Evidence for the Protocols

Evidence for Non-Invasive Protocol

The paper that allowed us to start non-invasive protocols=gamechanger. [1. Jones AE, Shapiro NI, et al.; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb;303(8):739?46.]

Is septic shock without lactate elevation as sick as those with? This retrospective study would say they are not. Maybe the alactemic septic patient can just be fluid resuscitated and get their pressors without having to worry about going further. [2. J Crit Care 2011;26:435] [3. Crit Care Res Pract. 2012;2012:536852]

Additional evidence [2. Crit Care 2008;12:R33],[2. Crit Care 2006;10:R80]

Napoli AM, Seigel TA. The role of lactate clearance in the resuscitation bundle. Crit Care. 2011;15(5):199. Epub 2011 Oct 24. PubMed PMID: 22078132;
PubMed Central PMCID: PMC3334784.

Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. PubMed PMID: 20179283; PubMed Central PMCID: PMC2918907.

Nguyen HB, Kuan WS, Batech M, Shrikhande P, Mahadevan M, Li CH, Ray S, Dengel A; ATLAS (Asia Network to Regulate Sepsis care) Investigators. Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation. Crit Care. 2011;15(5):R229. Epub 2011 Sep 27. PubMed PMID: 21951322; PubMed Central PMCID:PMC3334775.

Rivers EP, Elkin R, Cannon CM. Counterpoint: should lactate clearance be substituted for central venous oxygen saturation as goals of early severe sepsis
and septic shock therapy? No. Chest. 2011 Dec;140(6):1408-13; discussion 1413-9. PubMed PMID: 22147818; PubMed Central PMCID: PMC3244279.

Jones AE. Point: should lactate clearance be substituted for central venous oxygen saturation as goals of early severe sepsis and septic shock therapy? Yes.
Chest. 2011 Dec;140(6):1406-8. PubMed PMID: 22147817; PubMed Central PMCID: PMC3244278.

Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61. Epub 2010 May 12. PubMed PMID: 20463176.

Nguyen’s Asian quality improvement trial added lactate clearance to standard EGDT. These patients were hemodynamically stable with normal ScvO2 and good fluid loading before trial entrance. After multi-variate analysis, patients who cleared lactate had lower risk of death than those who did not. [2. Nguyen HB et al. Outcome Effectiveness of the severe sepsis resuscitation bundle with the addition of lactate clearance as a bundle item: a multi-national evaluation. Crit Care 2011;15:R229]

This flawed study question lactate non-expressors with septic shock. Unfortunately they looked at lactate level after initial resus [1. Dugas. J Crit Care 2012;27:344]

Lactate Non-Expressors are a distinct and less ill population [1. doi:10.1155/2012/536852]

Lactate predicts mortality all the way up to 20 mmol/L [1. Academic Emerg Med 2012;19:983]

Lactate normalization within 6 hours is the best predictor of survival [1. CHEST. 2012 doi:10.1378/chest.12-0878]

Even in the ICU lactate clearance was the best predictor of death [1. Annals of Intensive Care 2013, 3:3 ]

Evidence for the Invasive Protocol (ScvO2 & Lactate Guided Resuscitation)

Meta-Analysis. [1. Jones AE, Brown MD, et al.; Emergency Medicine Shock Research Network investigators. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis. Crit Care Med. 2008 Oct;36(10):2734-9.]

The original, the seminal ED sepsis work. [1. Rivers, E, Nguyen, B, et al. (for the Early Goal?Directed Therapy Collaborative Group). Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med. 2001 Nov; 345(19):1368-77.]

2nd RCT: A prospective, randomized controlled trial was performed involving 273 patients in the early stage of shock at risk of potential MODS development.

The incidence of MODS in the EGDT group was significantly lower than that in control group (P=0.002). The Lactate(2), Lactate(4), SOFA(T), SOFA(S), and the number of dysfunctional organs in EGDT group were also significantly lower (P=0.045, 0.016, 0.009, 0.010, 0.002). EGDT was associated with a significantly lower total mortality rate of MODS than the conventional therapy (P=0.007), and also with a significantly lower mortality rate of MODS after controlling for severe sepsis (P=0.047 and 0.044)[1. Chen ZQ, Jin YH, Chen H, Fu WJ, Yang H, Wang RT. Early goal-directed therapy lowers the incidence, severity and mortality of multiple organ dysfunction syndrome. Nan Fang Yi Ke Da Xue Xue Bao. 2007 Dec;27(12):1892-5.]

A point counterpoint debate with Rivers from Chest. [1. Rivers EP. Point: adherence to early goal-directed therapy: does it really matter? Yes. After a decade, the scientific proof speaks for itself. Chest. 2010 Sep;138(3):476?80;discussion 484-5.]

