NephMadness 2015: ProCESS ARISE ProMISe and the promise of Early Goal Directed Therapy

Boka Linkedin 2014Kamran 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:

  1.  Deliver high flow oxygen
  2. Take blood cultures
  3. Administer empiric IV antibiotics
  4. Measure serum lactate and complete blood counts
  5. Start IV hydration resuscitation
  6. 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.

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4 Comments on NephMadness 2015: ProCESS ARISE ProMISe and the promise of Early Goal Directed Therapy

  1. These are good points. Of course conclusions should not be made as a function of these simplistic trials which all used the guessed sepsis and septic shock criteria.

    None of the trials ARISE, PROcess, Promise ever had a chance of success. Of course they were going to fail.

    More importantly these studies tell us nothing about the utility of SVcO2, lactate, etc because the fundamental concept that septic shock is a unified phenotype definable by a few guessed thresholds and a few unified treatment targets is a 1980s myth.

    No large sepsis trial has been reproducible because they are all based on the myth and guessed definitions. This is classic “pathological science” (Langmuir) which gives the appearance of the scientific method but is based on guessed unified gold standards rather than sepsis phenotypes and therefore such research CANNOT be reproducible.

    It is time to increase the volume of the call to Reform Sepsis Science. It is “cargocultscience” and the cargo plane will never land.

    This paper tells the sad, almost unbelievable story of 25 years of sepsis science. No discerning scientist reading this would have thought Process, ARISE, or Promise would be successful. So why has the reform movement been so slow?

    After failure of Process the spin was that improved care reduced mortality in the controls. After ARISE failed the leaders were calling for a metanalysis. With Promise failing they have gone silent.

    Yet, short of serendipity, none of these trials had a chance because they were based on pathological science.

    Sepsis thought leaders are spinning like politicians. No more spin. The plane is not going to land. We need reform of sepsis science. We need that now. Read this sad, almost unbelievable story of the “science” of sepsis.

    Do you think the present science of sepsis is valid. We welcome open debate.

    Here is the sad story.

    Lawrence Lynn

    • Never has some one taken so much space to say so little.

      You complain that the diagnosis of sepsis was inadequate but never say why or how it should be diagnosed.

      You seem to argue that the three studies do not use a sepsis phenotype, I beg to differ, the SIRS criteria are well validated phenotypes of sepsis.

      To say that critics of PROMISE have fallen quiet could only be said if your head is in the sand, because in the week since publishing I have read at least a dozen insightful perspectives on the issue, including two on AJKDblog.

      And to argue that the results from these three trials are irreproducible is asinine as all three studies perfectly reproduced each other’s results.

      And lastly, you denigrate the entire field of sepsis study, yet that field has produced progressive, consistent and measurable reductions in mortality over the last decade. If this is pseudoscience, sign me up because it is saving lives.

      Joel Topf

      • Hello Dr.
        Thanks you for your courageous defense of the sepsis science. This is the type of open debate which is needed.

        Unfortunately, SIRS criteria (thresholds) were guessed by a few docs in the late 1980s for use in a failed trial of sepsis using high does methylprednisone. They were then incorporated into the 1991 consensus sepsis criteria and survive today as a function of tradition. As was typical of guessed thresholds in the late 20th century, SIRS criteria was largely based on the metric system (the numbers 10& 100) not human physiology. My editorial linked in my comment above tells the sad history of SIRS and the sepsis criteria.

        Not only is SIRS profoundly non specific, it is insensitive (as recently shown last week in the NEJM).

        SIRS (which are, in fact, actually the “sepsis criteria”) were guessed and one cannot perform science by studying guesses as standards. If a researcher does that the researcher is actually studying the guess and not the condition he or she thinks is under test.

        The “saved lives” you speak of may be those widely quoted based on billing code research (embellished as “administrative data”). However using billing codes there has been inflation of the sepsis code (sepsis code incidence has doubled) with a concomitant fall in pneumonia code.
        We don’t doubt that the awareness and early recognition efforts are effective but billing code research and research using non specific and a broad net for the definition of disease is not reliable evidence.

