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SGEM#69: Cry Me A River (Early Goal Directed Therapy) ProCESS Trial

SGEM#69: Cry Me A River (Early Goal Directed Therapy) ProCESS Trial

Podcast Link: SGEM69

Date:  April 2, 2014

Guest Skeptic: Dr. Suneel Upahdye Suneel is a founding member of the BEEM Team.

Case Scenario: You are working in a rural community emergency department. The next patient you see is a 71 year old man who has been sick for three days with fever, chills and a productive cough.  On arrival, the vital signs were as follows: Temp 38.7C, HR 110, RR 24, BP 95/60 (after a 500cc normal saline bolus by ambulance), oxygen saturations 88% on room air.  Skin looks mottled, and the patient seems to be confused on questioning.

You diagnose the patient to be in septic shock, and administer another IV crystalloid bolus, broad spectrum antibiotics and oxygen by mask.  Your hospital does not have critical care facilities, and if the patient requires intubation or invasive vascular monitoring (eg. CVP, arterial line for MAP), the patient will have to be transferred out to another larger centre.

You are aware that the Early Goal Direct Therapy protocols mandated in the 2013 Surviving Sepsis Campaign guidelines include such  invasive measures.  You are also aware that there have been numerous concerns that such aggressive invasive measures may not be necessary for resuscitating septic patients, and that more conservative measures (intravenous crystalloid boluses, broad spectrum antibiotics, lactate screening) may be just as effective.


Question: Is early goal directed therapy (EGDT) or other protocol-based care superior to usual care for septic shock patients in the ED?


Rivers_20080126_Emanuel Rivers 2007

Dr. E. Rivers

Background: It all started over 10 years ago when Dr. Emmanuel Rivers published in the NEJM his single centre RCT showing EGDT could reduce septic mortality from 47% to 31% (NNT=6).

Dr. River’s “bundle” put emphasis on early recognition, IV fluids, broad spectrum antibiotics. Also included vasopressors, iontropes and blood transusions. Monitoring required placement of a central venous catheter.

  1. Early Recognition – Every 60min delay can increase mortality by 7.5%
  2. IV Fluid – Volume is important (30cc/kg IV bolus)  with crystalloid better than colloids (Cochrane SR 2013)
  3. Normal Saline or Ringers Lactate – ringers lactate will not effect lactate levels
  4. Broad Spectrum Antibiotics – Usual source is respiratory genital urinary

Article: The ProCESS Investigators. NEJM 2014. doi: 10.1056/NEJMoa1401602

  • Population: Adult patients >18 years old with at least 2 systemic inflammatory response syndrome (SIRS) criteria, AND refractory hypotension (systolic BP <90mmHg after fluid challenge or requiring vasopressors) or lactate >4mM. Recruited in 31 US tertiary hospital ED’s.
    • Excluded: acute CVA/ACS/CHF/arrhythmia/seizure/GI bleed/status asthmaticus/overdose/burn/trauma/need for immediate surgery, known CD4 count< 50/mm2, advanced directive against resuscitation, CI to CVP line placement, high likelihood of refusing blood transfusion (ie. Jehovah’s witness), resuscitation deemed futile, pregnancy, transfer from other hospital, or participant in another ongoing study.
  • sepsismanagementchartIntervention: Early Goal Directed Therapy vs other protocol-based care
  • Comparison: “Usual care” (at discretion of MD)
  • Outcome:
    • Primary = In-hospital death any cause at 60 days.
    • Secondary = Any death at 90 days, cumulative death at 90 days and 1 year, duration of CV failure, respiratory failure and acute renal failure, hospital and intensive care unit length of stay, and hospital discharge disposition (eg. home, nursing/other long term care facility)

Authors’ Conclusions: “In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in emergency departments did not improve outcomes.”

checklist-cartoonQuality Checklist:

  1. Emergency department population – YES
  2. Randomized – YES
  3. Concealed Randomization – YES
  4. Analyzed in their group – YES
  5. Consecutively recruited – Unsure
  6. Patient groups similar at baseline – YES
  7. Unaware of group allocation – YES
  8. Groups treated equally – YES
  9. Follow-up complete – YES
  10. Patient oriented outcomes – YES
  11. Treatment effect was large and precise – It depends (Dr. Worster’s answer to any EBM question)

Key Results: 31 centres screened about 12,000 patients and ultimately included ~10% (n=1,341). There were about 450 patients in each group (EGDT n=439, Protocol-based n=446 and usual care n=456).

All ED physician/resuscitation teams trained in different protocols, ongoing telephone support 24/7, routine site visits and feedback support processes. Baseline characteristics of patients enrolled essentially identical. Sequential recruiting not reported; the primary author reports average  1 patient/month recruited at various sites (D. Yealy, as discussed on ALiEM podcast).

