Update in Sepsis

David Wyler, DOJanuary 16, 2014

Patient #1

58 year old diabetic male presents with AMS and decreased urine output About 2-3 weeks of increasing flank painInitial heart rate in the 120s. Respiratory rate in the mid 20s. Temperature of 39.0CBP 70s/40s. Lactate 4.5Subsequent imaging demonstrated renal calculi with obstruction and severe pyelonephritis

Epidemiology1979 estimated 164,000 cases per year1

1. “The epidemiology of sepsis in the United States from 1979 through 2000.” Martin GS, Mannino DM, Eaton S, Moss M. N Engl J Med. 2003;348(16):1546.Fig 1. “Septicemia in U.S. Hospitals, 2009.” Anne Elixhauser, Ph.D., Bernard Friedman, Ph.D., Elizabeth Stranges, M.S. October 2011. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb122.pdf. Downloaded 12/2014.

The increased rate of sepsis is thought to be a consequence of: Advancing age Immunosuppression Multidrug-resistant infection Awareness, screening, reimbursement, coding?

3. “Extending international sepsis epidemiology: the impact of organ dysfunction.” Esper AM, Martin GS Crit Care. 2009;13(1):120.

Baby Boomers age 50-68 in 2014

“Inpatient Care for Septicemia or Sepsis: A Challenge for Patients and Hospitals.” Margaret Jean Hall, Ph.D.; Sonja N. Williams, M.P.H.; Carol J. DeFrances, Ph.D.; and Aleksandr Golosinskiy, M.S. NCHS Data Brief. Number 62, June 2011.

CDC lists septicemia as the 11th leading cause of death.

Only 2% of hospitalizations in 2008 were for septicemia or sepsis, yet they made up 17% of in-hospital deaths.

5. “Deaths: Preliminary Data for 2010.” National Vital Statistics Reports. Volume 60, Number 4. January 11, 2012. http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf. Downloaded 12/2014.

Most expensive condition treated in U.S. hospitals.

More than $20 billion in 2011.6

Congestive heart failure. 5.1 million people with $32 billion per year, including inpatient/outpatient and loss of work and productivity.7

6. “Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project Statistical Brief No. 160 August 2013. National inpatient hospital costs: the most expensive conditions by payer, 2011.” http://www.hcup-us.ahrq.gov/reports/statbriefs/sb160.pdf. Downloaded 12/2014.7. “Centers for Disease Control and Prevention. Heart Failure Fact Sheet.”http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/docs/fs_heart_failure.pdf. Downloaded 12/2014.

Date of download: 12/27/2014Copyright © 2014 American Medical Association.

All rights reserved.

From: Mortality Related to Severe Sepsis and Septic Shock Among Critically Ill Patients in Australia and New Zealand, 2000-2012

JAMA. 2014;311(13):1308-1316. doi:10.1001/jama.2014.2637

Mean Annual Mortality in Patients With Severe SepsisError bars indicate 95% CI.

Figure Legend:

St Luke’s Treasure Valley

N=144

St Luke’s Treasure Valley

2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference

Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock

Emanuel Rivers, M.D., et al. N Engl J Med 2001 2001 Surviving Sepsis Campaign. Phase I.

Rivers, 2001 NEJM

9. “Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock.” Emanuel Rivers, M.D., M.P.H., et. Al. N Engl J Med 2001; 345:1368-1377November 8, 2001DOI: 10.1056/NEJMoa010307.

2004-2008,Grade B to C

Surviving Sepsis Guidelines

10. “Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock.” Dellinger RP, et al. Crit Care Med. 2004 Mar;32(3):858-73.11. “Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008.” R. Phillip Dellinger, et al. Intensive Care Med. Jan 2008; 34(1): 17–60.

12. “Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.” Dellinger RP . Crit Care Med. 2013 Feb;41(2):580-637.

Critiques of Rivers study

Higher than typical death rate in standard care group

25 patients excluded after randomization Possible conflict of interest with links to

industry Does not indicate what parts of bundle are

beneficial

13. “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.” Bone RC . Chest. 1992 Jun;101(6):1644-55.

Septic shock — Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation.

Questioning parametersCentral Venous Pressure

Survey of Canadian intensivists in 2007 showed 90% used CVP to guide fluid

Merick et al. in 2008 and in 2013 published meta-analysis.

14. “A survey of Canadian intensivists’ resuscitation practices in early septic shock.” McIntyre LA, Hebert PC, Fergusson D, Cook DJ, Aziz A: Crit Care 2007, 11:R74.

15. “Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares.” Marik PE, Baram M, Vahid B. Chest. 2008 Jul;134(1):172-8. doi: 10.1378/chest.07-2331.

