Kamran Boka, (@Boka_MD ) MD MS is a third-year pulmonary and critical care medicine fellow at Henry Ford Hospital, the cradle of EGDT. He is a board-certified internist, physician-educator, and active medical author. He hosts a blog at VagalThoughts and although loves all things Apple, is going public with his recent love of Android.
Do ProCESS, and ARISE ProMISe Away Early Goal-Directed Therapy? A Commentary on How Early Goal-Directed Therapy Actually is Usual Care
An Invited Critical Care Fellow on the Meaning of Usual Care in Early Goal Directed Therapy
From May 2014 until just recently on March 17, 2015, there has been significant controversy surrounding the concept of sepsis resuscitation known as early goal-directed therapy (EGDT) developed by Dr. Rivers in 2001.
EGDT and the 2001 Rivers Study (1)
Early goal-directed therapy per the Rivers Study includes
- early recognition of signs of sepsis at patient presentation
- SIRS criteria
- administration of crystalloid at 30 cc/kg
- maintaining adequate perfusion pressure (mean arterial pressure of ≥ 65 mmHg)
- sustaining a central venous pressure (CVP) of 8 to 12 mmHg (12-15 mmHg in mechanically ventilated patients)
- establishing a urine output of ≥ 0.5 mL/kg/hr
- preserving the central venous saturation (ScvO2) via a centrally placed venous catheter at ≥ 70%, or maintaining a mixed venous saturation (SvO2) via a pulmonary artery catheter at ≥ 65%
- otherwise increasing hematocrit to at least 30% via red blood cell transfusion
- and/or initiating dobutamine infusion to a maximum of 20 micrograms/kg/min
- commencing vasopressors within 6 hours of presentation in patients with hypotension despite aggressive fluid resuscitation
- monitoring of temperature, heart rate, blood pressure, mean arterial pressure, lactate as a surrogate marker of tissue hypoperfusion, and urine output, including clinical assessment
The goals introduced a number of physiologic goals. Using lactate levels provided a convenient a surrogate to provide the bedside clinician with information on tissue bed hypoperfusion (2). Increasing the hematocrit, provided a third way (after volume and inotropic support) to enhance oxygen delivery to ischemic tissues. Use of dobutamine provided another method to augment microvascular hypoperfusion by stimulating myocardial contractility.
Since its inception, implementation of EGDT protocols at emergency departments and intensive care units has intensified around the country and in Europe. The Rivers’ numbers on mortality spoke for themselves—eventually leading to the development of the Surviving Sepsis Campaign (3). In short, Dr. Rivers showed that EGDT saves lives in sepsis.
Over the past decade and a half, the global medical debate regarding EGDT and early sepsis/septic shock management boils down to protocolized care and the concept of equipoise. Does the entire medical community believe that EGDT works? The Rivers trial demonstrated that protocolizing early sepsis therapeutic interventions yielded results—in effect saving lives. Skeptics argue ScvO2 CVCs cost money that their institutions do not have, that frequent lactate checking is cumbersome, and these measures are not necessary for the improved outcomes.
The latest trials are finally bringing evidence to these long running arguments. A collaborative approach among researchers in the United States, the United Kingdom, and Australia/New Zealand has resulted in a trilogy of trials known respectively as ProCESS, ProMISe, and ARISE.
ProCESS Trial (4)
In March of 2014, the ProCESS trial was published in the NEJM. It is a randomized study of 1,341 patients with severe sepsis or septic shock (hypotension or SIRS criteria). The study was performed in 31 hospitals in the United States, comparing what they called “usual care” to protocol-based, early, goal-directed, therapy. The primary endpoint was 60-day mortality. Outcomes yielded no significant difference in the EGDT-arm compared to the “usual care” arm. Critics of the ProCESS study contend that the study was undertaken at academic centers where aspects of the Surviving Sepsis Campaign including lactate monitoring for sepsis were already common.
The ARISE Study (5)
ARISE (Australasian Resuscitation in Sepsis Evaluation) was the next trial after ProCESS to challenge protocolized early goal-direction. This study was published on October 1, 2014, in the NEJM. Dr. Sandy Peake and Dr. Rinaldo Bellomo, leading the ARISE investigators, or Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), questioned the use of early goal-directed therapy (EGDT) in adult patients with septic shock. The primary endpoint was 90-day mortality. Their usual care arm was devoid of frequent lactate and ScvO2 monitoring. EGDT did not reduce all-cause mortality.
