Sepsis Care in 2015
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This talk is a summary of 4 Objectives: 1. What is the ideal MAP in Sepsis (65 vs 85 mmHg) 2. What is the ideal Hb Transfusion Threshold (7 vs 9 g/dL) 3. SIRS Criteria for Screening of Severe Sepsis 4. Summary and Take Home Messages from the ProCESS, ARISE, & ProMISe Trials
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Sepsis Care in 2015
- 1. Sepsis Care in 2015 Salim R. Rezaie, MD UTHSCSA, San Antonio, TX
- 6. Surviving Sepsis Campaign MAP ≥65 mmHg Level 1C Rec
- 7. LeDoux D et al. Crit Care Med 2000 Bourgoin A et al. Crit Care Med 2005 10 Patients 28 Patients MAP 65mmHg 75mmHg 85mmHg Lactate Renal Fxn UOP
- 8. Dunser MW et al. Crit Care Med 2009 274 Patients MAP <75mmHg Increased Renal Replacement Therapy MAP <60mmHg Increased Mortality 3x
- 9. Does a Higher MAP Decrease Renal Failure in Sepsis?
- 10. 29 Centers in France with 776 Patients
- 11. Low Target Group MAP 65 – 70 mmHg High Target Group MAP 80 – 85 mmHg
- 12. Difference NO Difference 28 or 90 Day Mortality 28 Day Survival w/o Organ Support More Atrial Fibrillation Longer Pressor Duration & Dose
- 13. 3L IVF in 24h then Pressors Mortality = 34 – 36.6%
- 14. Don’t Chase MAP ≥65mmHg Bottom Line Give Fluids Early
- 16. Surviving Sepsis Campaign Maintain Hct ≥30% Hb ≤7g/dL Level 1B Rec
- 17. Liberal Transfusion Harms Hebert PC et al. NEJM 1999 838 Patients
- 18. Liberal Transfusion Benefits Vincent JL et al. Anesthesiology 2008 1,040 Patients Park DW et al. Crit Care Med 2012 407 Patients
- 19. Does a Liberal Transfusion Strategy Improve Mortality in Sepsis?
- 20. 32 Centers in Europe with 998 Patients
- 23. 50% Less Transfusions 36% No Transfusions No 90 Day Mortality Difference
- 25. Chatterjee S et al. JAMA Intern Med 2013 + Increased All-Cause Mortality 18.2% vs 10.2%
- 28. Severe Sepsis Infection Organ Dysfunction >2 SIRS Criteria 1992
- 29. How Good is SIRS at Screening for Severe Sepsis?
- 30. 172 ICUs in Australia & New Zealand With 109,663 Patients
- 31. SIRS + SIRS - 87.9% 12.1% Will Miss 1 in 8 Severe Sepsis
- 32. SIRS Criteria Screening 13% Incremental Increase
- 33. Bottom Line ≥2 SIRS Criteria Lacks Sensitivity & Specificity for Sepsis
- 35. ProCESS ARISE ProMISe Country Patients Primary Outcome 1351 12601600 60d Mortality 90d Mortality 90d Mortality
- 36. Before Randomization… A B C Then Followed for 1st 6 Hours
- 38. Trust the ProCESS 21% 18.2% 18.9%
- 39. EGDT Usual IVF Pressors CVC PRBC 4.9L 3.5L 27.4% 30.3% Mandatory Mandatory 64.1% 18.5% Rivers Study 1999
- 40. ProCESS EGDT Protocol Usual IVF Pressors CVC PRBC 5.0L 5.5L 4.4L 54% 52% 44% 93% 56% 57% 14.4% 8.3% 7.5%
- 42. Feasibility in the Community Mostly University EDs
- 43. The ARISE Trial
- 45. EGDT Pragmatic IVF Pressors CVC PRBC 1.96L 1.71L 66.6% 57.8% 90% 61.9% 13.6% 7.0% ARISE A-Lines 91% 76%
- 46. Community/Rural
- 47. Intravenous Fluids 3 – 4.5 L in 1st 6 Hours
- 48. 2001 Rivers Study Mortality 47 31% (NNT = 6) Sepsis Trilogy Mortality 18.2 – 29.5%
- 51. EGDT Usual IVF Pressors CVC PRBC 2.23L 2.02L 53.3% 46.6% 92.1% 50.9% 8.8% 3.8% ProMISE A-Lines 74.2% 62.2%
- 52. Nail in the Coffin for EGDT?
