An elderly man presented with urosepsis. He was in septic shock with a lactate of 8.2 on presentation. He was commenced on antibiotics and fluid resuscitated in the Emergency Department and his lactate was remeasured as 6.1. His ScvO2 was measured as 54%, rising to 63% after further fluid challenge. He was fluid resuscitated and commenced on noradrenaline to maintain a MAP of 65. He recovered from his urosepsis and was discharged from hospital 5 days later.

What is the evidence for and against Early Goal Directed Therapy for the management of severe sepsis?

Sam Clark

 

The term Early Goal Directed Therapy (EGDT) was first coined by Rivers et al in their paper published in the NEJM 2001 (1). EGDT was the protocolised management of severe sepsis via an algorithm that intensively monitored certain cardiological parameter to guide aggressive and timely treatment to optimize oxygen delivery to the tissues . Those parameters were: a CVP between 8-12mmHg; mean arterial pressure (MAP) between 65-90mmHg; urine output >0.5ml/kg/hr; mixed venous oxygen >65%/ central venous saturations >70%; and haematocrit greater than 30%. Their interventions to improve oxygen delivery included aggressive fluid resuscitation, reducing the work of breathing with the early use of mechanical ventilation, vasoactive drugs (noradrenaline and Dobutamine) and finally transfusion. The other important aspect of the original study was that the protocol had to be instituted early (within the first six hours of arrival in the Emergency department).
Rivers et al conducted a single centered prospective RCT with blinding of the clinicians assessing the patients in a nine-bedded resuscitation unit in a Detroit emergency department. They compared EGDT for the first 6 hours with standard therapy (aiming for a CVP 8-12mmHg, MAP> 65, a urine output greater than 0.5ml/kg/hr and admission to ICU as soon as possible). The primary outcome measure was in-hospital mortality, with secondary outcomes including resuscitation end point and organ failure. 288 patients were evaluated with 25 excluded, 133 in the standard therapy group and 130 in the EGDT group. In-hospital mortality was 30.5% in the EGDT group compared with 46.5% in the standard group assigned (CI 0.38-0.87, p=0.009, NNT=6). Patients in the group that received EGDT received more fluid, inotropic support, and blood transfusions during the first six hours than did control patients, who received standard resuscitation therapy. During the interval from 7 to 72 hours, patients in the group receiving early goal-directed treatment had a higher mean central venous oxygen concentration, a lower mean lactate concentration, a lower mean base deficit, and a higher mean pH than the control group.

Rivers study achieved spectacular effects, but was not without criticism and limitations: the trial specifically related to emergency department patients and not other hospital populations; it was a single centered with limited blinding at best; the control group had an above average mortality (46%) when compared to other centres in the US at the same time (2); the study was potentially an examination of a dedicated ICU and ED physician driving the success of the protocol. More recently, many individual elements of the protocol either lack an evidence-base (MAP > 65mmHg) or are difficult to implement quickly (beat to beat ScvO2 monitoring) or have been shown to be limited in their clinical usefulness (CVP 8-12mmHg).

Since 2004, the Surviving Sepsis Campaign guidelines have endorsed EGDT but the uptake of this resuscitation approach has been variable. Barriers to uptake include concerns regarding the generalisability of the original EGDT trial findings outside of a single US centre, the potential risks associated with individual elements of the protocol and the infrastructure and resource requirements needed to implement EGDT. This debate surrounding Rivers seminal study, as well as, INARC evidence that the incidence of severe sepsis was increasing, fuelled the desire for one of more large multi-centered RCTs to examine the importance of the EGDT bundle in the management of early severe sepsis. 3 such RCTs were devised with a degree of collaboration in their designs, each to be conducted on a separate continent: the PROCESS trial in North America (3), the ARISE trial (4) in Australasia and finally the PROMISE trial in Europe (5), with all being published in the last 12 months.

The first of these trials was the PROCESS trial (3). It was designed as a pragmatic non-blinded RCT conducted across 31 academic hospitals in North America from March 2008 to May 2013. The participants were randomized to one of three groups: EGDT group, which received highly protocolised care for 6 hours (based on Rivers et al 2001); Protocol-based standard therapy, which received a less stringent variation on EGDT based on published expert opinion for 6 hours; and, a control group with no extra staffing and all care individualised by the attending physician for 6 hours. The primary outcome was 60-day mortality, and secondary outcomes included 90-day and 1 year mortality. Overall, there was no significant difference between the groups for 60-day mortality. EGDT group’s mortality was 21.0%, Protocol-based therapy was 18.2% and the control group’s mortality was 18.9, with no significant difference between the groups. There was also no significant difference with respect to morbidity or 90-day and 1-year mortalities. It was a well-designed study that adhered to the CONSORT guidelines though there has been some criticism concerning the alteration in the protocol part of the way through the trial to adjust the fluid regime.

