20 October 2014 Rachael Pery-Johnston JOURNAL CLUB RBWH ICU 20 October 2014 Rachael Pery-Johnston

The paper: NHMRC / The Alfred Foundation funding

Background to this study:

A quick refresher…

EGDT: Rivers et al 2001 Clinical Question In adult patients with severe sepsis or septic shock, does early goal-directed therapy before admission to ICU reduce in- hospital mortality, multiorgan dysfunction and use of hospital resources? Design Randomised, controlled, partially blinded trial 263 randomized to 6 hours of either: Standard Rx (133) or EGDT (130) 236/263 completed 6 hour initial study (90%)

EGDT: Rivers et al 2001 Setting Consecutive eligible pts in one academic US ED March 1997 to March 2000 Population Inclusion: adults arriving in the emergency department (ED) with Suspected infection 2 or more SIRS criteria Refractory hypotension (BP<90 after 20-30ml/kg fluid) or hypoperfusion (lactate >/= 4) Baseline characteristics similar between groups

Protocol for early goal-directed therapy

Outcomes: Rivers

This lead to: Surviving Sepsis Campaign

Current guidelines:

ProCESS May 2014 Clinical Question In adult patients with sepsis, does protocol-based care compared to usual care reduce death within 60 days? Design Randomised, controlled trial of 3 groups in 1:1:1 ratio Protocolised EGDT vs Protocolised standard care vs Standard care Non-blinded design Setting 31 academic hospitals in USA March 2008 to May 2013

ProCESS May 2014 Population 1,351 randomised within 12 hours of arrival in ED Inclusion: adults arriving in the emergency department (ED) with: suspected sepsis refractory hypotension or lactate > 4 mmol/l two or more SIRS criteria Exclusion: if another primary diagnosis was present, such as acute myocardial infarction or CVA, and

ProCESS May 2014 Intervention Group Early goal-directed therapy (EGDT) group: strict protocolised care (based on Rivers study) for 6 hours Dedicated doctor, nurse and research assistant that provided prompts Control Groups Protocol-based standard therapy group: relaxed protocolised care (based upon published expert opinions) for 6 hours Usual care group: no extra staffing, with all care as directed by bedside physician for 6 hours. Research assistant collected data but provided no prompting.

ProCESS: Outcomes 60 Day Mortality: EGDT 21% Protocol Std 18.2% Usual Care 18.9% (P values 0.31-0.89)

ProCess Strengths Well designed Attempted to tease out impact of “early” care vs “protocolised” care with 2 controls Methods and statistical analysis defined and published a priori. Recruited adequate numbers as planned for 80% power to detect 6–7% mortality reduction with p<0.05

ProCESS Weaknesses Inclusion criteria altered during trial:  reduced amount of fluid required before "refractory hypotension" to 1L , but average vol still within Rivers‘ original definition of 20–30 ml/kg. Interim recruitment target reduction as became clear much lower mortality (20% vs 30-45%) Adherence to protocol was 88.1% in EGDT group and 95.6% in protocol-based standard therapy group. Reflects “real life” but may reduce between group differences Rivers 99% - ?assessment method

ProCESS Authors' Summary: Adults with sepsis in the ED have ~20% 60-day mortality Differing mortality rate found may reflect: much improved awareness of sepsis care since Rivers’ paper Rivers’ population older, more cardiac/liver disease, higher lactate ?more severe shock in Rivers’ group (but analysis of sickest in ProCESS still no difference) No significant advantage (morbidity/mortality) of protocol- based resuscitation over bedside care provided by a dedicated team according to the treating physician's judgement.

ARISE: In a nutshell: 8y from conception to publication Follow up to ProCESS (2014) and EGDT (2001) EGDT protocol vs “usual care” in septic shock One of 3 trials planned in “harmonized collaboration” ProCESS (USA) ARISE (Aus/NZ) ProMISE (UK)

ARISE: In a nutshell: 51 centres Australia NZ ED presentations sepsis EGDT vs usual care 90 day follow up for all-cause mortality 99% = NO SIG DIFFERENCE Only differences – they left ED earlier (for EGDT) and more vasopressor use (dictated by protocol)

Clinical question: “In adult patients presenting to the emergency department with severe sepsis, does early goal-directed therapy (EGDT) reduce mortality at 90 days when compared with ‘usual care’?”

Study design: Multi-centre, unblinded, randomised controlled trial Permuted block randomisation stratified by site to allocate eligible patients 1:1 Intention to treat analysis Sample size calculation based on assumed in-hospital rate of death in the usual-care group of 28% with an increase to 38% by 90 days based on recent high quality studies. 1600 patients provided a power of 85-90% to detect an absolute risk reduction of 7.6%

Study setting: 51 hospitals (45 in Australia or New Zealand and 6 centres in Finland, Hong Kong and the Republic of Ireland) Non tertiary and tertiary centres October 2008 - April 2014 None of centres followed bundle based protocols/ScvO2 guided Rx

Study population 1600 patients enrolled EGDT: N=793 vs Usual care N=798 Similar baseline characteristics

Antibiotics at baseline: no difference EGDT Usual care Antibiotics: time to admin (mins) Median (IQR) 70 (38-114) 67 (39-110) Appropriate antibiotics time to admin (mins) 91 (48-186) 89 (47-170)