- 53. >10 Years Later…
- 55. EGDT Usual Care The Gap Sepsis Care 2015
- 56. CVP ScvO2
- 57. Surviving Sepsis Campaign Updates 6 Hour Bundle
- 58. Surviving Sepsis Campaign 1. Check Lactic Acid 2. Send Blood Cultures 3. Give Antibiotics 4. 30mL/kg IVF (if low BP/High Lactate) Within 3 Hours…..
- 59. Surviving Sepsis Campaign 1. Vasopressors if MAP <65mmHg 2. Re-assess Volume Status & Tissue Perfusion 3. Re-Check Lactic Acid (Unless Initially Normal) Within 6 Hours….. CVP ScvO2 Cardiac US Passive Leg Raise
- 61. MAP ≥65 mmHg Give Fluids Early Restrictive Transfusion Hb ≤7g/dL SIRS Criteria Poor Sensitivity And Finally… Miss 1 in 8
Editor's Notes
- BP Threshold in Sepsis – MAP 65 vs 85mmHg Hb Transfusion Targets – 7 vs 9 g/dL SIRS for Screening of Sepsis Sepsis Trilogy (ProCESS, ARISE, & PROMISE)
- The Rivers Protocol: If CVP < 8 mmHg then IVF until CVP >8 mmHg If MAP <65 mmHg then start pressors until MAP ≥ 65 mmHg (i.e. worried about too much IVF) If ScvO2 <70% then start PRBC transfusion until HCT ≥ 30%
- Surviving Sepsis Campaign Recommends a MAP ≥ 65 mmHg in patients with septic shock Grade 1c Recommendation = Strong Recommendation, but founded on weak evidence Higher MAP may be beneficial
- Ledoux D et al: 10 patients with septic shock Increased pressors to MAP of 65, 75, and 85 mmHg Increasing the MAP from 65 mm Hg to 85 mm Hg with norepinephrine increased CO, but no diff in lactate or UOP Bourgoin A et al: 28 patients with septic shock Increased pressors to MAP of 65 to 85 mmHg Increased CO, but no difference renal function or UOP Increasing MAP had no effect on Lactate Clearance, Renal Fxn, or UOP
- Dunser et al Retrospective cohort study 274 septic patients One or more episodes of MAP <60 mmHg = increased risk of death by 2.96 One or more episodes of MAP < 75mmHg = increased need for renal replacement therapy
- SEPSISPAM Trial was published along side ProCESS trial April 2014 Multicenter, open label trial of 776 patients with septic shock from 29 hospitals in France Septic Shock = Sepsis with Refractory Hypotension after 30cc/kg bolus of IVF Primary Outcome: 28 day mortality Also looked to see if higher MAP beneficial in patients with chronic HTN
- No Difference in: High MAP vs Low MAP 28 Day Mortality: 36.6% vs 34.0% (p=0.57) 90 Day Mortality: 43.8% vs 42.3% (p=0.74) Survival w/o Need for Organ Support: 60.6% vs 62.1% (p = 0.66) Subgroup Analysis did show that patients with chronic HTN did have more doubling of Cr & Renal Replacement therapy in 1st week of care, but no difference at 28 days Difference in: High MAP vs Low MAP Rate of Afib: 6.7% vs 2.8% (p=0.02) Vasopressor Duration and Dose: Higher in High MAP Group (Levophed 0.40 ug/kg/min vs 0.35 ug/kg/min) and(4.7 days vs 3.7 days)
- Patients enrolled in SEPSISPAM Trial and ProCESS Trial fairly similar with similar pre-enrollment fluid administration and patients in ProCESS a bit sicker (i.e. Lower MAP, Higher Initial Lactate Levels) In the SEPSISPAM Trial patients were resuscitated with 3L IVF in the 1st 24 hours then started on pressors 28 Day Mortality 34.0 & 36.6% In the ProCESS Trial patients were resuscitated with 5L IVF in the 1st 6 hours Only half received pressors 60 Day Mortality 21.0%, 18.2%, and 18.9% Not definitive, but does tell me, we shouldn’t fear giving fluids early to patients in septic shock, we should push the fluids and not worry about the MAP as much
- Chasing CVPs and MAPs makes physicians feel better, but early IVF improves patient mortality
- The Rivers Protocol: If CVP < 8 mmHg then IVF until CVP >8 mmHg If MAP <65 mmHg then start pressors until MAP ≥ 65 mmHg (i.e. worried about too much IVF) If ScvO2 <70% then start PRBC transfusion until HCT ≥ 30%