ProMISe Trial (6)
In March of 2015, the ProMISe trial was published in the NEJM. ProMISe was a randomized study of 1,260 patients with septic shock. The study was performed in 56 hospitals in the United Kingdom, with comparators being again, “usual care” versus a protocol-based early goal-direction group. he endpoint was all cause mortality at 90 days with secondary endpoints: outcomes of health-related quality of life. No difference was shown in mortality at 90 days among those receiving EGDT versus usual resuscitation.
Interestingly, the ARISE Study shows similar outcomes to the ProCESS trial for primary endpoints of death. The argument for the Rivers Trial has always been that the patients in 2001 were sicker. This is acknowledged per ARISE: “In-hospital mortality for patients who are admitted to ICUs with severe sepsis and septic shock has been reduced by 1 percentage point per year during the past 2 decades.” (5)
If that is the case, then why are we, as a medical community, seeking to abandon continuous central venous co-oximetry and frequent lactate monitoring? CVCs when tied to CVP and ScvO2 monitors have always given us vital information to tune fluid resuscitation to the appropriate and respective slopes of the sepsis mortality and superimposed Frank-Starling curve. If invasiveness is the issue, shouldn’t we wait until septic biomarkers are better validated and understood for global practice?
Sure, opponents will say “no.” They will say that as it stands, the metrics that we are using are not the greatest, such as CVP. They will argue that central venous pressure is a useless and meaningless (7), archaic measure of fluid status and responsiveness. After all, it is a poor surrogate for left ventricular end-diastolic volume. Then why do we continue to use it? The ProMISe investigators claim that “EGDT” via protocol is cost-prohibitive (8).
The challenge, thus far, in sepsis management since the 1970s has been the search for that objective measuring cup for sepsis therapy (8). The parameters of EGDT are clearly delineated in Rivers study, but if these subsequent studies tell us to pursue usual care instead of EGDT, then we must ask: what is usual care? What do we mean by “usual care?”
Usual care as defined in two neighboring hospitals sans protocolized care could be radically different in their approach to early sepsis management. Without the defining Holy Grail biomarker that we have yet to discover and implement in the sepsis treatment paradigm, tools are all we have to engage in resuscitation therapy.
A cursory Google search of the hospitals involved in the ARISE study will show that they already had institutional protocols and policies in place for early goal directed therapy in their emergency departments prior to enrollment in the study. Would that constitute usual care?
In England and Scotland, the Sepsis 6 program has been around since its development in 2006, and based upon the initial 2003 Surviving Sepsis Campaign. The Sepsis 6 program contains the following tasks:
- Deliver high flow oxygen
- Take blood cultures
- Administer empiric IV antibiotics
- Measure serum lactate and complete blood counts
- Start IV hydration resuscitation
- Document accurate urine output measurements (9)
Here’s the kicker: the Sepsis 6 guidelines state that these measures should take place within the first hour of patient care in the emergency room and initial point of care. Doesn’t that put the early in early goal direction?
Furthermore, these are six core measures that have been repeatedly shown to save lives since the original Rivers study in 2001. The National Health Service (NHS) of England delivers an annual report regarding its Sepsis 6 state: “achieving 80% compliance would expect an estimated 15,000 lives saved per year across the NHS.” I question the investigators of the ProMISe trial: Sepsis 6, which is a program that comes out of the United Kingdom, does it not constitute both usual care and protocolized care?
What does the bottom line become? Are we shelving our physiology books in belief that our patients are healthier than in the time of hourly lactates and central venous lines? Or are we more comfortable with less data?
These questions and more have stimulated conversation in journal clubs around the country as well as online. ProCESS and ARISE (and most recently ProMISe) have created a viral discussion among physicians and clinicians not only in the emergency room and ICU, but also on blogs and Twitter. The prevailing hashtags and keywords were #deathtoEGDT,” “nail in the coffin for EGDT,” and “Is early goal-directed therapy necessary?” earlier in the year.
Lately, many prominent blogs and media centers have changed their headlines and realized that visceral reactions and quick commentaries may confuse clinicians who are reading for discourse and seeking constructive criticism of the topics (10). This is good etiquette and appreciated, because semantically thrashing EGDT (especially in the burgeoning Venn diagram of blogging, physicians, and Twitter) has the potential to cause a dangerous and slippery slope.
Although the past three trials have shown that objective means such as ScvO2 CVC monitoring may not be necessary for endpoints, doing away with EGDT as frontline management of sepsis may place blinders on unsuspecting clinicians who only seek the bottom line.
Intrinsic to early goal-directed therapy is early recognition and triage of those who may have sepsis and shock states, maintaining a high-index of suspicion for SIRS criteria, early blood culturing and administration of appropriate broad-spectrum antibiotics, rapid and appropriate fluid resuscitation, and objective monitoring of hypoperfusion (lactate). This is integral to the term EGDT. This is and should be usual care.