Area under the receiver operating characteristic curve (AUC)

between the central venous pressure and change cardiac performance

following an intervention that altered cardiac preload. From 191 articles screened, 43 studies met inclusion criteria

and were included for data extraction.

Healthy controls (n = 1) and ICU (n = 22) and operating room (n = 20)

The summary AUC was 0.56 (95% CI, 0.54–0.58)

16. “Hemodynamic parameters to guide fluid therapy.” Marik et al. Annals of Intensive Care 2011, 1:1.

Fluid Responsiveness

16. “Hemodynamic parameters to guide fluid therapy.” Marik et al. Annals of Intensive Care 2011, 1:1

ScVO2%?

17. “High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality.” Textoris et al. Critical Care 2011, 15:R176.

Lactate v ScVO2%

Date of download: 12/27/2014Copyright © 2014 American Medical Association.

All rights reserved.

From: Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy:  A Randomized Clinical Trial

JAMA. 2010;303(8):739-746. doi:10.1001/jama.2010.158

Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.

Date of download: 12/27/2014Copyright © 2014 American Medical Association.

All rights reserved.

From: Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy:  A Randomized Clinical Trial

JAMA. 2010;303(8):739-746. doi:10.1001/jama.2010.158

Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.

Lower versus Higher Hemoglobin Threshold for

Transfusion in Septic Shock

19. Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock. Lars B. Holst, M.D, et al. N Engl J Med 2014; 371:1381-1391October 9, 2014.

Primary and Secondary Outcome MeasuresOutcome Lower

Hemoglobin Threshold

Higher Hemoglobin Threshold

Relative Risk (95% CI)

P Value

Primary outcome: death by day 90 – no./total no/ (%) 216/502 (43.0) 223/496 (45.0) 0.94 (0.78-1.09) 0.44

Second outcomes        

Use of life support- no./total no/ (%)        

At day 5 278/432 (64.4) 267/429 (62.2) 1.04 (0.93-1.14) 0.47

At day 14 140/380 (36.8) 135/367 (36.8) 0.99 (0.81-1.19) 0.95

At day 28 53/330 (16.1) 64/322 (19.9) 0.77 (0.54-1.09) 0.14

Ischemic event in the ICU – no./total no. (%) 35/488 (7.2) 39/489 (8.0) 0.90 (0.58-1.39) 0.64

Severe adverse reaction – no./total no. (%) 0/488 1/489 (0.2) - 1.00

Alive without vasopressor or inotropic therapy – mean % of days

73 75 - 0.93

Alive and out of the hospital – mean % of days 30 31 - 0.89

Choice of Fluids

20. “Albumin versus Other Fluids for Fluid Resuscitation in Patients with Sepsis: A Meta-Analysis.” Jiang L . PLoS One. 2014 Dec 4;9(12):e114666.

Chloride

760 patients admitted consecutively to the intensive care unit (ICU) during the control period (February 18 to August 17, 2008)

Compared with 773 patients admitted consecutively during the intervention period (February 18 to August 17, 2009)

Single center University-affiliated hospital in Melbourne, Australia

21. Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults. JAMA. 2012;308(15):1566-1572. doi:10.1001/jama.2012.13356

Date of download: 12/27/2014Copyright © 2014 American Medical Association.

All rights reserved.

Stage 2 or 3 defined according to the Kidney Disease: Improving Global Outcomes clinical practice guideline.

Figure Legend:

From: Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults

JAMA. 2012;308(15):1566-1572. doi:10.1001/jama.2012.13356

Rivers, 2001 NEJM

x

x xx

Do we continue with EGDT?

Do we continue with EGDT?

ARISE

ProCESS

PROMISE (ongoing)

ARISE trial

Goal-Directed Resuscitation for Patients with Early Septic Shock

51 center Australia/New Zealand

1600 enrolled patients assigned to EGDT or “usual-care.”

22. “Goal-Directed Resuscitation for Patients with Early Septic Shock.” The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014;371:1496-506.

ProCESS trial

A Randomized Trial of Protocol-Based Care for Early Septic Shock

31 tertiary US emergency departments

1341 enrolled patients assigned to EGDT, protocol based standard therapy, or “usual-care.”

23. “A Randomized Trial of Protocol-Based Care for Early Septic Shock.” The ProCESS Investigators. N Engl J Med. 2014;370:1683-93.

Back to the 90s?

Something is working

Surviving Sepsis Campaign Response

(CVP) and central venous oxygen saturation (ScvO2) via a central venous catheter as part of an early resuscitation strategy does not confer survival benefit.

Requiring measurement of CVP and ScvO2 in all patients who have lactate results >4 mmol/L and/or persistent hypotension after initial fluid challenge and who have received timely antibiotics is not supported by the available scientific evidence.