- Surviving Sepsis Campaign: Transfuse to maintain Hct 30% in presence of hypoperfusion in 1st six hours, then…. Transfusion threshold is Hb ≤7g/dL with goal of maintaining Hb between 7 – 9g/dL Level 1B Rec Strong Recommendation with moderate evidence to support
- Hebert PC et al. NEJM 1999: Restrictive vs Liberal Transfusion strategy in critically ill Mortality rate during hospitalization was lower in restrictive group 22.3% vs liberal group 28.1% (p = 0.05), but 30 day mortality had no difference 18.7% vs 23.3% (p = 0.11)
- Vincent JL et al. Anesthesiology 2008: multicenter, observational study (198 European ICUs) Higher 30 day survival rate in the transfusion group Park DW et al Crit Care Med 2012: multicenter, observational study (22 ICUs in Korea) transfused patients had a lower mortality at…. 7 Days (9.2 vs 27.0%) 28 Days (24.3% vs 38.8%) In-Hospital (31.6% vs 41.8%)
- Transfusion Requirements In Septic Shock (TRISS): Multicenter, parallel group trial of patients in the ICU with septic shock and Hb ≤9g/dL 32 ICUs in denmark, sweden, norway, and finland (998 patients) compared liberal transfusion strategy (Hb ≤9g/dL) vs Restrictive strategy (Hb ≤7g/dL)
- Restrictive vs Liberal Transfusion Strategy: 90D Mortality: 43% vs 45% (p = 0.44) 1545U vs 3088 Units PRBCs Transfused 36.1% vs 1.2% Did not require Transfusion 50% less transfusions, 1/3 didn’t require transfusions No diff in 90D mortality
- Patients with Acute Myocardial Infarction Excluded from Study
- Chatterjee S et al. JAMA Intern Med 2013 Meta-Analysis of Blood transfusion strategy in patients with myocardial infarction Transfusion vs No Transfusion in AMI Increased all-cause mortality with transfusion 18.2% vs 10.2%
- SIRS Temp > 100.4 or < 95.0 RR > 20 or PaCO2 < 32mmHg HR > 90/min WBC >12k or <4k or Band > 10% Sepsis = SIRS + Infection Severe Sepsis = Sepsis + Organ Dysfuncion Septic Shock = Severe Sepsis + Persistent Hypotension after 30cc/kg IVF Resuscitation Infection isn’t the only thing that can cause SIRS (poor specificity, but maybe also poor sensitivity)
- Severe Sepsis = Infection + Organ Dysfunction + 2 or more SIRS criteria This definition was created as a consensus statement from ACCP & SCCM in 1992 (Over 20 years ago)
- Retrospective Analysis of 109,663 patients in the 1st 24 hours in the ICU
- Positive Infection with Organ Dysfunction, then looked to see who had SIRS criteria Majority of Severe Sepsis patients had 2 or more SIRS Criteria But using 2 or more SIRS Criteria alone will miss 1 in 8 patients with Severe Sepsis
- APACHE III Severity of Illness (Pts SIRS+ were sicker) (24 vs 11) More Renal Failure in SIRS+ Severe Sepsis (18.9% vs 11.7%) Higher Mortality in SIRS+ Severe Sepsis (24.5% vs 16.1%)
- SIRS + Severe Sepsis: Mortality 36.1% 18.3% SIRS – Severe Sepsis: Mortality 27.7 8.5% SIRS+ with higher mortality rates, but the two had the exact same rate of decline in Mortality
- Each Additional SIRS Criteria Increased Mortality by 13% in a linear fashion without a transitional increase when 2 criteria were met….there is nothing magical about two SIRS Criteria
- The Big 3 Sepsis Studies: 1. ProCESS May 2014 2. ARISE October 2014 3. ProMISe…March 2015
- In order to be randomized in the studies….3 things had to happen… Septic shock recognized IVF 1 - 2 L before randomization Abx
- 3 arms in the ProCESS Trial No statistical difference in 60 day mortality Protocol Arm: Like EGDT, but A-lines not mandatory, and type of fluid and vasopressor not specified
- Single Center Study - More IVF & PRBC transfusions in 1st 6hrs in EGDT
- IVF in 1st 6 hours similar to Rivers Study Our usual care is a blend of EGDT: Pressors, CVC PRBC: Fewer most likely due to fewer ScvO2 readings
- Take Home Message: No clear superior method in management of septic shock patients, but did make it clear no one resuscitative pathway is bad or better. This gives flexibility in the management.
