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Early goal directed therapy does not improve outcomes in septic shock (ProCESS)
Can we finally “Just Say No” to the mandatory use of central venous catheters and central venous saturation in severe sepsis and septic shock?
In a single center study published in 2001, Rivers et al reported that patients with severe sepsis and septic shock had significantly lower mortality (30.5% vs 46.5%) when a 6-hour protocol of early goal-directed therapy (EGDT) was instituted. The protocol for EGDT called for placement of a central venous catheter (CVC) and monitoring of central venous saturation (ScVO2) and central venous pressure (CVP) to guide use of intravenous fluids (IVF), vasopressors, inotropes and packed red-cell (PRBC) transfusion. Trigger points were recommended for these interventions: crystalloids or colloids were recommended if CVP <8; vasoactive agents when CVP goals were met but mean arterial pressure (MAP) remained <65 mm Hg; and ScVO2 of < 70% triggered transfusion of packed red blood cells to target hematocrit of 30% (or the use of inotropic agents like dobutamine, if hematocrit was already >30%). Early goal directed therapy rapidly became standard care for patients with severe sepsis; protocols were implemented at hospitals around the world incorporating all elements of the care bundle, but it was never clear which interventions were responsible for the observed benefits. Since then, various investigators have asked whether all elements of the standard EGDT protocol are necessary or helpful, in light of evidence that dobutamine does not improve microvascular perfusion in septic shock, transfusion to hematocrit of 30% appears harmful in critically ill patients, lactate measurements may be an adequate substitute for the invasively obtained ScVO2, and single center studies often show exaggerated or erroneous results. In other words, a multicenter randomized trial to assess the efficacy of all elements of protocol-based care suggested by EGDT was long overdue. Big news: the landmark results of the ProCESS trial were reported in the March 18, 2014 New England Journal of Medicine.
What They Did
Investigators randomized 1341 patients with severe sepsis or septic shock (hypotension + SIRS criteria) at emergency departments in 31 U.S. hospitals to either:
Protocol based early goal-directed therapy emulating the Rivers protocol, with mandatory placement of a central line to continuously monitor ScVO2 and CVP, administration of IVF, vasopressors, dobutamine and PRBC (n=439),
Protocol-based standard therapy, defined as 6-hour protocol prompted resuscitation with administration of IVF till “clinical” euvolemia and PRBC transfusion to goal hemoglobin of 7.5 g/dl or more; CVC placement and ScVO2 measurements were not mandatory (n=446);
Usual care: bedside provider directed all care without any prompted protocol (n=456).
During the study:
APACHE II illness severity scores were ~21 in all groups.
Central venous catheters were placed in 93.2% of patients in the EGDT group, 56.5% in the protocol-based standard therapy group and 57.9% in the usual care group. Similarly, ScVO2 was monitored in 93.6% patients in EGDT group, 4.0% patients in protocol-based standard therapy and in 3.6% patients in usual care group. Arterial lines for blood pressure monitoring were not required.
Patients in the usual care group received the least amount of IVF during the first 6 hours (2.3 L in usual care vs 2.8 L in EGDT and 3.3 L in the protocol-based standard therapy group).
Patients in the EGDT group received more dobutamine and PRBC during first 6 hours than protocol-based standard therapy and usual care. (dobutamine use, 8.0% vs. 1.1% and 0.9%, respectively; packed red-cell transfusions, 14.4% vs. 8.3% and 7.5%, respectively).
Patients in both protocol-based groups received more vasopressors although use of antibiotics, glucocorticoids and activated protein C was same. All these differences disappeared between 6-72 hours.
It's critical to recognize sepsis early, and this imperative was incorporated into trial design: early treatment with antimicrobials (76% received antibiotics in approximately 3 hours after arrival to ED; 97% received in 6 hours after randomization).
What They Found
There were no differences observed in 60-day mortality (19-21%), 90-day mortality or 1-year mortality between groups. Protocol adherence was good (89.1% adherence in EGDT group and 95.6% adherence in protocol based standard therapy group). No differences were observed in secondary endpoints including cardiovascular failure, respiratory failure, hospital length of stay or discharge disposition; incidence of acute renal failure was higher in protocol-based standard therapy (6% vs. 3% in the other groups).
What It Means
In this multicenter randomized trial, use of central hemodynamics and oxygen saturation monitoring did not result in better outcomes than usual conscientious care not incorporating these interventions. Similarly, the study found no significant advantage of protocol-based resuscitation with respect to morbidity or mortality when compared to the clinical judgment of bedside treating physician. This study confirms the most important elements in management of sepsis: early recognition, early administration of antibiotics, early adequate volume resuscitation using clinical parameters and avoiding over transfusion. If these essential aspects of care are in place, protocolized measurements of central hemodynamics and oxygen saturation apparently do not improve patient outcomes measurably. PulmCCM Editorial: This study was 5 times the size of Rivers et al in NEJM 2001, a single center trial inherently more prone to error and bias, and challenged by some as methodologically unsound. "Usual care" has progressed significantly since 2001 -- in part due to increased recognition brought by the Rivers trial. Although that trial created what now looks like a lot of unnecessary extra testing and invasive catheters (not to mention all the reams of paper to print those protocols), Rivers et al did prompt everyone to "think sepsis" and give antibiotics and fluids earlier, undoubtedly saving many lives. The good news for practicing physicians is that we fought the EGDT protocol to a tie. It's not needed in most patients with severe sepsis, as long as we do our jobs well: acting early, then closely monitoring septic patients for perfusion and response to therapies. Eliminating the indication for dobutamine (likely useless) and transfusion triggers of Hct < 30% (possibly harmful) are surely steps out of the darkness as well. More than half of the patients in the non-EGDT arms received central venous catheters, but since so few of them (4%) were used to monitor ScvO2, the ProCESS trial essentially proves that -- given good care otherwise -- serially measuring ScvO2 is not helpful in treating sepsis. Some will point out that the patients in the original EGDT trial were somewhat sicker (true), but this is not a valid argument given that APACHE scores were roughly similar and there would have to be gross dissimilarities present to overcome the huge power advantages of ProCESS over Rivers et al. (When ProCESS authors restricted their analysis to the sickest patients, protocols still showed no benefit.) Besides, the question is not "whose trial represents truth?" -- it is "whose trial represents truth today?" -- and that answer seems manifestly clear. All that said, protocols built a culture of vigilance for sepsis care: urgent action, frequent bedside examinations and therapy tweaks -- which probably improved usual care enough to produce the negative finding here. (The same phenomenon has possibly occurred with sedation interruptions.) It would be a tragedy in slow-motion if abandoning sepsis protocols led to a deterioration of usual care into apathetic care, losing the hard-won improvements in survival from severe sepsis and septic shock.
Clinical Takeaway: Protocols don't improve survival in severe sepsis and septic shock, but especially in the golden early hours, they might still have value as a handy checklist to keep everyone on top of their game. Early antibiotics, adequate fluid resuscitation and vasopressor support are the essential components of care for severe sepsis and septic shock. The ProCESS Investigators. A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med: DOI: 10.1056/NEJMoa1401602 Craig Lilly. The ProCESS Trial — A New Era of Sepsis Management: NEJM editorial. Should lactate clearance replace SvO2 in sepsis protocols? (Pro/Con, CHEST) Surviving Sepsis Guidelines: PulmCCM Review & Update March 28, 2014: The Surviving Sepsis committee issued a statement responding to the results of the ProCESS trial, in which they “continue to recommend all elements of the current bundles”: http://www.survivingsepsis.org/News/Pages/SSC-Responds-to-ProCESS-Trial.aspx