A Randomised Trial of Protocol-Based Care for Early Septic Shock The ProCESS Investigators

Middle Ages “The physicians say it happens in hectic fever, in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning it becomes easy to detect but difficult to cure”

Rivers 2001 Protocolized early goal directed therapy initiated in the ED in severe sepsis and septic shock patients improved resuscitation parameters and reduced mortality 263 patients – severe sepsis or septic shock SBP <90 despite 30ml/kg fluid Lactate >4mmol/L Randomised to standard of care vs. EGDT Central venous pressure and central venous oxygen saturation to guide the use of IV fluids, vasopressors, packed red cell transfusions and dobutamine in order to achieve pre-specified physiological targets EGDT Central line for ScvO2 Maintain CVP 8-12mmHg Map > 65 ScvO2 >70% HCT >30% Primary endpoint (hospital mortality) lower with EGDT 30.5% vs. 46.5%

Rivers Trial Launched the EGDT era of sepsis management Encouraged Coordinated efforts Earlier identification of septic shock Increased earlier larger volume resuscitation ProCESS trial allows refinement of the EGDT approach to fluid administration by defining lower boundaries that are associated with equivalent outcomes and setting limits that are needed to avoid the twin problems of renal failure and pulmonary dysfunction

Research Question Is protocol based cared (EGDT and standard-therapy groups combined) superior to usual care Is protocol based (EGDT) superior to protocol-based standard therapy

Study Design Multicentre vs. Rivers Randomised protocolased study 31 hospitals in the US All academic hospitals >40 000 yearly admissions Funded by national institute of general medical sciences Centres had to use the measurement of serum lactate levels as the method for screening for shock and had to adhere to the surviving sepsis campaign guidelines but could not have routine resuscitation protocols and couldn’t use continuous Scvo2 catheters

Study subjects 31 emergency departments in the US March 2008 – May 2013 In the emergency department in whom sepsis was suspected according to the treating physician >18 Refractory hypotension OR lactate >4mmol SBP <90 or required vasopressor to maintain 90mmHg even after IV fluid challenge >20ml/kg over 30min, in April changed to a challenge of 1000ml or more administered over 30min Patients randomly assigned to (1341) Protocol based EGDT (439) Protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotrope, blood transfusions (446) Usual care (456) Randomisation was performed with the use of a centralised web-based program

Interventions Randomly assigned 1:1:1 Protocol based EGDT Protocol based standard therapy Usual care Same physician led team implemented both the protocols One physician who was trained in the protocol guided resuscitation interventions Study coordinator – monitored adherence to protocols Bedside nurse All study physicians were trained in emergency medicine or critical care medicine and had completed a web based certificate examination Therapy could be continued outside of emergency

All 3 arms No arterial line Did not specify type of fluid Did not specify type of inotrope

Protocol based standard therapy 6 hour resuscitation instruction Designed on bases of review of literature, 2 independent surveys of emergency physician and intensivist practice world wide Consensus feedback from investigators Adequate peripheral access Administration of fluids and vasoactive agents to reach goals for SBP and shock index (ratio of HR to SBP) and to address fluid status and hypoperfusion which were assessed clinically at least once an hour PRBC only if Hb <75 Administration of IVF until the team leader decided fluids were replete

Usual care group Bedside providers directed all care with the study provider collecting data but not prompting any actions Lead investigators could not serve as the bedside treating physician for patients in this group

Outcome variables Primary end point: 60 day in hospital mortality Secondary outcomes Longer term mortality (1 year) Duration of cardiovascular failure - need for vasopressors Duration of respiratory failure – need for ventilation Duration of acute renal failure – need for dialysis

Statistical analysis With a sample of 1950 patients, study would have at least 80% power to detect a reduction in mortality of 6-7%, assuming mortality of 30-46% Mortality on half way analysis – 20% - re-analysed would need 1350 patients

Patients well matched at baseline

60 days 92 deaths in EGDT (21%) 81 deaths in the protocol-based standard therapy (18.2%) 86 deaths in the usual group (18.9%)

No significant differences in 60 day mortality or 1 year mortality

No difference in duration of organ support

Renal failure - Higher in protocol based standard therapy group Rate of admission to ICU higher in EGDT group No significant difference in incidence and duration of cardiovascular failure or respiratory failure No differences in the length of stay in hospital or discharge disposition

Resuscitation Volume of fluids 2.8L EGDT 3.3L protocol based group 2.3L in usual care group 96% crystalloids Vasopressors 54.9% 52.2% Vs. 44.1% P=0.003 Dobutamine 8% 1.1% 0.9% p<0.001 PRBC 14.4%, 8,3%, 7.5% p=0.001

