M. Zia Sadique, Ph.D., Richard D. Grieve, Ph.D., Rahi Jahan, B.A., Sheila E. Harvey, Ph.D., Derek Bell, M.D., Julian F. Bion, M.D., Timothy J. Coats, M.D., Mervyn Singer, M.D., J. Duncan Young, D.M., and Kathryn M. Rowan, Ph.D., for the ProMISe Trial Investigators* n engl j med 372;14 nejm.org april 2, 2015

established in 1812 may 1, 2014 vol. 370 no. 18 established in 1812 may 1, 2014 vol. 370 no. 18 established in 1812 may 1, 2014 vol. 370 no. 18 The new england journal of medicine A Randomized Trial of Protocol-Based Care for Early Septic Shock The ProCESS Investigators* The new england journal of medicine original article Goal-Directed Resuscitation for Patients with Early Septic Shock The ARISE Investigators and the ANZICS Clinical Trials Group* The new england journal of medicine original article Trial of Early, Goal-Directed Resuscitation for Septic Shock Paul R. Mouncey, M.Sc., Tiffany M. Osborn, M.D., G. Sarah Power, M.Sc., David A. Harrison, Ph.D., M. Zia Sadique, Ph.D., Richard D. Grieve, Ph.D., Rahi Jahan, B.A., Sheila E. Harvey, Ph.D., Derek Bell, M.D., Julian F. Bion, M.D., Timothy J. Coats, M.D., Mervyn Singer, M.D., J. Duncan Young, D.M., and Kathryn M. Rowan, Ph.D., for the ProMISe Trial Investigators* n engl j med 372;14 nejm.org april 2, 2015 Study Setting Patients EGDT Usual Care Protocol Based Rivers Single Center 263 44.3 56.9 ProCESS ARISE ProMISE % Mortality The new england journal of medicine A Randomized Trial of Protocol-Based Care for Early Septic Shock The ProCESS Investigators* The new england journal of medicine original article Goal-Directed Resuscitation for Patients with Early Septic Shock The ARISE Investigators and the ANZICS Clinical Trials Group* The new england journal of medicine original article Trial of Early, Goal-Directed Resuscitation for Septic Shock Paul R. Mouncey, M.Sc., Tiffany M. Osborn, M.D., G. Sarah Power, M.Sc., David A. Harrison, Ph.D., M. Zia Sadique, Ph.D., Richard D. Grieve, Ph.D., Rahi Jahan, B.A., Sheila E. Harvey, Ph.D., Derek Bell, M.D., Julian F. Bion, M.D., Timothy J. Coats, M.D., Mervyn Singer, M.D., J. Duncan Young, D.M., and Kathryn M. Rowan, Ph.D., for the ProMISe Trial Investigators* n engl j med 372;14 nejm.org april 2, 2015 % Mortality Study Setting Patients EGDT Usual Care Protocol Based Rivers Single Center 263 44.3 56.9 ProCESS USA (31) 1341 21 18.9 18.2 ARISE Aus/NZ (51) 1591 18.6 18.8 ProMISE England (56) 1251 29.5 29.2 The new england journal of medicine A Randomized Trial of Protocol-Based Care for Early Septic Shock The ProCESS Investigators* The new england journal of medicine original article Goal-Directed Resuscitation for Patients with Early Septic Shock The ARISE Investigators and the ANZICS Clinical Trials Group* The new england journal of medicine original article Trial of Early, Goal-Directed Resuscitation for Septic Shock Paul R. Mouncey, M.Sc., Tiffany M. Osborn, M.D., G. Sarah Power, M.Sc., David A. Harrison, Ph.D., M. Zia Sadique, Ph.D., Richard D. Grieve, Ph.D., Rahi Jahan, B.A., Sheila E. Harvey, Ph.D., Derek Bell, M.D., Julian F. Bion, M.D., Timothy J. Coats, M.D., Mervyn Singer, M.D., J. Duncan Young, D.M., and Kathryn M. Rowan, Ph.D., for the ProMISe Trial Investigators* n engl j med 372;14 nejm.org april 2, 2015 % on Pressors % with CVC Study EGDT Usual Care EGDT Usual Care Rivers 27 30 100 NA ProCESS 55 44 97 58 ARISE 66 58 98 62 ProMISE 53 46 99 51

CVP is useless for assessing volume status Shippy CR. Crit Care Med 1984. 12:107-112. A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. CXR shows right lower lobe consolidation. Wbc 14, Creatinine 2.1, Lactate 2.1 The patient s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 70 kg) What are the next best steps? A. Get blood cultures B. Give broad spectrum C. Place a central line to measure CVP D. A and B E. All the above A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes and CHF. CXR shows right lower lobe consolidation. Wbc 14, Creatinine 2.1, Lactate 2.1 The patient s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 70 kg) What are the next best steps? A. Get blood cultures B. Give broad spectrum C. Place a central line to measure CVP D. A and B E. All the above

A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes, CHF and hypertension (usual BP is 150/100). She has pneumonia and septic shock. You ve given 3L of saline and the patient s BP is still low (86/40). Her oxygenation has worsened. Its time to start pressors. What s the next best step? A. Start norepinephrine to achieve MAP of 80 B. Start norepinephrine + vasopressin to achieve MAP > 65 C. Start dopamine A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes, CHF and hypertension (usual BP is 150/100). She has pneumonia and septic shock. You ve given 3L of saline and the patient s BP is still low (86/40). Her oxygenation has worsened. Its time to start pressors. What s the next best step? A. Start norepinephrine to achieve MAP of 80 B. Start norepinephrine + vasopressin to achieve MAP > 65 C. Start dopamine By the way, your friendly neighborhood intensivist is tied up. Is it ok to start a pressor through a peripheral IV? What s the worst that can happen?

