Trials and guidelines for sepsis and infectious disease

A trainee has pointed out that this might be useful. Readers are reminded of numerous other (better) resources which compile this information, of which the best has to be Critical Care Reviews. Still, there seemed to be some merit in creating a list for quick reference.  Wherever possible, the links of the trial eponym or author reference lead to a free full text version of the paper, and the year is a link to the corresponding page at The Bottom Line

Early goal-directed therapy in sepsis

Rivers et al - 2001 -  EGDT in Detroit; n=268. A trial of protocolised care for sepsis, vs. apparently no care at all (as the mortality difference was stark: 29.2% vs 44.4%).

ProCESS - 2014 - EGDT around US; n= 1,351. A faithful reenactment of the River's trial; no difference in mortality (18.2% vs 18.9%)

ARISE - 2014 - EGDT around Australia and NZ; n=1600. No difference in mortality (18.6% vs. 18.8%); patients were largely rather less sick 

ProMISE 2015 - EGDT around the UK; n=1260. No difference in mortality (29.5% vs. 29.2%); the main difference between groups was SvO2 and CVP guided management.

ANDROMEDA-SHOCK - 2018 - goals: lactate vs cap refill time; n=424, from Central America. Mortality was higher in the lactate group (43.4% vs 34.9%), but not statistically significant, plus for some reason they used 28-day mortality.

Vasopressors in sepsis

CATS - 2007 - adrenaline vs. noradrenaline+dobutamine; n=330 in France. No mortality difference (47% vs 44%), nor any difference in adverse events.

Myburgh - 2008 - adrenaline vs noradrenaline, with MAP goals as the primary outcome.  n=280 in Australia. No difference (a pressor is a pressor) but 12.9% dropped out of the adrenaline arm for "significant but transient metabolic effects"

VASST - 2016 - noradrenaline and vasopressin? n=802 in Canada, Australia, US. No difference in mortality (35.4% vs 39.3%), but the patients were not especially sick.

VANISH - 2016 - does early vasopressin prevent AKI? n=409, in the UK. No, it does not (56.8% vs 59.7% went dialysis-free)

CENSER - 2019 - but what if early norad, and peripherally? n=310, single centre in Thailand. Shock resolved faster in 76.1% vs 48.4% (mortality 15.5% vs 21.9%)

Albumin in sepsis

SAFE - 2004 - not really a sepsis study, just saline vs albumin (n=6997 in Australia). Septic subgroup (n=1218) found better mortality (30.7% vs 35.3%) on post-hoc analysis.

ALBIOS - 2014 - but what if albumin was kept over 30? n=1818 in Italy.  No difference in mortality (31.8% vs 32.0%), using 20% albumin. 

ALPS - 2022 - what if albumin, but only in cirrhotic septic patients? n=100, in India. No difference in mortality (58% vs 62%), just faster resolution of hypotension.

Steroids in sepsis

CORTICUS - 2008 - hydrocortisone 50mg qid; n=499, in Europe. No difference in mortality (34.3% vs. 31.5%)  but shock reversed much faster (3.2 vs 5.4 days). 

COIITSS - 2010 - what if steroids and intensive insulin therapy (which we now know doesn't work)? n=509, in France. Unsurprisingly it didn't work (45.9% vs 42.9%).

HYPRESS - 2016 -  but what if steroids before shock? n=380, in Germany.  No difference in progression to shock (21.2% vs 22.9%); mortality was low (8.5%).

ADRENAL - 2018 - hydrocort infusion, n=3658 all over the world.  No difference in mortality (27.9% vs 28.8%), but many secondary outcomes were improved (ICU LOS, ventilation time, shock resolution) 

APROCCHSS - 2018 - but what if also fludrocortisone? n = 1241 in France. Mortality improved (43.0% vs 49.1%); these were extremely sick patients (1mcg/kg/min norad!)

Blood pressure targets in sepsis

SEPSISPAM - 2014 - is MAP of 85 necessary? n=776, in France. No difference in mortality (36.6% vs. 34%), but it did protect the kidneys of the chronically hypertensive patients (NNT=9.5), which is not nothing.

65 2020 - is MAP of 60 enough for the over-65s? n=1221, in the UK. No difference in mortality (41% vs 43.8%), so ... yes, it is enough. Survival was better for the chronically hypertensive group (38.2% vs. 44.3%) and trended higher the older you were.

Fluid resuscitation in sepsis

SOAP - 2006 - observational study of fluid use in European ICUs, n=3147. OR for mortality increased by 1.1 for every additional 1L of fluid balance in the first 72 hours.

FEAST - 2011 - fluid boluses vs. no boluses, in African children (n=3141) with mainly malaria (57%) who only got transfused if their Hb dropped below 50. Fluid bolus group had more mortality (10.5% vs 7.3%). Worth knowing because often referred to.

6S - 2012 - evil death-starch is bad for everyone, but what about sepsis? n=804, northern Europe. The answer is yes; it's still bad (higher risk of death,  51% vs 43%, as well as dialysis, 22% vs 16%)

TRISS - 2014 - what if Hb was over 90? n=1005, from Scandinavia. No difference in mortality (43% vs 45%); a Hb of 70 g/L is enough. They excluded acute coronary syndromes. 

