GUIDELINES AND APPLICATION TO SEPSIS MANAGEMENT

MICHAEL H. HOOPER, MD, MSc

Assistant Professor of Medicine Eastern Virginia medical School

Disclosures
I have received an honorarium from Biomerieux for consultation on the use of procalcitonin in the management of sepsis.

Goals
Sepsis Overview and Guidelines The Importance of a System-based Approach The Experience of Other Institutions The Acute and Chronic Phases of Sepsis Care

Terminology
Systemic Inflammatory Response Syndrome (SIRS)
Temp > 38 or < 36 HR > 90 RR > 20 or PaCO2 < 32 WBC > 12 or < 4 or Bands > 10%
TWO out of four criteria acute change from baseline

Sepsis
The systemic inflammatory response to infection.

Severe Sepsis
Organ dysfunction secondary to Sepsis. e.g. hypoperfusion, hypotension, acute lung injury, encephalopathy, acute kidney injury, coagulopathy.

Septic Shock
Hypotension secondary to Sepsis that is resistant to adequate fluid administration and associated with hypoperfusion.

Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6), 16441655.

Infection, SiRS, Sepsis

Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6), 16441655.

Sepsis Pathogenesis
Unbalanced Immune Reaction
Mediators of Inflammation

Tissue Factor

Procoagulant State

ROS
Microvascular Thrombosis Vasodilation

Capillary Leak

Organ failure in sepsis

P/F Platelets Bili BP GCS Cr/UOP

Vincent, J.-L., Sakr, Y., Sprung, C. L., Ranieri, V. M., Reinhart, K., Gerlach, H., Moreno, R., et al. (2006). Sepsis in European intensive care units: results of the SOAP study. Critical Care Medicine, 34(2), 344353.

Epidemiology
Incidence of Sepsis
[1993-2001]...a 75% increase in... severe sepsis...

Mortality of Sepsis

[1993 - 2001]...a 17% reduction in mortality.

Martin, G. S., Mannino, D. M., Eaton, S., & Moss, M. (2003). The epidemiology of sepsis in the United States from 1979 through 2000. New England Journal of Medicine, 348(16), 15461554.

Brun-Buisson, C., Meshaka, P., Pinton, P., Vallet, B., EPISEPSIS Study Group. (2004). EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Medicine, 30(4), 580588.

Harrison, D. A., Welch, C. A., & Eddleston, J. M. (2006). The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Critical Care, 10(2), R42.

Evolution of Sepsis care

Established Core Rx: Source Control Antibiotics Resuscitation Supportive Care Established Core Rx: Source Control More Antibiotics Faster Resuscitation Better Supportive Care
In general the process of care has improved

Steroids

No Steroids

Endotoxin Antagonists Xigris LPS/LPS receptor antagonist Tight Immunonutrition Glycemic Steroids Control anti-TNF NSAIDs Nitric Oxide Synthase Inhibitors Tissue Factor Pathway Inhibitors anti-TLR4

Loose Immunonutrition? ?Not Glycemic NoSteroids Xigris Control ?

62yo male smoker with diabetes, HTN. Has onset of shaking chills, followed by a subjective fever. Later presents with dyspnea, fever to 102.7. BP of 80/40 with a HR of 125. CXR c/w RUL consolidation.

Guidelines for sepsis

Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Critical Care Medicine 2013;41(2):580637.

48 pages with NO magic bullets Very few specific therapies directed at the early stages of sepsis pathophysiology Numerous important recommendations (and numerous controversial ones) Requires repetitive, complex assessments Many interventions are time-sensitive

How do you Quickly deliver complex care? Mobilization and coordination of people and resources.

System-based Approaches to sepsis

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 13681377.

System-based Approaches to sepsis

Early-Goal Directed Therapy
INCLUSION = SEPSIS AND [BP < 90 after fluid OR Lactate > 4]

Control
CVP 8-12

Intervention
Fluids

EGDT
CVP 8-12

MAP > 65

Vasopressors

MAP > 65

Transfusions Dobutamine

ScvO2 > 70%

49% mortality

33% mortality

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 13681377.

