Protocols in sepsis: Do we need them?

Transcription

1 Protocols in sepsis: Do we need them? Loh Tsee Foong Director Children ICU KKH Dy/Director Education Office Paeds ACP A/Professor Duke NUS SoM Lead, Child Protection Team Director PFCCS Singapore

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3 Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria. Angus DC, van der Poll T. N Engl J Med 2013;369:

4 Defining sepsis in children (clinical phenotypes) Systemic inflammatory response syndrome (SIRS) The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count: Core temperature of greater than 38.5 C (101.3 F) or less than 36 C (96.8 F). Tachycardia Mean respiratory rate greater than 2 SD Leukocyte count elevated or depressed Infection A suspected or proven infection caused by any pathogen or a clinical syndrome associated with a high probability of infection. Sepsis SIRS in the presence of or as a result of suspected or proven infection. Severe sepsis Sepsis plus one of the following: cardiovascular organ dysfunction or acute respiratory distress syndrome or two or more other organ dysfunctions. Septic shock Sepsis and cardiovascular organ dysfunction. Goldstein B et al PCCM 6: 2-8

5 EGDT in Sepsis Shock 2/4 SIRS Golden hour of sepsis resuscitation sbp <90 mm or Hg blood lactate >4mmol/l CVP & IA line EGDT vs control SCVO 2 Treated 6hr transfer to ICU Physicians blinded n=268 Rivers E et al. N Engl J Med 2001;345:

6 EGDT in Sepsis Shock goal-directed therapy provided at the earliest stages of severe sepsis and septic shock has significant benefits these benefits maybe due early identification of patients at high risk for cardiovascular collapse early therapeutic intervention to restore a balance between oxy- gen delivery and oxygen demand

7 Sepsis Protocol Bundles Goal directed therapy 6hr CVP, MAP, Urine, SCVO2 Use of controlled fluid resuscitation Vasopressor, inotropy, afterload reduction Antibiotic therapy 1hr & cultures to optimise therapy Attempt to localise and control source Wills BA et al NEJM 353: Maitland K et al CID 40: Steroid replacement Haemoglobin targets Lung protective strategies in ALI/ARDS PEEP Low Vt Head elevation Sedation Anaglesia Stress ulcer, DVT prophylaxis rapc Varpula M et al ICM 31: Reinhart K et al ICM 30: Trezciak S et al Chest 129:

8 Improve Mortality? Early treatment reduces mortality and morbidity Implementation of sepsis program Adherence to guidelines Targeted therapy e.g. vital parameters, SCVO2 Inotrope use & fluid resuscitation Improved survival with OR of 3-6 Data extrapolated into Paeds data last update in 2012 Giradrdis M et al CC 13: R143 Paul R et al Pediatrics 130: e Nhan NT et al CID 32: Han YY et al Pediatrics 112: Booy R et al Arch Dis Child 85: Finfer S et al NEJM 350: Ninis et al BMJ 330: 1475 Rivers E et al NEJM 345: De Oliveira CF et al ICM 34: Karapinar B et al CCM 32(12supp3) A161 Maat M et al CC 11:172 Odetola FO et al Pediatric 119: 487-4

9 Improve Mortality? Benefits in protocolisation of in sepsis and septic shock Kortegen A et al CCM 34: Sebat F et al Chest 127: Shapiro NI et al CCM 34: Micek SST et al CCM 34: Nguyen HB et al CCM 35: Shorr AF et al CCM 35:

10 ACCM/PALS Sepsis Protocol Bundles Fluid resuscitation Inotrope & vasodilator therapy Targeted therapy e.g. SCVO2 Lactate Vital parameters Early antibiotic treatment and infection control Use of steroids & ECMO Delay in treatment? Underestimation Less experienced staff or workload More exposure better outcome Which part is effective? Is it generalisable? Arias Y et al Paediatrics 113: e530-4 Kutko MC et al PCCM 4: Launay E at al PCCM 11: Powell ES et al CCM 38: Parker MM et al PCCM 6: 83-4 Carcillo JA et al Pediatrics 124: Cruz AT et al Pediatrics 127: e Paul R et al Pediatrics 130: e Kumar A et al CCM 34: Kumar A et al Chest 136: Gaieski DF et al CCM 38:

11 Does EGDT work? Issues of Complexity in delivery Costs External validation ProCESS US ARISE Australiasian ProMISe UK ProCESS Yealy DM et al NEJM 370: ARISE Peake SL et al NEJM 371: ProMISE Mouncey PR et al NEJM 372:

12 ProCESS N= US sites EGDTprotocol vs Usual protocol vs Usual care EGDT protocolised 6hr CVP>8 MAP>65 ScVO 2 >70 Fluid resuscitation Vasoactive drugs PCTs Usual Protocol Fluid, Vasoactive drug 92-95% overall compliance

13 Outcomes. 38% vs 59% In summary, in our multicenter, randomized trial, in which patients were identified early in the emergency department as having septic shock and received antibiotics and other nonresuscitation aspects of care promptly, we found no significant advantage, with respect to mortality or morbidity, of protocol-based resuscitation over bedside care that was provided according to the treating physician's judgment. We also found no significant benefit of the mandated use of central venous catheterization and central hemodynamic monitoring in all patients.

14 ARISE N=1600 ANZICS + HK, Ireland.. EGDT vs Usual care EGDT protocolised 6hr CVP>8 MAP>65 ScVO 2 >70 Fluid resuscitation Vasoactive drugs PCTs 85% overall compliance

15 Study Outcomes. 38% vs 59% The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014;371:

16 Probability of Survival and Subgroup Analyses of the Risk of Death at 90 Days. In conclusion, the results of our trial show that EGDT, as compared with usual resuscitation practice, did not decrease mortality among patients presenting to the emergency department with early septic shock. Our findings suggest that the value of incorporating EGDT into international guidelines as a standard of care is questionable. The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014;371:

17 ProMISe N=1260 UK NHS EDGT-naive EGDT vs Usual care EGDT protocolised 6hr CVP>8 MAP>65 ScVO 2 >70 Fluid resuscitation Vasoactive drugs PCTs 85% overall compliance

18 Interventions Delivered during and after the 6-Hour Intervention Period. Mouncey PR et al. N Engl J Med 2015;372:

19 Mouncey PR et al. N Engl J Med 2015;372: Kaplan Meier Survival Estimates.

20 NHS hospital have achieved levels of in hospital survival in patients receiving usual care that were similar to those achieved with EGDT in earlier study Additional of SCVO2 and strict protocolisation did not help 38% vs 59%

21 Revise Sepsis Bundles TO BE COMPLETED WITHIN 3 HOURS OF TIME OF PRESENTATION*: Measure lactate level Obtain blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30ml/kg crystalloid for hypotension or lactate 4mmol/L * Time of presentation is defined as the time of triage in the emergency department or, if presenting from another care venue, from the earliest chart annotation consistent with all elements of severe sepsis or septic shock ascertained through chart review. TO BE COMPLETED WITHIN 6 HOURS OF TIME OF PRESENTATION: Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) 65mmHg In the event of persistent hypotension after initial fluid administration (MAP < 65 mm Hg) or if Re-measure lactate if initial lactate elevated.

22 Revise Sepsis Bundles DOCUMENT REASSESSMENT OF VOLUME STATUS AND TISSUE PERFUSION WITH: EITHER 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. While no suggestion of harm was indicated with use of a central line in any trial, and published evidence shows significant mortality reduction using the original SSC bundles (5), the committee has taken a prudent look at all current data and, despite weaknesses as in all studies, determined the above bundles to be the appropriate approach at this time.

23 What is Usual Care? Is usual care almost protocolised care? Ultimate form of clinical audit

24 Alternatives to Protocols? Taiwan CCM Soc nation wide education program 2004 based on SSC guidelines to physicians Conducted before and after study design to look at practises based on utilisaton of items, equipment according to coding for SSC from Analysed hospitalisations before ( ) after (2005-8) program Increased incidence of severe sepsis to 5.07 Mortality Pre intervention 48.2% Post 45.9% Decrease 1.5% post intervention cf 0.3% SSC items utilisation increased significantly Lactates, cultures, antibiotics and steroids Yu Chun C et al PLOS 8: e77414

25 Alternatives to Protocols? Spanish ICU National educational program reduce mortality 44% to 39% Hospital wide quality improvement programs Orders sets or operating procedure US led MCT n=15000 mortality 37% to 30.8% Spanish ICUs mortality 57% to 37.5% Yu Chun C et al PLOS 8: e77414 Ferrer R et al JAMA 299: Levy MM et al ICM 36: Micek ST et al CCM 34: Kortgen A et al CCM 34: 943-9