Use of antibiotics, glucocorticoids and APC was similar

Antibiotics 76% of patients received antimicrobial agents by the time they underwent randomisation – mean of 3 hours 97% had received antibiotics by mean 9 hours Ongoing role of early recognition of sepsis and antibiotic treatment for sepsis in improving survival (kumar – duration of hypotension before initiation of effective antimicrobial therapy)

Need for central monitoring in managing sepsis guidelines? In the non EGDT 56.5% and 57.9% had a CVC inserted but later then the EGDT , and CVC used for monitoring in only 4% in other groups Use of central hemodynamic and oxygen-saturation monitoring in the EGDT group did not result in better outcomes than those achieved with clinical assessment of the adequacy of circulation

Limitations Adherence to protocols Enrolled patients who were recognised to be in septic shock – does not address extent to which any of these strategies offer advantages in settings where septic shock is not recognised promptly Septic shock occurs in a heterogeneous population and care before randomisation can be variable Limited power to address whether particular strategies were more effective in specific subgroups Two ongoing multicentre trials ARISE ProMIse In hospital mortality amongst patients requiring life support is strongly influenced by varying practices regarding withdrawal of care

Rivers Process Arise Promise Study Single center, EGDT vs. Standard therapy Multi center, EGDT vs. protocol based standard therapy vs. standard therapy Mute center, RCT of the effect of EGDT, compared to standard care Multi center RCT of the clinical and cost-effectiveness of EGDT, protocoled resuscitation for septic shock Design Central line – continuous ScvO2 and protocoled care to maintain CVP 8-12 MAP >65 ScvO2 >70% HCT >30% EGDT and Protocol based VS standard therapy EGDT vs. Protocol based therapy EGDT 6 hours vs. Standard care Effect of EGDT, protocoled resuscitation vs. usual care at 90days To compare the incremental cost effectiveness at one year Power 263 patients 1341 patients 1600 patients over 2.5 years Outcome Difference at 72 hours of APACHE II score Mortality at 28 and 60 days 60 day in hospital mortality 90 day mortality Cost effectiveness Inclusion criteria Suspected or confirmed infection AND the presence of 2 or more Core T <36 or >38 HR >90 RR >20 WCC >12 <4 AND Hypoperfusion – SBP <90mmHg despite 30mL/kg fluid bolus or lactate >4 Hypoperfusion – SBP <90mmHg despite 30mL/kg fluid bolus (later changed to 1L) or lactate >4 Evidence of either refractory hypotension or hypoperfusion SBP <90 after 1L IVF OR Lactate >4 First dose of IV Abs commenced prior to randomization Exclusion criteria Age <18 Pregnancy ACS Acute Cerebrovascular event APO Contraindication to CVL Active GIT haemorrhage Seizure Drug overdose Burn Trauma Requirement for surgery Uncured cancer Immunosuppression Limitation therapy order Contraindication to blood products Inability to fulfill EGDT Haemodynamic instability due to active bleeding Inpatient transfer Underlying disease with life expectancy <90 days Limitation of therapy order Death is deemed imminent Contraindication to CVC insertion

So, why and where are the differences coming from? So, why and where are then the differences coming from…..? So, why and where are the differences coming from?

Difficulty replicating a study Statistics can be milked to get desired answers

Why rivers worked? Comparing famine with feast Mean initial ScVo2 49% but measured pre fluid administration in new study measured after fluids Managing sepsis guidelines 2002

Why ProCESS didn’t work Early recognition of sepsis and antimicrobial agents as specified in the surviving sepsis campaign guidelines was incorporated into all groups Low tidal volume ventilation Moderate glycaemic control Clinical assessment of the adequacy of circulation

ProCESS versus rivers - TIME Advances in care of critically ill Use of lower Hb levels Lung protection studies Use of tighter control of BSL Publication of managing sepsis guidelines 2002 May have helped lower mortality and reduced the marginal benefit of alternative resuscitation strategies

ProCESS versus rivers - ADHERENCE 100% Adherence to protocol in Rivers vs. 88.1% in ProCESS

ProCESS versus rivers - POPULATION Enrolled populations differed Rivers – slightly older, higher rates of pre-existing liver and heart disease, higher initial serum lactate

Patients managed without a protocol had same outcome as those managed with a protocol Refinement of EGDT approach to fluid administration by defining lower boundaries that are associated with equivalent outcomes and setting limits to avoid too little fluid (renal failure) vs. fluid overload (pulmonary dysfunction)

Early recognition of sepsis Early antibiotics Adequate volume resuscitation Clinical assessment of the adequacy of circulation

QUESTIONS