- Most of the centers in the ProCESS trial were large tertiary centers….maybe usual care not as feasible in smaller centers?
- 2 arms in the ARISE Trial No statistical difference in 90 day mortality EGDT Pragmatic Care: Whatever physicians thought best; Not checking Scv02
- 2.5L of IVF before randomization Similar IVF in 1st 6 hours But again a blend of EGDT in care: Pressors, A-Lines, CVC
- This trial took place in a significant proportion of non-tertiary metropolitan and rural EDs, which allows for more generalizability of results, unlike ProCESS which took place in mostly University, Tertiary Care Hospitals
- In an empiric fluid strategy patients should get 3 – 4.5 L IVF in 1st 6 hours based off ProCESS and ARISE
- We have lower mortality rates now compared to the 2001 Rivers et al study now….why?
- 2 arms in the ProMISe Trial No statistical difference in 90 day mortality
- This study was set in a real-world context with 29% of recruiting hospitals being teaching facilities. 1L in 60 minutes of IVF prior to randomization Looking at the results, a significant portion of “usual” care patients still get arterial catheters (62.2%), CVCs (50.9%), and vasopressors (46.6%).
- Is this the end of EGDT?!?
- First of all we should give credit to Emanual Rivers….He has forever changed who we managed patients with sepsis…..but even after >10years since his landmark trial….none of these other trials proved superiority
- The 2001 Rivers et al study has changed how we manage sepsis (i.e. We are more aggressive in identifying these patients, and our “usual care” has changed to early identification, early IVFs and early antibiotics), which may explain why we have lower mortality rates now compared to the 2001 Rivers et al study
- What this tells me is that our “usual” care has components of the EGDT algorithm engrained in it. Sick patients need fluids, antibiotics, and supportive therapies (i.e. Early critical care and resuscitation), but they don’t need CVP and SCVO2 monitoring to dictate their care .
- Sick patients need fluids, antibiotics, and supportive therapies (i.e. Early critical care and resuscitation), but they don’t need CVP and SCVO2 monitoring to dictate their care
- SSC 6 Hour Bundle Updated April 2015
- SSC 6 Hour Bundle Updated April 2015 Repeat focused exam (after initial fluid resuscitation) by licensed independent practitioner including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings. OR TWO OF THE FOLLOWING: • Measure CVP • Measure ScvO2 • Bedside cardiovascular ultrasound • Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge Of note, the 6-hour bundle has been updated; the 3-hour SSC bundle is not affected.
- SSC 6 Hour Bundle Updated April 2015 Repeat focused exam (after initial fluid resuscitation) by licensed independent practitioner including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings. OR TWO OF THE FOLLOWING: • Measure CVP • Measure ScvO2 • Bedside cardiovascular ultrasound • Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge Of note, the 6-hour bundle has been updated; the 3-hour SSC bundle is not affected.
- Questions
- Simply put, in septic shock, we need to be AGGRESSIVE in our care EARLY. If patients are identified EARLY, given IVF EARLY, and antibiotics EARLY, again the key being EARLY, then the pathway used afterwards (i.e EGDT, Protocolized, or "usual care") is less important in management and resuscitation.