System-based Approaches to sepsis

Used to promote: 1. CVP > 8 as an initial target 2. Use of Svo2 monitoring and use of blood/dobutamine

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 13681377.

System-based Approaches to sepsis

Control
49% mortality

EGDT
33% mortality

...treated at the clinicians discretion according to a protocol for Do whatever you hemodynamic support, with criticalcare consultation, normally do.and were admitted for inpatient care as soon as possible...

...treated in the emergency Use a rigid protocol department (by ER attending, 2with residents, 3 nurses) according to a multiple dedicated team protocol for early goal-directed members therapy...for at least six hours...

They did not control for the system of care.

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 13681377.

A Multidisciplinary Community Hospital Program for Early and Rapid Resuscitation of Shock in Nontrauma Patients

BEFORE (control)

AFTER (protocol)

Do what you normally do. We will be watching.

Screening Protocol, Educational Initiative, Shock Team, Treatment Protocols.

Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest, 127(5), 17291743.

A Multidisciplinary Community Hospital Program for Early and Rapid Resuscitation of Shock in Nontrauma Patients

Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest, 127(5), 17291743.

A Multidisciplinary Community Hospital Program for Early and Rapid Resuscitation of Shock in Nontrauma Patients

Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest, 127(5), 17291743.

A Multidisciplinary Community Hospital Program for Early and Rapid Resuscitation of Shock in Nontrauma Patients

Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest, 127(5), 17291743.

Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis

BEFORE

AFTER

Do whatever it is that you normally do. We will be watching.

All physicians, nurses, and patient care technicians in the emergency department and intensive care units received formal order set clinical education. Additionally, all hospital floor clinical nurse specialists and advance practice nurses, along with the house staff physicians in these areas, were in-serviced on the order sets....These educational endeavors included training in sepsis pathophysiology, monitoring of central venous pressures, assessment of central venous blood oxygen saturation, and the pharmacotherapy of sepsis

1. EDUCATION 2. ORDER SET with recommendations and

goals for sepsis treatment.

Thiel, S. W., Asghar, M. F., Micek, S. T., Reichley, R. M., Doherty, J. A., & Kollef, M. H. (2009). Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis*. Critical Care Medicine, 37(3), 819824. doi:10.1097/CCM.0b013e318196206b

Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis

After

Before

Thiel, S. W., Asghar, M. F., Micek, S. T., Reichley, R. M., Doherty, J. A., & Kollef, M. H. (2009). Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis*. Critical Care Medicine, 37(3), 819824. doi:10.1097/CCM.0b013e318196206b

Summary of Trials
Rivers 2001 RCT Sebat 2005 Before-After Nguyen 2007 Complete or Not Thiel 2009 Before-After Levy 2011 Before-After

Goals

CVP >8 MAP > 65 ScVO2 >70% HCT >30

MAP > 70 SaO2 > 92 UOP > 30ml/h SvO2 > 60 CI > 2.5

ABX in 4 h Early ABX, Blood CVP > 8, MAP > Appropriate ABX Cultures, 65, ScVO2 > in 4 h, CVP > 8, Appropriate 70%, HCT > 30 MAP > 65, ABX, CVP > 8, Check Lactate ScVO2 > 70% MAP > 65, Steroids SvO2 > 70%
ABX, Fluids, Pressors, Steroids, Xigris, Other Supportive Care ABX, Fluids, Pressors, Steroids, Xigris, Other Supportive Care

Specific Interventions

Fluids, Blood, Pressors

ABX, Fluids Pressors Screening, Education, Shock Team, Protocols

ABX, Fluids, Blood, Pressors

System Interventions
Absolute Change in Mortality

ED-based Sepsis Team

Education, Inservices, Protocols

Education, InScreening, services, Order Education, Order Set, Protocols Sets

-16%

-12%

-19%

-16%

-7%

Does Everyone Know what to do?

62yo male smoker with diabetes, HTN. Has onset of shaking chills, followed by a subjective fever. Later presents with dyspnea, fever to 102.7. BP of 80/40 with a HR of 125. CXR c/w RUL consolidation.

Acute Phase
Identify Sepsis as early as possible Broad Spectrum antibiotics ASAP and Identify source(s) of infection Identify severity: Vitals, mental status, UOP, LACTATE, other labs.