The results of the ProCESS and ARISE trials have not demonstrated any adverse outcomes in the groups that utilized CVP and ScvO2 as end points for resuscitation. Therefore, no harm exists in keeping the current SSC bundles intact until a thorough appraisal of all available data has been performed.

In light of the evidence from the ProCESS and ARISE trials, the SSC guidelines committee will immediately review the evidence and assess whether the guidelines need to be updated now.

Surviving Sepsis compliance mortality association

PURPOSE: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality.

DESIGN: 29,470 subjects entered into the SSC database from January 1, 2005, through June 30, 2012. Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe.

Mortality rate decreased 4% (95% CI: 1% - 7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle.

24. “Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study.” Levy MM . Crit Care Med. 2015 Jan;43(1):3-12.

What has lead to improved mortality?

Recognition as medical emergency– Surviving sepsis campaign– Screening protocols

Early antibiotics

Training

Tracking and reporting quality

Treatment

Screening/early recognition

Broad spectrum antibiotic based on suspected source and local antibiogram

Initial fluid administration 30ml/kg

Lactate

Cultures

Vasopressors – adequate perfusion pressure

Assess fluid responsiveness and response to treatment

References1. “The epidemiology of sepsis in the United States from 1979 through 2000.” Martin GS, Mannino DM, Eaton S, Moss M. N Engl J Med. 2003;348(16):1546.2. Fig 1. “Septicemia in U.S. Hospitals, 2009.” Anne Elixhauser, Ph.D., Bernard Friedman, Ph.D., Elizabeth Stranges, M.S. October 2011. http://www.hcup- us.ahrq.gov/reports/statbriefs/sb122.pdf. Downloaded 12/2014.3. “Extending international sepsis epidemiology: the impact of organ dysfunction .” Esper AM, Martin GS Crit Care. 2009;13(1):120.4. Fig. 2. “Inpatient Care for Septicemia or Sepsis: A Challenge for Patients and Hospitals.” Margaret Jean Hall, Ph.D.; Sonja N. Williams, M.P.H.; Carol J. DeFrances, Ph.D.; and Aleksandr Golosinskiy, M.S. NCHS Data Brief. Number 62, June 2011.5. “Deaths: Preliminary Data for 2010.” National Vital Statistics Reports. Volume 60, Number 4. January 11, 2012. http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf. Downloaded 12/2014.6. “Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project Statistical Brief No. 160 August 2013. National inpatient hospital costs: the most expensive conditions by payer, 2011.” http://www.hcup-us.ahrq.gov/reports/statbriefs/sb160.pdf. Downloaded 12/2014.7. “Centers for Disease Control and Prevention. Heart Failure Fact Sheet.” http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/docs/fs_heart_failure.pdf. Downloaded 12/2014.8. Mortality Related to Severe Sepsis and Septic Shock Among Critically Ill Patients in Australia and New Zealand, 2000-2012.” JAMA. 2014;311(13):1308-1316. 9. “Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock.” Emanuel Rivers, M.D., M.P.H., et. Al. N Engl J Med 2001; 345:1368-1377.10. “Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock.” Dellinger RP, et al. Crit Care Med. 2004 Mar;32(3):858-73.11. “Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008.” R. Phillip Dellinger, et al. Intensive Care Med. Jan 2008; 34(1): 17–60.12. “Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.” Dellinger RP . Crit Care Med. 2013 Feb;41(2):580-637.13. “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.” Bone RC . Chest. 1992 Jun;101(6):1644-55.14. “A survey of Canadian intensivists’ resuscitation practices in early septic shock.” McIntyre LA, Hebert PC, Fergusson D, Cook DJ, Aziz A: Crit Care 2007, 11:R74.15. “Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares.” Marik PE, Baram M, Vahid B. Chest. 2008 Jul;134(1):172-8.16. “Hemodynamic parameters to guide fluid therapy.” Marik et al. Annals of Intensive Care 2011, 1:1.17. “High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality.” Textoris et al. Critical Care 2011, 15:R176.18. “Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy:  A Randomized Clinical Trial.” JAMA. 2010;303(8):739-746. 19. “Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock.” Lars B. Holst, M.D, et al. N Engl J Med 2014; 371:1381-1391October 9, 2014.20. “Albumin versus Other Fluids for Fluid Resuscitation in Patients with Sepsis: A Meta-Analysis.” Jiang L . PLoS One. 2014 Dec 4;9(12):e114666.21. “Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults.” JAMA. 2012;308(15):1566- 1572. 22. “Goal-Directed Resuscitation for Patients with Early Septic Shock.” The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014;371:1496-506. 23. “A Randomized Trial of Protocol-Based Care for Early Septic Shock.” The ProCESS Investigators. N Engl J Med. 2014;370:1683-93. 24. “Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study.” Levy MM . Crit Care Med. 2015 Jan;43(1):3-12.