26 What can we do to better use protocols Adapt to local setting Better use exisiting equipment efficiently esp low resource Use QI & RCA to develop and finetune SHOCK teams Involve stakeholders Flexibility to respond to feedback Culture receptive to change Extend practice to OPDs increase sensitivity Tend to over treat, modify ICU admission Use US to tell warm and cold shock Raina P et al 130: e Cruz AT et al Pediatric 127: e758 Larsen Gy et al Pediatric 127: e1585 Weera M et al PLoS 7: e29858 Andrea T et al Pediatrics 127: e758-66

27 QI initiatives in protocols Prospective Cohort n=240 ED septic shock 5 component sepsis bundle Increase recognition;vascular access; IV fluid; haemodynamic support; timely adequate antibiotic Use PDSA cycles to improve adherence Demonstrated 100% adherence for all measures Fluids base 37% Haemodynamci support 35% Combined adherence 19% Raina P et al Pediatrics 133:

28 So are Sepsis Protocols relevant? Impact of sepsis remain significant Variability in practise within same settings certainly in diverse setting Not just the protocol but the prinicple of what it is trying to achieve Extending SSC to non ICU areas eg district hosp transport community Localisation of Sepsis protocols through QI initiatives Complements professional education program on sepsis treatment Pair general sepsis protocol with specific targets? Yende S et al Curr Infect Dis Rep 9: Reade MC et al Emerg Med J 27: 110-5

29 So are Sepsis Protocols relevant? Physicians often re-interpret existing international guidelines into local context Use of clinical metrics to guide therapy Resource limited setting Patient advocates

30 Who uses a protocol for sepsis and septic shock? Yes! Improves outcomes Which part? Reduce variability in care Patient safety No! What For? How well are you doing? Why Not? Risk management Research audit purposes Resource intensive

31 Adult vs Child Can adult literature be directly translated to paediatrics? Farris RW et al PCCM 14: Dalton HJ et al RESOLVE PCCM 13: El-Wiher N et al Open Inflamm J 4(s) 101-9

32 Cumulative Mortality. EGDT in Paediatric Sepsis Retrospective review n=90 developing nation 83% septic shock 17% severe sepsis 90% comorbidities Barriers to implementation of sepsis guidelines Oliveira CF et al Paed Emerg Care The ProCESS Investigators. N Engl J Med 2014;370:

33 EGDT in Paediatric Sepsis ACCM/PALS 2008 guidelines on septic shock with and without ScvO2 goaldirected therapy for 6hr N=102 enrolled patients ScvO2 +ve Mortality 11.8% vs. 39.2% Fewer new organ dysfunctions 2 vs 3 more crystalloid 28 (20 40) vs. 5 (0 20) ml/kg PCTs 45.1% vs. 15.7% Inotropic 29.4% vs. 7.8% Oliveira CF et al ICM 34:

34 EGDT in Paediatric sepsis Supports the current ACCM/PALS guidelines. Goal-directed therapy using the endpoint of a ScvO2 70% has a significant and additive impact on the outcome of children and adolescents with septic shock

35 EGDT in Paediatric Sepsis Prospective cohort study ScVO 2 exposed vs control N=120 Modified EGDT Not blinded Sankar J et al PCCM 15: e157-67

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37 EGDT using intermittent ScvO 2 monitoring seemed to reduce the mortality rates and improved organ dysfunction in children with septic shock.

38 Paediatric Characteristics of the Patients Sepsis at Baseline. in Community Retrospective review n=91 Shock reversal using 2002 ACCM PALS Before transfer to CHOP Overall 29% mortality Transport team arrived 75min if shock reversed 96% survived vs 60% Mortality Guidelines adhered 38% vs 8% 30% patient adhered to guidelines Han YY et al Pediatrics 112: The ProCESS Investigators. N Engl J Med 2014;370:

39 Paediatric Sepsis Audit UK Paediatric severe sepsis care 17 PICU N=200 62% non adherence with 2002 ACCM PALS Shock reversed at arrival of transport team mortality 6% vs 27% 17% mortality Inwald DP et al Arch Dis Child 94:

40 Paediatric Sepsis ED implemented QI project to triage and treat septic shock in paediatrics Triage ACCM PALS 2009 update Guideline ED physician within 15 min Oxygen given with VS monitoring - no lines inserted Fluid resuscitation max 60ml/kg in 1hr Antibiotics in 3hr N=345 SCT US site 96% compliance No difference in mortality rates before and after implementation 6.4 vs 7.1% Reduced LOS d Larsen GY et al Pediatrics 127:e

41 Impact of Sepsis Japan 28% US 10% Italy 51% Higher mortality in Co-morbidities Develop organ failures esp ALI/ ARDS, DIC, AKI Some nations 34-58% Developed nations 13% Developing nations 18-24% MCTs 17% Nadel S et al Lancet 369: Shime N et al ICM 38: Watson RS et al AJCCM 167: Khan MR et al Ind J Pediatr 79: Sankar J et al PCCM 14: e70-6 Wolfer A et al ICM 34: Haase R et al Klinics Paediatric 223: Yu WL et al ICM 35: Hu X et al Acta Paediatr 99: Zhu YF et al Chin Med J 125:

42 Implementing Sepsis protocols Compliance and adherence variable Availability of technologies Local protocol or adopted? Acceptance of data and translation to practise Access challenges Yuanyuan W et al PCCM 15: Inwald DP et al PICS-SG Arch Dis Child 94: Kennebeck SS et al Acad Emerg Med 18: Miriam S et al Annuals Int Care 3:7-13 Marik PE et al AM J Emerg Med 28: Mathonnet A et al Reanimation 19: Brunkhorst Fm at al CCM 36: Maat M et al CritCare 11: R 112 Lampin ME et al Acta Pediatr101: e DeBacker D et al NEJM 362: Annane D et al ICM 31: 325-6

43 Resource Poor countries Variable access Maitland K FEAST et al NEJM 364: Long distance to care Lack of triage Lack of cosummables eg antibiotics, oxygen, fluids Lack of human expertise Lack of equipment Etiologies and microbes of sepsis may vary eg malaria, TB, dengue etc HIV? Varied and different co-morbidities eg nutrition, OTC drugs, attitudes

44 Resource rich countries Barriers to use guidelines Lack of vascular access Late recognition Lack of healthcare providers Non use of goals or protocols Implementation delays 40% mortality vs 9hr delays Lack of local clinical protocols and treatment goals Lack of transport team Lack of understanding of ED role and nursng role Lack of ICU beds Difficult airway & back aches Compliance 26-30% CVL intubation and following protocol Nursing don t understand and not prepared Oliveira CF et al Pediatric Emergency Care 24: 810-5

45 Sepsis Research Can we better define what we are doing? Use of Prospective Ob trials over Prospective RCTs Practice variability in real world Rely on clinical metrics for early recognition Van de Voorde P et al Eur J Pediatric 172: Thompson GC et al J Emerg Med (in press) Jones AE et al JAMA 303: Kaukonen KM et al JAMA 311:

46 QI initiatives in protocols Evidence-based practice for improving QA methods (EPIQ) Providing NICUs with QI training and practise change guidelines on NI, BPD NICU EPIQ trained showed sustained reduced in incidence of NI and BPD cf NICU non EPIQ NICU that were not new to EPIQ showed significant improvements Lee SK et al Paediatr Child Health 20(1): e1-9

47 Definitions Sepsis and variants International Consensus Protocols ACCM APLS SCCM SSC Guidelines/Bundles Fluid resuscitation Inotropes Antibiotics Variability in details Rivers E et al NEJM 345: Rivers E et al Minerva Anestesiol 78: Wang He et al CCM 35: Outcomes Mortality 30-90d Organ dysfunction Need for support eg MV inotropes RRT Transfusions LOS ICU/Hosp QOL/ Performance scores Healthcare costs Goldstein B et al PCCM 6: 2-8 Brierley J at al CCM 13: Dellinger RP et al CCM 36:

48 Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock. Angus DC, van der Poll T. N Engl J Med 2013;369:

49 Guidelines for the Treatment of Severe Sepsis and Septic Shock from the Surviving Sepsis Campaign. Angus DC, van der Poll T. N Engl J Med 2013;369:

50 2002 ACCM-PALS clinical practice parameters for haemodynamic support of paediatric and neonatal patients in septic shock.

51 Surviving Sepsis Campaign 2008 update Dellinger RP et al CCM 36:

52 Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine

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56 Pathophysiology of lactic acidosis in sepsis and severe sepsis