Volume and physiologic resuscitation ASAP with GOALS.

Tweak your system so these things happen FAST

Sepsis Identification
Train all providers Vital sign/Laboratory alerting systems ?Biomarkers

Antibiotics
No randomized-controlled data
Time from EDGT qualification to ABX Time from hypotension to appropriate ABX

Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department*. Critical Care Medicine 2010;38(4):104553.

Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*. Critical Care Medicine 2006;34(6):158996.

Antibiotics
Multiple large, observational studies have shown the time to administration of antibiotics to be strongly associated with improve survival. Im not aware of a single physician that recommends withholding or slowing down the time to antibiotics in a patient with severe sepsis. Our time to needle or door to balloon metric.

Source Control
No randomized-controlled data
In necrotizing fasciitis, multiple case series have shown improvement with an aggressive operative approach.
Sudarsky LA, Laschinger JC, Coppa GF, Spencer FC. Improved results from a standardized approach in treating patients with necrotizing fasciitis. Ann Surg 1987;206(5):6615. Moss RL, Musemeche CA, Kosloske AM. Necrotizing fasciitis in children: Prompt recognition and aggressive therapy improve survival. J Pediatr Surg 1996;31:1142-6. Freischlag JA, Ajalat G, Busuttil RW: Treatment of necrotizing soft tissue infections: The need for a new approach. Am J Surg 149:751-755, 1985

Expert opinion supports identifying the source of infection and aggressively managing it when possible.
Marshall JC, Maier RV, Jimenez M, et al. Source control in the management of severe sepsis and septic shock: an evidence-based review. Crit Care Med 2004;32:S513-26

Source Control
Dont be satisfied with a diagnosis of sepsis and no source. If a source exists and is potentially removable, get the ball rolling.

Defining the severity of sepsis

Importance of looking for organ failure is self evident. Identification of shock dramatically alters the treatment and mortality.
Blood Pressure, Response to Fluid, LACTATE

Lactate
Evidence is clear that Lactate levels are predictive of death and MODS

Clearance of lactate is associated with improved survival

Algorithms of care based on lactate clearance appear to work as well or better than other approaches.

Jones AE, Shapiro NI, Trzeciak S, et al. Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy: A Randomized Clinical Trial. JAMA: The Journal of the American Medical Association 2010;303(8):739 46. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, openlabel, randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2010;182(6):75261.

Goals in resuscitation
Early, quantitative resuscitation goals vs. standard care have resulted in improved mortality

The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis *. Jones, Alan E. MD; Brown, Michael D. MD, MSc; Trzeciak, Stephen MD, MPH; Shapiro, Nathan I. MD, MPH; Garrett, John S. MD; Heffner, Alan C. MD; Kline, Jeffrey A. MD; on behalf of the Emergency Medicine Shock Research Network investigators Critical Care Medicine. 36(10):2734-2739, October 2008.

Goals in resuscitation
Initial fluid resuscitation: CVP 8-12, MAP > 65, UOP 0.5 mL/kg/hr, ScVO2 70% and Lactate Clearance.

Give enough volume to maximize stroke volume. Start with 20cc/kg in most patients. Goal? Give vasopressors to raise the MAP enough to maintain adequate end-organ perfusion. Assessment of Cardiac Function UOP and Lactate Clearance are nice global indicators of success.

CO

Resuscitation
Crystalloids are favored as the initial fluid Hydroxyethyl starches are likely harmful Albumin may have a role, particularly if alot of fluid is given A lower Hb target (~7) is generally accepted

Chronic Phase

Monitor for and prevent recurrence of sepsis VAP, CLABSI, UTI. Infection Control Practices. Lung Protective Ventilator Strategies Protocolized Sedation, Daily Awakenings Nutritional Support Early Mobilization Success with these measures is most likely with a multidisciplinary approach.

Summary

System-based strategies are effective for improving sepsis care Processes should aim to: Identify patients early and identify the severity of sepsis Quickly administer appropriate antibiotics and source control Establish institutional goals for physiologic resuscitation Multidisciplinary chronic phase of care to ensure compliance

Questions??

Michael Hooper, MD, MSc hoopermh@evms.edu 615-414-6866