Protocol-based fluid loading was based on CLINICAL findings (jugular venous destention, rales, decreased pulse oxymetry readings), hypoperfusion and CLINICAL features (mottled skin, oliguria, altered sensorium, MAP <65mmHg with systolic BP>100, arterial lactate >4)


No significant difference in hospital death at 60 days


  • Outcomes:
    • Primary outcome was in hospital death 60 days: NO DIFFERENCE (EGDT 21%, Protocol 18.2%, Usual care 18.9%)
    • Death 90 days: NO DIFFERENCE (31.9%/30.8%/33.7%)
    • ICU admissions: More EGDT admissions (91.3% vs. 85.4% vs. 86.2%)
    • Hospital LOS: NO DIFFERENCE (11.1 days vs 12.3 vs. 11.3)
    • Adverse organ system failures: NO DIFFERENCE for cardiovascular/respiratory/renal; slight increase in acute renal failure requiring dialysis in Protocol group
    • Adverse Events: NO DIFFERENCE (5.2% vs 4.9% vs 8.1%)
    • Disposition Destinations: NO DIFFERENCES
  • Protocol Performance: The protocol-based algorithm was based on 6 hours of resuscitative care but less aggressive/invasive than EGDT (based on literature review, 2 surveys of ED and ICU physicians worldwide)
    • Adherence to Protocols (0-6hrs): EGDT = 89.1%,  Protocol  = 95.6% and not applicable to Usual care
    • Intravenous Fluids: 96% crystalloid overall (colloids not encouraged/excluded): more fluid given in Protocol arm (3.3L) than EGDT (2.8L) or usual care (2.3L)
    • Intravenous Antibiotics: 97% in all 3 arms
    • CVP line placement: EGDT 94% vs Protocol 56.5% vs Usual care 57.9%; SVO2 rarely measured in latter two groups (4% and 3.5% resp). Those who got CVP lines in latter groups received them much later than the EGDT arm patients who got them right away
    • Vasopressor use: 54.9% EGDT vs 52.2% Protocol vs 44.1% Usual
    • Dobutamine use RARE: 8% EGDT vs 1.1% Protocol vs 0.9% Usual
    • Blood transfusion rate: 14.4% EGDT vs 8.3% Protocol vs 7.5% Usual; transfusion threshold set at Hb <7.5g/dl (4.5mmol/L)
photo-1

Dr. Suneel Upadhye

BEEM Comments: This was a well executed three arm randomized clinical trial looking at three likely resuscitation scenarios.  Block randomization 1:1:1 to ensure adequate numbers in each group.

Blinding was not explicitly described in paper or Supp Appendix; but outcomes data locked until Dec 2013 so clinical investigators unaware of different arm outcomes.  No industry sponsorship. Near perfect follow-up for outcomes.

They did change their sample size part way through the study. The initial sample size was 1950 and based on a power calculation on the difference seen in the Dr. River’s trial. Then they changed the sample size. Initial sample size calculation modified at first planned interim analysis due to less observed mortality in control arm (attributed to the changing trend in improved sepsis care over last decade); reduced from 1950 to 1350 patients with preserved power metrics.  The limitations discussed are appropriate and likely irrelevant to the overall conclusions.  Overall quality was super.

This landmark ED-based study further refines the revolutionary care pioneered in the original Rivers EGDT paper in 2001.  It refutes the need for universal invasive monitoring, which will be welcome for most ED clinicians in smaller/rural settings who may not have the full technical support/expertise to fully execute the original EGDT protocol.

This study also reaffirms the importance of early antibiotics, IV crystalloid resuscitation, and following serial lactates to monitor resuscitation success.  The options outlined here can likely be extrapolated easily to those patients with severe sepsis as well as septic shock.

Importantly, this article does NOT refute the value of bundled care, which has been proven in prior trials/metaanalyses to be of significant benefit to reduce patient mortality/morbidity, but does suggest that an all-or-nothing super-invasive strategy (a la EGDT) is not universally required.  Furthermore, the emphasis on crystalloids for IV resuscitation is congruent with SSC guidelines (update 2013) and a 2013 Cochrane update on fluid resuscitation of critically patients.

Finally, although no vasopressor is specified, the results here again are congruent with use of norepinephrine (NE) vs. dopamine (DA) recommendations from the SSC 2013 update and a recent metaanalysis published supporting NE over DA (De Backer et al. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis. Crit Care Med 2012).

