ARISE: Goal-Directed Resuscitation for Patients with Early Septic Shock

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This is part of the infamous triad of NEJM studies showing no benefit of EGDT compared to usual care. Take a look at the Rivers study and compare them to ProCESS (done in USA), ProMISe (done in England) and ARISE (done in Australia/New Zealand).


Clinical Question

In adult patients with septic shock, does early goal-directed therapy (EGDT) compared with standard therapy reduce mortality at 90 days?

  • Type of Trial: RCT

  • Blinding: non-blinded design

  • Setting: 51 hospitals (45 in Australia or New Zealand and 6 centres in Finland, Hong Kong and the Republic of Ireland) from Oct 2008 - April 2014

PICO

  • Population:

    • 1600 adults presenting to the ED with suspected or confirmed infection and 2 or more SIRS criteria AND

    • Evidence of either refractory hypotension OR hypoperfusion

      • Refractory hypotension: presence of a systolic blood pressure (SBP) < 90 mmHg or mean arterial pressure (MAP) < 65 mmHg after a 1000ml intravenous (IV) fluid challenge within 60 minutes (including IV fluids administered pre-hospital)

      • Hypoperfusion: confirmed by the presence of a blood lactate concentration ≥ 4.0 mmol/L

    • Excluded: contraindications to CVL insertions/blood products; inability to commence EGDT within 1 hour of randomization; HD unstbale due to active bleeding; pregnancy; in-patient transfer from OSH; patient has life expectancy <90 days; a “limitation of therapy” order

  • Intervention:

    • EGDT. A-line and CVL capable of continuous SCVO2 placed within 1 hour after randomization; treatment algorithm was commenced based on River’s original algorithm for 6 hours

    • Intervention was provided by study team trained in EGD; care providers + location of delivery were dependent on local resources

  • Control:

    • Usual resuscitation care - A-line and CVL in clinically appropriate, SCVO2 measurement was not allowed, decisions about all care at discretion of treating clinician

  • Outcome:

    • Primary outcome: 90 day mortality after randomization

      • No difference (18.6% in intervention, 18.8% in usual care, p<0.09)

    • Secondary outcomes:

      • Median LOS in ED (1.4h EGDT vs 2h usual care)

      • Hospital & ICU LOS: no difference

      • The need for, and duration of, organ support

        • vasopressor requirement: EGDT 76.3% vs.  usual care group 65.8%, P<0.001

        • median duration of vasopressor infusion – no difference

        • no difference in number receiving mechanical ventilation or RRT

    • Tertiary outcome:

      • 28d all cause mortality

        • 14.8% EGDT vs. 15.9% usual care group (RR 0.93, P=0.53)

      • mortality at ICU discharge

        • 10.9% EGDT vs. 12.9% usual care group (RR 0.85, P=0.28)

      • hospital mortality (censored at 60d mortality)

        • 14.5% EGDT vs. 15.7% usual care group (RR 0.92, P=0.53)

      • Volume of fluid administered during the first 6 hours:

        • EGDT 1964+/-1415 vs. Usual-care group 1713+/-1401ml P<0.001

    • Subgroup analyses: No difference in any categories

      • Country: no difference between country (Australia/NZ/’others’)

      • APACHE II < 25 vs. >25

      • Presence or absence of invasive mechanical ventilation

      • Presence or absence of refractory hypotension

      • Lactate level (<4.0mmol/l or<4.0mmol/L)

      • Intravenous fluid administration (<20ml/kg or >20ml/kg of body weight)

Conclusions

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


Strengths

  • Clinical relevance and high impact

  • Large multi-center study

  • Use of original EGDT algorithm in the intervention group

  • A pragmatic study which allowed clinician discretion in managing the ‘usual care’ group and also not limiting involvement of some centres because of resource limitations

  • Information supplied regarding timing of first dose antibiotics. A sensible inclusion criteria of antimicrobials being started before enrolment addressed the potential confounding effect of late administration

  • Subgroup analyses for variation in mortality between countries

  • Statistical analysis plan published before recruitment was completed eliminates the risk of analytical bias

Weaknesses

  • Lower APACHE scores than ProCESS and Rivers study but this has been addressed with a subgroup analysis of those with APACHE II scores of < 25 and > 25. There was still no difference in mortality between EGDT and usual-care in the sicker group although the total numbers were small in > 25 group (n=69)

  • Low recruitment rate per month across all centres. The largest recruiting centre (Austin Health) recruited at a mean rate of just over 2 patients per month. However, adherence with EGDT protocol was high and management of sepsis well established in usual care practice. This low rate reflects the complexities of conducting research studies. Multi-centre involvement is essential both for ensuring generalisability and appropriately powered trials

Take note:

  • This particularly puts a nail in the coffin not just for EGDT but also for continuous SCVO2, liberal blood transfusion and probably dobutamine

  • Despite stark differences between ProCESS, ARISE compared to Rivers paper, it is still important for IVF resuscitation, abx therapy and source control to remain fundamental

Sources:

https://www.thebottomline.org.uk

Rachel MulderComment