Inclusion criteria: Suspected or confirmed infection AND 2 or more SIRS criteria AND Either refractory hypotension OR hypoperfusion: Refractory hypotension: SBP < 90 mmHg or MAP < 65 mmHg after 1 litre IV fluid bolus over 60 mins Hypoperfusion: Lactate ≥ 4.0 mmol/L AND first dose of IV antibiotics given prior to randomisation

Inclusion criteria: First dose of IV antimicrobial Rx commenced prior to randomisation Standard ED care Lactate

Exclusion criteria: Contra-indication to CVC insertion / blood products Inability to start EGDT protocol within 1h of randomisation Inability to complete 6h EGDT Haemodynamic instability due to active bleeding Pregnancy (confirmed or suspected) In-patient transfer from other facility Death deemed imminent and inevitable Life expectancy <90 days due to underlying disease Limitation of therapy order

ARISE: EGDT protocol Within 1 hour from randomisation Adherence to protocols and resuscitationgoals = 95-99%

Control group: usual care Usual resuscitation care: Arterial line/CVL if clinically appropriate ScVO2 measurement not permitted during 6 hour intervention period Decisions about: location of care delivery, Investigations / monitoring / treatment = at the discretion of the treating clinician

Comparison of interventions: Fluid

Comparison of interventions: Tranfusions

Comparison of interventions: Monitoring

Comparison of interventions: Vasopressor use (Dobutamine use in 15.4% of patients vs. 2.6% in the usual care arm)

Primary outcome: no difference Measure EGDT Usual Care AD 95% CI P Value 90-day mortality Mean (SD) 18.6% 18.8% -0.3% -4.1 to 3.6% 0.90 AD = absolute difference; CI = confidence intervals; p = p value

Secondary outcomes: 2 differences Measure EGDT Usual Care RR 95% CI p Vasopressor support 76.3% 65.8% 1.16 1.09 to 1.24 < 0.001 ED LOS hours 1.4 2.0 n/a ICU LOS days  2.8 0.81 Hospital LOS days 8.2 8.5 0.89 Renal replacement Rx 13.4 13.5 0.99 0.77 to 1.27 0.94 Mechanical vent 30 31.5 0.95 0.82 to 1.11 0.52 28-day mortality 14.8% 15.9% 0.93 0.73 to 1.17 0.53 LOS = Length of Stay; ED = Emergency Department; ICU = Intensive Care Unit; RR = Relative Risk

Subgroup analyses: no outcome differences

Authors’ conclusions: In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. 

Study strengths: Clinical relevance, high impact Large multi-centre study, international, external validity Difficult setting – crowded EDs with acute care pressures Rivers’ original EGDT algorithm used - comparison Pragmatic, reflects “real life” practice clinician discretion in 'usual care' Mx/location care Inclusion of centres with resource limitations Timing of first dose antibiotics recorded (sensible enrolment criterion to avoid confounding effect of late administration) Subgroup analyses reassuring regarding variation in mortality between countries Very little loss to follow up – 99% “Data massage” avoided by publication of statistical analysis plan before recruitment completed

Study weaknesses: Lower APACHE scores than ProCESS and Rivers – subgroup analysis somewhat reassuring but small numbers small (150) ?Correct population recruited – ~70% in both groups with shock: - lactate levels similar.. Rivers group criticize much lower fluid volume given ?less sick population Some elements of EGDT utilized in usual care group BUT there were significant differences in key elements of EGDT (PRC/dobutamine etc) Real life mortality rates likely to be higher – study meant special team and early senior involvement for all Low recruitment rate at all centres – 2 patients per month at largest (Austin)-reflects difficulty of research- but multicentre trials needed to ensure external validity, numbers and power to detect differences

ARISE: comparison with ProCESS: Similar to ProCESS: EGDT vs usual care 6h Rx regimen Inclusion criteria identical Differences from ProCESS: Enrolled earlier (6h vs 12h) Simpler – 2 arms Aus/NZ/other countries Non tertiary centres included

Comparisons of Rivers with ARISE/ProCESS: Sicker patients: = Baseline APACHE II – 20 in Rivers trial with higher rates of cardiac/liver (ARISE = 15, ProCESS=20) All 6 hour care given in ED in Rivers trial Adherence to protocols 99% After 6h, clinicians blinded to patient allocation Mortality rates from sepsis MUCH higher: = 30-46% vs around 20% for ProCESS ARISE – 70% hypotense but received substantially less IV fluid than Rivers pts

Discussion points: 1 “Sicker patients” in Rivers Attitudes to end of life care ANZ now Dying not recruited 2 Hawthorne effect Those being observed in a study try harder 3 Team focused on enrolled patient/ senior involvement early No substitute for an excellent clinician standing there, joining the dots 4 Surviving sepsis campaign response to ProCESS and ARISE – no evidence of HARM shown with invasive monitoring so: wait until all 3 studies results/meta-analysis is available 5 Ways to improve? -QAS lactate/antibiotics – modified SIRS criteria – no WCC

Summary of impact of ARISE 1 Reinforces EARLY as the factor having impact - supports ProCESS conclusion - early adequate fluids and antibiotics and appropriate environment is key 2 Results achievable: - across the world - in non-tertiary settings - in ED or ICU, without elaborate monitoring devices 3 Highlights work still to be done: - ~ 20% mortality still - significant delays to antibiotics

Sepsis fundamentals Early recognition Early appropriate antimicrobial Rx Early source control Be careful at intubation Right amount of fluid resuscitation Early vasopressors Early admission to monitored area and REASSESS

Or, in essence….

THANK YOU