Surviving Sepsis Campaign (SSC) Response to ProCESS Trial:Screen Shot 2014-04-05 at 1.59.15 PM

  1. Importance of Early Recognition
  2. 18% mortality rate in “usual” care is much better than the 46% seen in 2001
  3. Because the low mortality rate in the control arm and two other large trials (ARISE and ProMISe) they are not going to revise the bundles at this time
  4. ProCESS does not answer the question about using a protocol to manage patients with severe sepsis without septic shock
  5. Regarding the SSC 6 hour Bundle
    1. Supports MAP target of 65mmHg
    2. Repeat lactate testing no addressed in the ProCESS trial
    3. More than half of the usual care and protocol based care got central lines

Overall, the SSC are a little more reserved in embracing the ProCESS results, but do support overall principles in conjunction with their recent SSC updates. They do refer to a companion paper that supports a target MAP of 65mmHg (NEJM 2014).


The Bottom Line: Effective care for septic shock hinges on early recognition, lactate screening, intravenous crystalloid resuscitation and early broad spectrum antibiotics


Clinical Application: This information is what most ED physicians have been waiting for since the original EGDT paper in 2001, and confirms what most already suspected: generate a protocol based on early recognition, intravenous crystalloids, broad-spectrum antibiotics and lactate screening. This is READY FOR PRIME TIME, NOW!

What do I tell my Patient: It looks like you have a serious infection. We are going to give you intravenous fluids, intravenous antibiotics and admit you to hospital.

Case Resolution: 71 year old man with sepsis probably from a respiratory infection. You have given him 2L of fluid now and intravenous antibiotics. He is looking a little better, his blood pressure is responding and lactate level is going down. You discuss the case with the patient and the family. Ask them if they would like to be transferred to a higher level of care with central monitoring or stay locally. They decide to stay in your rural facility and consider transfer if takes a turn for the worst.

Keener Kontest: Last weeks winner was Jarosław Gucwa from Krakówl. He knew more than five reasons a child would have sinus tachycardia (pain, fever, anxiety, dehydration, malignant hyperthermia, hypovolemia with hypotension/shock and anemia).

If you want to play the Keener Kontest listen to the podcast for the question. Email me your answer at TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

FOAM logoAdditional FOAMed Reviews of the ProCESS Trail:

Shout_OutSpecial shout out to Lauren Westafer and Jeremy Faust. Both have appeared on previous episodes of the SGEM. Lauren was on SGEM#17: Best of FOAM 2012 and Jeremy was on SGEM#49: Fives Stages of EBM Grief. These two bright FOAMed advocates suggested the theme music for todays podcast “Cry me a River” by Joe Cocker.

 


Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.


  • RE:
    IV Fluid – Volume is important (30cc/kg IV bolus) with crystalloid better than colloids (Cochrane SR 2013)
    I think this is an inaccurate statement – there is no good evidence that one is better than the other (SAFE trial subgroup analysis even suggested albumin was better in sepsis, though I wouldn’t touch a subgroup analysis with a barge pole)… and albumin is free to hospitals in Australia!
    Chris

    • TheSGem

      Thanks Chris for listening to the podcast and providing feedback. I will share this with Suneel to see if he wants to clarify.

      Agree that the statement could be viewed as inaccurate. Here is what the Cochrane group concluded. “There is no evidence from RCTs that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery. As colloids are not associated with an improvement in survival, and as they are more expensive than crystalloids, it is hard to see how their continued use in these patients can be justified outside the context of RCTs.”

  • LALynn

    Most excellent clinical discussion. Love to see it taken to the real bedside like that. Well done.

    However, as clinical sepsis researchers we we see another dimension of ProCESS. This study is another in a long line of large sepsis trials which show consistent lack of reproducibilty of results of earlier trials.

    This suggests that the fundamentals of the research, the standards, are flawed. Lack of reproducible results is the hallmark of “pathological science”.

    The present form of Sepsis science based on guessed static thresholds is unchanged and largely unquestioned for 24 years. It is long past time for reformation of sepsis science.

    It is up to the young to reform this antiquated oversimplified 20th century dinosaur. Read the editorial below to learn the unbelievable, but true, story of a “science” built on a few guesses made by a few docs in the 1991 which, overtime became goldstandards. http://t.co/BFWs5nC8mg

    • TheSGem

      Thank you for the positive feedback. We do try to provide a clinical context to move the EBM discussion to the bedside.

      As a skeptic I enjoy learning and considering new information. Your attached editorial was very interesting. I have already shared it with our ClinEpi gurus at BEEM.
      Ken

    • ArnoldMD

      I can’t agree with your conclusion Lynn that the lack of “reproducibility of results from earlier trials” is due to flawed fundamentals of the research. If anything, the heterogeneity of results speaks more to the heterogeneity of the population, not improper research methodology.

      If you are talking broadly in reference to the article you wrote, I can agree in theory, but operationally, short of a better validated diagnostic tool, we are stuck with the consensus guidelines. For now.

      While we don’t have a diagnostic test for sepsis, we have made marked improvement in our approach with the use of better sub-group analysis using descriptive tools as the PIRO score.