Best Review Article on ScvO2 [3. Am J Resp Crit Care Med 2011;184:514]

One argument to continue to use invasive strategy is that lactate may not detect low, but persistent levels of oxygen debt. [22. Crit Care Med 2004;32:1825]

Reanalysis of the Jones trial shows ScvO2 clearance did not have as good a mortality benefit as lactate clearance, but remember; very view patients needed anything more that fluids/pressors in this trial [11. Puskarich et al. Prognostic Value and Agreement of Achieving Lactate Clearance or Central Venous Oxygen Saturation Goals During Early Sepsis Resuscitation. Acad Emerg Med 2012;19:252]

GENESIS Project  [1. J Intensive Care Med. 2012 Aug 17.  The GENESIS Project (GENeralized Early Sepsis Intervention Strategies): A Multicenter Quality Improvement Collaborative.]

Intermittent ScvO2 is just as good as Continuous in this prospective cohort trial (10.1136/emermed-2012-201356) (Emerg Med J. 2013;30(11):906-909.)

Sonography of the IVC for Prediction of Fluid Responsiveness

Fluid Assessment Conference Call Handout

Fluid Assessment Sheet

[1. Brennan JM, Blair JE, et al. A comparison by medicine residents of physical examination versus hand?carried ultrasound for estimation of right atrial pressure. Am J Cardiol. 2007 Jun;99(11):1614-6.],[2. Brennan JM, Ronan A, et al. Handcarried ultrasound measurement of the inferior vena cava for assessment of intravascular volume status in the outpatient hemodialysis clinic. Clin J Am Soc Nephrol. 2006 Jul;1(4):749?53. Epub 2006 May 24.],[3. Carr, Brendan G., Dean, Anthony J., et al.; Intensivist Bedside Ultrasound (INBU) for Volume Assessment in the Intensive Care Unit: A Pilot Study. Journal of Trauma?Injury Infection & Critical Care. 2007 Sept: 63(3): 495?502.],[4. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol. 1990 Aug;66(4):493?6.],[1. Moretti R, Pizzi B. Inferior vena cava distensibility as a predictor of fluid responsiveness in patients with subarachnoid hemorrhage. Neurocrit Care. 2010 Aug;13(1):3?9.],[2. Nagdev AD, Merchant RC, et al. Emergency department bedside ultrasonographic measurement of the caval index for noninvasive determination of low central venous pressure. Ann Emerg Med. 2010 Mar;55(3):290?5. Epub 2009 Jun 25.],[1. Weekes A., Tassone H., Tayal V.S. et al. 233: The Sonodynamic Study: Comparison of Qualitative Versus Quantitative Assessment and Inter-Rater Reliability In Serial Ultrasonography Evaluations of Inferior Vena Cava Dynamics and Left Ventricular Systolic Function In Fluid Resuscitation of Emergency Department Patients With Symptomatic Hypotension. Annals of Emergency Medicine. 2010 Sept: 56(3), Supplement , Page S77.],[1. Yanagawa, Youichi; Sakamoto, Toshihisa; Okada, Yoshiaki. Hypovolemic Shock Evaluated by Sonographic Measurement of the Inferior Vena Cava During Resuscitation in Trauma Patients. Journal of Trauma?Injury Infection & Critical Care. 2007 Dec. 63(6):1245?1248.][1. Intensive Care Med. 2004 Sep;30(9):1740-6. Barbier C. et al. Respiratory changes in inferior vena cava diameter are helpful in predicting fluid responsiveness in ventilated septic patients]

Dialysis study shows IVCCI of >30% predicts hypotension and when it is safe to continue fluid removal [1. Intensive Care Med 2010;36:692]


Marik Meta-Analysis

New study showed ok spec for CVP < 8 and shock index [2. Journal of Critical Care Volume 27, Issue 6, December 2012 Pages 609–615]

Lactate as a Marker for Adequate Resuscitation

Elevated lactate is a marker of severe sepsis

[1. Jansen TC, van Bommel J, et al for the LACTATE study group. Early lactate-guided therapy in Intensive Care Unit patients: A multicenter, open?label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sept;182(6): 752-761]|[1. Levy MM, Dellinger RP, et al.; Surviving Sepsis Campaign. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010 Feb;38(2):367?74.]|[9. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, Bellamy SL, Christie JD: Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009, 37:1670-1677.]|[10. Okorie ON, Dellinger P: Lactate: biomarker and potential therapeutic target. Crit Care Clin 2011, 27:299-326.][1. Nichol AD, Egi M, Pettila V, et al. Relative hyperlactatemia and hospital mortality in critically ill patients: a retrospective multi-centre study. Crit Care 2010;14:R25.]|[3. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992;20:80-93.]

|[4. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med 2007;33:1892-9.]|[5. Shapiro NI, Howell MD, Talmor D, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med 2005;45:524-8.]|[6. Cady LD, Jr., Weil MH, Afifi AA, Michaels SF, Liu VY, Shubin H. Quantitation of severity of critical illness with special reference to blood lactate. Crit Care Med 1973;1:75-80.]

|[7. Aduen J, Bernstein WK, Khastgir T, et al. The use and clinical importance of a substrate-specific electrode for rapid determination of blood lactate concentrations. JAMA 1994;272:1678-85.]

Persistent elevation of lactate is associated with dismal outcome. Lactate clearance is associated with better outcome.