The new england journal of medicine established in 1812 april 24, 2014 vol. 370 no. 17 High versus Low Blood-Pressure Target in Patients with Septic Shock Pierre Asfar, M.D., Ph.D., Ferhat Meziani, M.D., Ph.D., Jean-François Hamel, M.D., Fabien Grelon, M.D., SEPSISPAM Multicenter randomized controlled trial at 29 centers in France 776 patients with septic shock Randomized to either: Goal MAP 60-65 Goal MAP 80-85 Post hoc analysis for prior history of chronic hypertension The new england journal of medicine established in 1812 april 24, 2014 vol. 370 no. 17 High versus Low Blood-Pressure Target in Patients with Septic Shock Pierre Asfar, M.D., Ph.D., Ferhat Meziani, M.D., Ph.D., Jean-François Hamel, M.D., Fabien Grelon, M.D., Percent of Patients 60 50 40 30 20 10 Creatinine Doubling Low MAP High Map * Percent of Patients 60 50 40 30 20 10 Renal Replacement Therapy Low MAP High Map * 0 No HTN Chronic HTN 0 No HTN Chronic HTN Vasopressors A Brief Summary Norepinephrine is your go-to vasopressor Induces robust vasoconstriction Has modest inotropic, mild chronotropic effects Vasopressin is ok to add at fixed dose (.04U / min) No mortality benefit above norepinephrine alone

Vasopressors A Brief Summary Norepinephrine is your go-to vasopressor Induces robust vasoconstriction Has modest inotropic, mild chronotropic effects Vasopressin is ok to add at fixed dose (.04U / min) No mortality benefit above norepinephrine alone Dopamine causes tachycardia, tachyarrhythmias Avoid unless the patient is bradycardic Dobutamine can be added for patients with systolic dysfunction Causes vasodilation, reflex tachycardia Peripheral IV versus CVC Ricard. Critical Care Medicine. 41(9):2108-2115, 2013. Infiltration of Pressor Agents Treatment 1. If the pt is relying on the agent for hemodynamics, switch the pressor to another IV or place an immediate IO or central line. 2. Do not pull the cannula yet! 3. Withdraw as much fluid from the cannula as you can 4. Administer subcutaneous phentolamine mesylate using 25 G or smaller needle Inject 0.1 to 0.2 mg/kg (up to a maximum of 10 mg) through the catheter and subcutaneously around the site. Comes in 5 mg per 1 ml vials. Place in 9 ml of NS Administer as soon as the extravasation is detected, even if the area initially looks just a little white or OK. Should see near immediate effects; otherwise consider additional dose May cause systemic hypotension 5. Now pull the catheter! 6. Consult Plastics

A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes, CHF and hypertension (usual BP is 150/100). She has pneumonia and septic shock. You ve given 3L of saline and the patient s BP is still low (86/40). Her oxygenation has worsened. Its time to start pressors. What s the next best step? A. Start norepinephrine to achieve MAP of 80 B. Start norepinephrine + vasopressin to achieve MAP > 65 C. Start dopamine D. Both A and B are correct A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes, CHF and hypertension (usual BP is 150/100). She has pneumonia and septic shock. You ve given 3L of saline and the patient s BP is still low (86/40). Her oxygenation has worsened. Its time to start pressors. What s the next best step? A. Start norepinephrine to achieve MAP of 80 B. Start norepinephrine + vasopressin to achieve MAP > 65 C. Start dopamine D. Both A and B are correct A 62 year-old female presents to the ED with fever, cough, dyspnea. She has a history of diabetes, CHF and hypertension (usual BP is 150/100). She has pneumonia and septic shock. You ve given 3L of saline and the patient s BP is still low (86/40). Her oxygenation has worsened. Its time to start pressors. What s the next best step? A. Start norepinephrine to achieve MAP of 80 B. Start norepinephrine + vasopressin to achieve MAP > 65 C. Start dopamine D. Both A and B are correct OK to use peripheral IV? Yes

Questions? CMS - Septic Shock Bundle 0 3 hr 6 hr A. measure lactate level B. obtain blood cultures prior to C. administer broad spectrum CVP ScVO2 Echo Dynamic assessment D. administer 30 ml/kg crystalloid E. apply vasopressors for hypotension that does not respond to initial fluid resuscitation (MAP 65) F. re-assess volume status and tissue perfusion and document findings.* G. Re-measure lactate if initial level was elevated Physical exam Fluid Administration Summary and Additional Notes Starch is bad leads to renal failure and increased mortality Albumin appears to be safe but no benefit over crystalloid (ALBIOS and SAFE studies) Don t use blood to volume expand Crystalloids are best studied Give a minimum of 30 cc/kg in first 6 hrs (CMS guidelines) Most patients needed at least 4L in multicenter trials Use your clinical skills to determine the optimum amount LR may be better than saline (ph 3-6, chloride 150) Physiologic electrolyte fluids are being studied