Protocols in sepsis: Do we need them? -...

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

Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria.

Angus DC, van der Poll T. N Engl J Med 2013;369:840-851

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

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

• SCVO2

• Treated 6hr transfer to ICU

• Physicians blinded

• n=268

Rivers E et al. N Engl J Med 2001;345:1368-1377

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 oxygen delivery and oxygen demand

• 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

• Steroid replacement

• Haemoglobin targets

• Lung protective strategies in ALI/ARDS

• PEEP

• Low Vt

• Head elevation

• Sedation Anaglesia

• Stress ulcer, DVT prophylaxis

• rAPC

Sepsis Protocol Bundles

Wills BA et al NEJM 353: 877-89

Maitland K et al CID 40: 538-45

Varpula M et al ICM 31: 1066-71

Reinhart K et al ICM 30: 1572-8

Trezciak S et al Chest 129: 225-32

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: e273-80

Nhan NT et al CID 32: 204-12

Han YY et al Pediatrics 112: 793-9

Booy R et al Arch Dis Child 85: 386-90

Finfer S et al NEJM 350: 2247-56

Dellinger RP et al ICM 39: 165-228

Irazuzta J et al J Pediatr (Rio J) 83: s36-45

Carcillo JA et al CCM 30: 1365-78

Khilnani P et al Ind J CCM 14: 41-52

Carcillo JA et al JAMA 266: 1242-45


De Oliveira CF et al ICM 34: 1065-75

Ceneviva G et al Pediatrics 102: e19

Jhuma S et al PCCM 15: e157-67

Ninis et al BMJ 330: 1475

Rivers E et al NEJM 345: 1368-77


Karapinar B et al CCM 32(12supp3) A161

Maat M et al CC 11:172

Odetola FO et al Pediatric 119: 487-4

Improve Mortality?

• Benefits in protocolisation of in sepsis and septic

shock

Kortegen A et al CCM 34: 943-9

Sebat F et al Chest 127: 1729-43

Shapiro NI et al CCM 34: 1025-32

Micek SST et al CCM 34: 2707-13

Nguyen HB et al CCM 35: 1105-12

Shorr AF et al CCM 35: 1257-1262

Dellinger RP et al ICM 39: 165-228

Irazuzta J et al J Pediatr (Rio J) 83: s36-45

Carcillo JA et al CCM 30: 1365-78

Khilnani P et al Ind J CCM 14: 41-52

Carcillo JA et al JAMA 266: 1242-45



Ceneviva G et al Pediatrics 102: e19

Jhuma S et al PCCM 15: e157-67

• 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: 333-7

Launay E at al PCCM 11: 469-74

Powell ES et al CCM 38: 2161-8

Parker MM et al PCCM 6: 83-4

Carcillo JA et al Pediatrics 124: 500-8

Cruz AT et al Pediatrics 127: e758-66

Paul R et al Pediatrics 130: e273-80

Kumar A et al CCM 34: 1589-96

Kumar A et al Chest 136: 1237-48

Gaieski DF et al CCM 38: 1045-53

ACCM/PALS

Does EGDT work?

• Issues of

• Complexity in delivery

• Costs

• External validation

• ProCESS US

• ARISE Australiasian

• ProMISe UK

ProCESS Yealy DM et al NEJM 370: 1683-93

ARISE Peake SL et al NEJM 371: 1496-506

ProMISE Mouncey PR et al NEJM 372: 1301-11

ProCESS

• N=1351

• 31 US sites

• EGDTprotocol vs Usual protocol vs Usual care

• EGDT protocolised 6hr

• CVP>8 MAP>65 ScVO2>70


• Vasoactive drugs

• PCTs

• Usual Protocol

• Fluid, Vasoactive drug

• 92-95% overall compliance

Outcomes.

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.

38% vs 59%

ARISE

• N=1600

• ANZICS + HK, Ireland..

• EGDT vs Usual care


• CVP>8 MAP>65

ScVO2>70



• PCTs

• 85% overall compliance

Study Outcomes.

The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014;371:1496-1506

38% vs 59%

Probability of Survival and Subgroup Analyses of the Risk of Death at 90 Days.

The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014;371:1496-1506

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.

ProMISe

• N=1260

• UK NHS EDGT-naive

• EGDT vs Usual care


• CVP>8 MAP>65

ScVO2>70



• PCTs

• 85% overall compliance

Interventions Delivered during and after the 6-Hour Intervention Period.

Mouncey PR et al. N Engl J Med 2015;372:1301-1311

Kaplan–Meier Survival Estimates.