CLASSIC - 2022 - restrictive vs. liberal; n=1554, Denmark and Finland. No difference in mortality (42.3% vs 42.1%), but then again at 5 days both groups had a fluid balance around 8-10L. 

CLOVERS - 2023 - liberal fluids vs early vasopressors; n=1563 in the US. No difference in mortality (14.0 vs 14.9%), or in adverse events.

Antibiotic strategy

Kumar - 2006 - the observational study from which SSG got their recommendation to give early antibiotics. n=2731 in Canada, US, Saudi Arabia. Mortality increased with every hour of delay following the onset of hypotension (by about 7.6%) 

STOP-IT - 2015 - short course (4 days) of antibiotics in abdominal sepsis with good source control. n=517 in US and Canada. None of the primary outcomes were any worse with the short course.

BLING2 - 2015 - continuous vs intermittent β-lactams, n=432, Australia and NZ. No difference in any of the outcome measures (mortality 26% vs 28%) but also not powered to detect mortality differences.

BLISS - 2016 - continuous vs intermittent β-lactams; n=140 in Malaysia. Much higher cure rate (56% vs 34%) but no mortality benefit, and not blinded.

Procalcitonin

PRORATA - 2010 - procalcitonin used to guide antibiotics; n = 621 in France. 23% less antibiotic exposure, but the mortality difference favoured the control group (30% vs 26.1%), even though this did not reach statistical significance.

Guidelines for infectious diseases and sepsis

For antibiotic recommendations, the Australians should start with the electronic edition of the Therapeutic Guidelines. Many (most) of those working in Australia will have institutional access. The Sanford Guide is the next best option. 

ISDA practice guideline list - a comprehensive set of recommendations, from which the following critical-care-relevant gems were mined: 

ASIDthe Australian version of the ISDA, have their own list of guidelines, but it is somewhat anaemic. Of interest are their guidelines on investigations and management of encephalitis

CDC guideline list is excellent for:

References

Rivers, Emanuel, et al. "Early goal-directed therapy in the treatment of severe sepsis and septic shock." New England Journal of Medicine 345.19 (2001): 1368-1377.

Yealy, Donald M., et al. "A randomized trial of protocol-based care for early septic shock." The New England journal of medicine 370.18 (2014): 1683-1693.

Mouncey, Paul R., et al. "Trial of early, goal-directed resuscitation for septic shock." New England Journal of Medicine 372.14 (2015): 1301-1311.

ARISE Investigators and the ANZICS Clinical Trials Group. "Goal-directed resuscitation for patients with early septic shock." New England Journal of Medicine 371.16 (2014): 1496-1506.

Meyhoff, Tine S., et al. "Restriction of intravenous fluid in ICU patients with septic shock." New England Journal of Medicine 386.26 (2022): 2459-2470.

Holst, Lars B., et al. "Lower versus higher hemoglobin threshold for transfusion in septic shock." New England Journal of Medicine 371.15 (2014): 1381-1391.

Hernández, Glenn, et al. "Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial." Jama 321.7 (2019): 654-664.

Lamontagne, François, et al. "Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial." Jama 323.10 (2020): 938-949.

Russell, James A., et al. "Vasopressin versus norepinephrine infusion in patients with septic shock." New England Journal of Medicine 358.9 (2008): 877-887.

Gordon, Anthony C., et al. "Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial." Jama 316.5 (2016): 509-518.

Permpikul, Chairat, et al. "Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial." American journal of respiratory and critical care medicine 199.9 (2019): 1097-1105.

Venkatesh, B., et al. "ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock." N Engl J Med 378.9 (2018): 797-808.

Perner, Anders, et al. "Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis." New England Journal of Medicine 367.2 (2012): 124-134.

Annane, Djillali, et al. "Hydrocortisone plus fludrocortisone for adults with septic shock." New England Journal of Medicine 378.9 (2018): 809-818.

Keh, Didier, et al. "Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial." Jama 316.17 (2016): 1775-1785.

Abdul-Aziz, Mohd H., et al. "Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis." Intensive care medicine 42.10 (2016): 1535-1545.

Sawyer, Robert G., et al. "Trial of short-course antimicrobial therapy for intraabdominal infection." New England Journal of Medicine 372.21 (2015): 1996-2005.

Kumar, Anand, et al. "Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock." Critical care medicine 34.6 (2006): 1589-1596.

Maitland, Kathryn, et al. "Mortality after fluid bolus in African children with severe infection." New England Journal of Medicine 364.26 (2011): 2483-2495.

Maiwall, Rakhi, et al. "A randomized-controlled trial comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis-induced hypotension [ALPS trial]." Journal of Hepatology (2022).

COIITSS study investigators. "Corticosteroid Treatment and Intensive Insulin Therapy for Septic Shock in Adults." JAMA 303.4 (2010): 341-348.

Bouadma, Lila, et al. "Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial." The Lancet 375.9713 (2010): 463-474.

Myburgh, John A., et al. "A comparison of epinephrine and norepinephrine in critically ill patients." Intensive care medicine 34.12 (2008): 2226-2234.

Annane, Djillali, et al. "Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial." The Lancet 370.9588 (2007): 676-684.

Dulhunty, Joel M., et al. "A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis." American journal of respiratory and critical care medicine 192.11 (2015): 1298-1305.