      I do agree with you that use static measurements alone is inadequate to truly understand the sepsis syndrome in an individual or a population of patients, however such a request requires larger, more robust studies…like ProCESS.

      But, we can’t ignore the most expensive and deadly disease entity in currently and on-going studies until we get a better performing diagnostic standard, because tomorrow morning I will undoubtedly treat a patient with severe sepsis and having some an algorithm in place will likely guide me and my clinical team to more timely optimization of pre-defined treatment goals than if I operated without them.

      • LALynn

        I agree that the clinical protocols which include early antibiotics and fluid were a major step forward. This is an excellent point you have made which was not clear from my post.

        The problem relates to the science of sepsis. Indeed, when a gold standard is simply a concensus by a small group, future research the concensus not the disorder. As pointed out bt Gaieski et al. the original definition was made by Bones et al. for the high dose methylprednisolone trial which also failed.

        One of the first thing one discovers when doing sepsis research is the difficulty in distinguishing the data of uncomplicated infection from sepsis. This problem is not solved by arbitary selection of threshold cutoffs because this artificially selects the “true state” rendering nonreproducibility.

        There is no doubt that we have to solve the problem of heterogeneity. However we first have to define what sepsis is. We also would do well to immediately accept that sepsis is NOT two SIRS criteria plus a suspicion of infection. That is an artifact generated by some well meaning docs nearly 30 yrs ago seeking to determine if high dose corticosteroids given early would preempt the inflammation cascade.

        Continued use of an arbitrary gold standard and the application of statistical models to the outputs responsive to the arbitrary gold standard will render threshold related anomalies and is a form of “pathological science”. The hallmark of pathological science is nonreproducibly.

        While many clinicians may find the sepsis definition useful they should keep in mind it was NOT based on data from a clinical trial and therefore many without sepsis will meet the definition and many WITH sepsis will not.

        This is, of course, the same reason research using the arbitary sepsis definition as a gold standard is not reproducible.

  • Darin Abbey

    Greetings
    Thanks for the review of ProCESS.
    Here in BC we have provincial ED based Sepsis guidelines. In an effort to support both the understanding and adherence to this standard of care, we recently created a free online learning module which is available at the link below:
    http://bcpsqc.ca/clinical-improvement/sepsis/resources
    [The page has many other excellent Sepsis resources.]

    One curiosity I have is, during ProCESS how often, if at all was bedside ultrasound used to guide fluid resuscitation?
    Thanks again for the podcast.
    Darin Abbey RN
    CNE NRGH ED

    • Ken Milne

      Greetings Darin:
      Thanks for the free (my fav price) online learning module for sepsis from BC. I will check with Suneel about the bedside u/s use for fluid resuscitation.
      Stay well,
      Ken

  • Dr MP

    Do you have a reference for a large trial showing LR does not change serum lactate levels?

    • TheSGem

      Dr. MP:
      I will send that question over to Suneel to see if he can provide the information.
      Thanks for asking.
      Ken

      • Suneel Upadhye

        Hi Dr MP, I’m not sure about large trials showing that Ringer’s lactate does not change serum lactate levels, but two small trials I found confirm this (Didwania et al Crit Care Med 1997, n=24 healthy adult volunteers; Cieza et al, J Infect Dev Ctries 2013, n=40 severely dehydrated patients with choleriform diarrhea)…The Didwania group had previously shown that drawing lactate samples from IV catheters that had not been properly cleared of IV crystalloid prior to blood sampling CAN influence serum lactate level (falsely elevated if RL used, falsely decreased if NS used), however, if the IV line was properly flushed of crystalloid prior to sampling blood, there was no difference…Hope this helps…

  • Luciano Pilla

    Great discussion. Good news.
    Next step: no more CVP measures. They are also misleading.
    Who dares?

    • Suneel Upadhye

      Hi Luciano, thanks for an interesting question…I am not an ICU physician so I did some searching for an answer to CVP question in ICU vs ED settings. Recent med/surg ICU data comparing invasive CVP measure vs US IVC-CI measures showed an inverse relationship (Stawicki et al, 2014: PMID: 24662857) which I don’t know what to make of. Di Lorenzo et al (2012) showed a weak correlation of US IVC diameter with CVP (PMID: 22197199), but again no comments on need to monitor CVP for resuscitation outcomes. The most damning evidence refuting use of CVP for fluid resuscitation was reviewed by Marik et al (Crit Care Med 2013, PMID: 23774337) suggesting a poor correlation of CVP with fluid responsiveness in various critical resuscitation trials…I have not read this in great detail, but it fits with my general historical understanding that CVP is not a useful clinical resuscitation endpoint, at least in the ED…hope this helps…

  • Luciano Pilla

    I meant CVP measurements, sorry.
    When will CVP measurements be abandoned?
    I would like to leave this suggestion for a future podcast.
    Thanks

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