Mouncey PR et al. N Engl J Med 2015;372:1301-1311

• 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%

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.

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.

What is Usual Care?

• Is usual care almost protocolised care?

• Ultimate form of clinical audit

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 1997 - 2008

• Analysed 40000 hospitalisations

• before (2000-2003) after (2005-8) program

• Increased incidence of severe sepsis1.88 1000-1 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

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: 2294-2303

Levy MM et al ICM 36: 222-231

Micek ST et al CCM 34: 2707-13

Kortgen A et al CCM 34: 943-9

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: e273-80

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

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: 1358-66

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: 382-6

Reade MC et al Emerg Med J 27: 110-5

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

Who uses a protocol for

sepsis and septic shock?

Yes!

• Improves outcomes

• Which part?

• Reduce variability in care

• Patient safety

• Risk management

• Research audit purposes

• Resource intensive

No!

• What For?

• How well are you doing?

• Why Not?

Adult vs Child

• Can adult literature be directly translated to

paediatrics?

Farris RW et al PCCM 14: 835-42

Dalton HJ et al RESOLVE PCCM 13: 639-645

El-Wiher N et al Open Inflamm J 4(s) 101-9

Cumulative Mortality.

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

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


• ACCM/PALS 2008 guidelines on septic shock

• with and without ScvO2 goal-directed 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: 1065-75

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


• Prospective cohort study

• ScVO2 exposed vs control N=120 Modified EGDT

• Not blinded

Sankar J et al PCCM 15: e157-67

EGDT using intermittent ScvO2 monitoring seemed to reduce the mortality rates

and improved organ dysfunction in children with septic shock.

Characteristics of the Patients at Baseline.

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

Paediatric Sepsis 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


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: 348-53

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 180140d

Larsen GY et al Pediatrics 127:e1585-92

Impact of Sepsis

• Japan 28%

• US 10%

• Italy 51%

• Some nations 34-58%

• Developed nations 13%

• Developing nations 18-24%

• MCTs 17%

• Higher mortality in

• Co-morbidities

• Develop organ failures esp

ALI/ ARDS, DIC, AKI

Nadel S et al Lancet 369: 836-843

Shime N et al ICM 38: 1191-1197

Watson RS et al AJCCM 167: 695-701

Khan MR et al Ind J Pediatr 79: 1454-8

Yu WL et al ICM 35: 136-43

Hu X et al Acta Paediatr 99: 715-21

Zhu YF et al Chin Med J 125: 2265-71

Sankar J et al PCCM 14: e70-6

Wolfer A et al ICM 34: 1690-1697

Haase R et al Klinics Paediatric 223: 142-6

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: 814-20

Inwald DP et al PICS-SG Arch Dis Child 94: 348-53

Kennebeck SS et al Acad Emerg Med 18: 1380-5 Miriam S et al Annuals Int Care 3:7-13

Maat M et al CritCare 11: R 112

Lampin ME et al Acta Pediatr101: e426-30

DeBacker D et al NEJM 362: 779-789

Annane D et al ICM 31: 325-6

Marik PE et al AM J Emerg Med 28: 243-5

Mathonnet A et al Reanimation 19: 154-62

Brunkhorst Fm at al CCM 36: 2719-25

Resource Poor countries

• Variable access

• 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

• Applicable to this setting?

Maitland K FEAST et al NEJM 364: 2483-95

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

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: 667-74 Jones AE et al JAMA 303: 739-46 Kaukonen KM et al JAMA 311: 1308-16

Thompson GC et al J Emerg Med (in press)

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

Definitions

• Sepsis and variants

• International Consensus

• Protocols

• ACCM APLS

• SCCM SSC

• Guidelines/Bundles


• Inotropes

• Antibiotics

• Variability in details

• 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 13:666-688

Dellinger RP et al CCM 36: 296-327

Rivers E et al NEJM 345: 1368-77

Rivers E et al Minerva Anestesiol 78: 712-24

Wang He et al CCM 35: 1928-36

Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock.


Guidelines for the Treatment of Severe Sepsis and Septic Shock from the Surviving Sepsis Campaign.


2002 ACCM-PALS clinical

practice parameters for

haemodynamic support of

paediatric and neonatal

patients in septic shock.

Surviving Sepsis Campaign

2008 update Dellinger RP et

al CCM 36: 296-327

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

Pathophysiology of lactic acidosis in sepsis and severe sepsis

Protocols in sepsis: Do we need them? -...

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