        However you miss the point. We do not argue against sepsis awareness, SEPSIS 6, SIRS, or EGDT or its components for clinical use. We have long advocated assessment of sufficiency of oxygen delivery as a reasonable pathophysiology based goal. I am personally in favor of SVO2, and serial lactate and bicarbonate testing in some phenotypes of septic shock. In fact the arguments are coming now against SVcO2 and lactate on the very basis of this pathological research and this is what we do not want to happen. These diagnostic methods probably work well in specific phenotype hidden in the large non-specific net.

        We question a “science” which applies a set of “one size fits all rules” to define and a set of “one size fits all rules” to treat treat a heterogeneous set of infection related conditions (phenotypes) and then tries to draw conclusion about all phenotype of sepsis based on those results. That is not statistically valid work as the population subsets (phenotypes) are not defined by a valid standard. Treating sepsis as a single phenotype is a bit like treating real failure as a single phenotype.

        So what is a phenotype of sepsis. First it is a dynamic relational pattern. Consider the phenotype of septic shock caused by beta step. Beta strep is a primary human predator, it has evolved to predate us. Therefore the genome of beta strep manifests a significant portion of its phenotype (as a function of its predating proteins) in its prey. Human septic shock due to beta strep is therefore “the extended phenotype of the beta strep genome”. The same is true of H1N1 influenza virus. The phenotype of H1N1 is not limited to the viral structure but rather extends to the pattern of infection in the host (which it codes for). The human phenotypic response affects combined with the extended phenotype defines the sepsis phenotype of beta strep observed at the bedside.

        Is the phenotype of beta step septic shock the same as e coli bacteremia with hypotension? Look for example at the Ebola Sepsis phenotype in this link. Note that the dynamic pattern starts as a viral syndrome but then evolves into a dynamic condition which looks like a phenotype of enteric bacterial sepsis.

        So even a single phenotype of sepsis may change in morphology over time. How does one determine that change in dynamic morphology if only one phenotype of sepsis (SIRS) is accepted as the standard.

        Sepsis is comprised a group of phenotypes, each of which are complex dynamic relational condition. This is hard stuff and not intended for the awareness effort or for those who do better at the bedside thinking of disease in simple protocol and threshold terms. My comments are meant for young scientists. Those who might be ready to accept that one size fits all p values of data fragments might not be valid statistical measures of dynamic relational conditions for which the time of onset is not known.

        Karl Popper stated ” ‘Normal’ science, in Kuhn’s sense, exists. It is the activity of the non-revolutionary, or more precisely, the not-too-critical professional: of the science student who accepts the ruling dogma of the day… in my view the ‘normal’ scientist, as Kuhn describes him, is a person one ought to be sorry for… He has been taught in a dogmatic spirit: he is a victim of indoctrination… I can only say that I see a very great danger in it and in the possibility of its becoming normal…”

        We have been respectfully calling for reform of sepsis science for years. No one was listening. With our predictions coming true it is time to up the volume as many more of the young scientists may now be listening.

        The world depends on us, there is no backup.

        Lawrence Lynn

  2. Let me clarify.

    Septic shock, as a unified phenotype, does not exist. For example Septic shock in Ebola comprises an extended phenotype of the viral RNA. So to staph sepsis or toxic shock is the extended phenotype of a super antigen producing Staphylococcus. For many organisms that prey on humans, sepsis is their extended phenotype like a dam is the extended phenotype of beaver DNA.

    However, each phenotype of septic shock is also a hybrid of the host phenotype and the extended phenotype of the microbe.

    This is why EGDT (one size fits all) protocols fail. There is no such thing as “sepsis” as an “all” entity. Sepsis is comprised of a range of phenotypes which are in turn defined by the microbe DNA, the
    host DNA, and the site of infection.

    So we have to stop thinking in 20th century terms when sepsis was considered simply as a unified pathway of immune dysregulation triggered by infection.

    We have to define the actual phenotypes. We have to stop thinking we can guess criteria for purposes other than awareness. We have to stop drawing conclusions from simplistic sepsis billing codes studies. We have to stop drawing conclusions from simplistic trials which study the 20th century unified mythical sepsis (as defined by the guessed sepsis criteria).

    We have to stop thinking in such simple terms. We have to reform sepsis science now.

    The world depends on us. There is no backup.

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