The ARISE trial had the same definition of severe sepsis and septic shock as the PROCESS trial, and had a similar design. Again, it was a multi-centered unblinded RCT and it was analysed on an intention to treat basis. Conducted in 51 hospitals between 2008 and 2014. 1,600 patients with severe sepsis with mean baseline APACHE II score 15.4 & 15.8 and admission lactates of 6.7 and 6.6mmol/l in the EGDT and control groups respectively. The EGDT group received an algorithm based heavily on Rivers original protocol including inserting a CVC line that measured ScVO2 continuously. The control group received usual care except ScVO2 could not be measured in the first 6 hours. There was no significant difference in the primary outcome (90-day mortality); the EGDT group mortality was 18.6% compared to 18.8% in the control (ARR, -0.3%; 95%CI, -4.1 to3.6; p=0.9). There was also no difference in ICU and hospital length of stay, nor in renal replacement therapy and mechanical ventilation. There was an increased requirement for vasopressors in the EGDT group (66.6% vs. 57.8%), red cell transfusion (13.6% vs. 7%) and dobutamine (15.4% vs. 2.6%) (p<0.001 for all comparisons) though this is likely related to the strict demands of the algorithm.

The final of the three studies was the European contribution: the PROMISE trial (5). Again designed in a similar vein to the Australasian and North American Trials as a pragmatic large multi-centered trial to compare EGDT with current standard care. The intended benefit of PROMISE was that the power calculations were designed to detect a 20% reduction in 90-day mortality with EGDT. It was a well-designed and conducted study. Secondary outcomes included SOFA scores, 28-day mortality, 1-year mortality and cost assessments. Patients had to be randomized within 2 hours of ED arrival. 6,192 patients met the inclusion criteria, however, 2415 also met the exclusion criteria, and another 2517 were eligible but did not undergo randomization. The remaining 1260 were divided evenly between EGDT and usual care groups. 90-day mortality for EGDT was 29.5% and 29.2% for usual care (RR for EGDT was 1.01; 95% CI 0.85 to 1.2; p=0.9). EGDT led to significantly higher SOFA scores, more vasoactive drugs, more transfusions, increased volumes of fluid and longer ICU lengths of stay. There were no other significant differences except that, perhaps predictably with more intensive therapy and no survival advantage, there were increased costs with EGDT. The authors’ conclusions were that there were no demonstrable advantages to ScvO2 monitoring or strict protocolization, and that this may be due to the natural evolution in usual resuscitation over the last 15 years since Rivers et al.

Most recent, a conglomeration of the ARISE, PROCESS and PROMISE trial authors, Angus et al published a meta-analysis of recent trials in EGDT (6). Its purpose was to examine whether EGDT reduces mortality compared to other resuscitation strategies in ED patients with severe sepsis from 2000 to 2015. Of the 2395 abstracts reviewed, 5 trials were included (n=4735 patients). There was no effect on the primary mortality outcome (EGDT: 23.2 % (495/2134) versus control: 22.4 % (582/2601); pooled OR 1.01 (95 % CI 0.88–1.16, p = 0.9). The 90-day mortality from the three recent multicentre studies (n = 4063), described above, showed no difference (pooled OR 0.99 (95 % CI 0.86–1.15), p = 0.93). EGDT increased vasopressor use (OR 1.25 (95 % CI 1.10–1.41); p<0.001) and ICU admission (OR 2.19 (95 % CI 1.82–2.65); p< 0.001). The authors concluded that there was no clinical advantage to employing EGDT and it leads to increased utilization of ICU resources. This last meta-analysis provides excellent quality, pragmatic evidence that cleared demonstrates that EGDT does not provide clinical benefit beyond standard practice and any of original benefits shown by Rivers, such as concentrated, dedicated early care with prompt antibiotics and adequate resuscitation, probably have been subsumed into modern ED/ICU practice.

Conclusions:

This case summary has allowed me the opportunity to review the literature that both initially underpinned the introduction of EGDT and the more recent multi-centered trials that have questioned the efficacy of strict protocols for initial resuscitation of patients in septic shock. There appears that there little room for doubt that in the current ICU/ED era that usual care as practiced throughout the Western World is clinically as effective as a variations on EGDT strict protocols, more practical to institute and more cost effective than EGDT. This not to imply that Rivers et al work is not without merit. Their study was hypothesis driving and has probably been responsible for a number of changes in standard practice that have rendered their own protocol obsolete. Those changes have corresponded with an ever-improving survival profile sepsis (7). However, while it appears sensible to regularly review individual goals for patients suffering from sepsis, strict predetermined structure can no longer be advocated.
References:
(1) Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy Collaborative Group Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;34519:1368-1377.
(2) Jones A. Should Lactate Clearance Be Substituted for Central Venous Oxygen Saturation as Goals of Early Severe Sepsis and Septic Shock Therapy: Rebuttal from Dr Jones. Chest. 2011;140(6):1413-1415.
(3) The ProCESS Investigators (2014) A randomised trial of protocol-based care for early septic shock. N Engl J Med 370:1683–1693
(4) The ARISE Investigators and the ANZICS Clinical Trials Group (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506.
(5) Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RG, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM, ProMISe Trial Investigators (2015) Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 372(14):1301–1311.
(6) Angus D., Barnato A., Bell D. et al. A Systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. DOI 10.1007/s00134-015-3822-1.
(7) Kaukonen, K., Bailey, M., Suzuki, S. et al Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13):1308-1316.