[11. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL: Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg 1996, 171:221-226]'[12. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC: Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004, 32:1637-1642]'[13. Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E, Parrillo JE, Dellinger RP, Trzeciak S: Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009, 32:35-39]'[16. Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, Edwards J, Cho T, Wittlake WA: Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med 2007, 35:1105-1112.]'[10. Nguyen HB, Loomba M, Yang JJ, et al. Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock. J Inflamm (Lond) 2010;7:6.]'[11. Broder G, Weil MH. Excess Lactate: An Index of Reversibility of Shock in Human Patients. Science 1964;143:1457-9.]'[12. De Backer D. Lactic acidosis. Minerva Anestesiol 2003;69:281-4.]

For more on Lactate, see the FAQ.

Alactemic Sepsis

In this study, 9.1% of the hypotensive patients had a lactate < 2 and 24.2% had a lactate < 4. [1. Na S. Implementation of a 6-hour severe sepsis bundle in multiple asian countries is associated with decreased mortality. Chest. 2009;136: 20S.]

In this second study, 11.6% of the patients had the lactate <2 and 25% had lactates <4 [2. Cannon CM. The GENESIS Project (GENeralization of Early Sepsis InterventionS): A Multicenter Quality Improvement Collaborative.]

Patients without lactate elevations don’t seem to be particularly sick [1. Crit Care Res Pract. 2012;2012:536852.]

Cryptic (Occult) Sepsis

In abstract form, this demonstrated that the cryptic shock patients probably got the lion’s share of mortality benefit as opposed to the patients that were already on the downslope. [1. Donnino MW. Cryptic Septic Shock: A Sub-analysis of Early, Goal-Directed Therapy http://meeting.chestpubs.org/cgi/content/abstract/124/4/90S-b]

In a newly published study, they compared cryptic and overt shock patients; the mortality between the two groups was the same. This was a reanalysis of the Jones paper. Of interest, many of the patients in the Occult Shock group had lactates < 4; are these patients less sick? [1. Resuscitation 2011;82:1289]

Early Antibiotics

Kumar proved antibiotic timing is incredibly important in septic shock. [1. Kumar A, Roberts D, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589-96.]

And it needs to be the correct antibiotic. [1. Kumar A, Ellis P, et al.; Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009 Nov;136(5):1237?48.]

If antibiotics were delayed until after shock recognition, severe sepsis patients did markedly worse. Delay for patients not in shock did not seem to have an effect on mortality [4. Puskarich et al. Crit Care Med 2011;39:2066]

Time from EGDT Criteria to ABX assoc with mortality [1. Crit Care Med 2010; 38:1045–1053]

Source Control

Get the operation within 6 hours in perforated viscous [1. Critical Care 2014, 18:R87}

Vasopressor Choice

De Backer’s Meta-Analysis of dopamine vs. norepi, may be the final piece in making norepi the 1st choice pressor for sepsis [1. CCM 2012;40:725]

RBC Transfusion

Small study only capable of suggesting hypotheses: In patients with Hb 6-8, transfusion improved micro-dialysis assessed lactate/pyruvate ratio. But some patients improved and some got worse. Patients with bad L/P pretransfusion were most likely to improve with transfusion. (Intensive Care Med 2012;38:1843)

Propensity analysis showed decreased mortality in patients who received PRBC transfusion [1. CCM 2012;40:3140]

Barriers to Implementation

Carlbom DJ, Rubenfeld GD. Barriers to implementing protocol?based sepsis resuscitation in the emergency department??results of a national survey. Crit Care Med. 2007 Nov; 35(11):2525?32.

Mikkelsen ME, Gaieski DF, et al. Factors associated with nonadherence to early goaldirected therapy in the ED. Chest. 2010 Sep;138(3):551?8. Epub 2010 Feb 19. Surviving Sepsis Campaign Guidelines

Dellinger RP, Levy MM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan; 36(1):296?327. Erratum in: Crit Care Med. 2008 Apr;36(4):1394?6. Normal Vital Signs do not predict adequate resuscitation

Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med. 1996 Mar; 14(2):218?25. Intubation will improve organ perfusion

Hernandez G, Peña H, et al. Impact of emergency intubation on central venous oxygen saturation in critically ill patients: a multicenter observational study. [1. Crit Care. 2009; 13(3):R63. Epub 2009 May 4.]

In an ED study, placing A-line, CVP, or getting ScvO2 was v. hard [2. Journal of Emergency Medicine  Volume 42, Issue 5, May 2012, Pages 503–510]


Still patient benefit even if we miss the 6-hour time window for bundle completion [1. Shock 2011;36(6):542]

When we look at the microcirculation, some patients will actually benefit from MAPs of >65. They used NE and pushed MAP to 85 mm Hg and then checked micro-circ effects with NIRS and SDF [1. Crit Care 2011;15:R222]

Meta-analysis shows norepi is better than dopamine for severe sepsis [1. Crit Care Med 2011;Oct 27-De Backer]

Dopamine causes a-fib–If you wind up with new a-fib in severe sepsis, you have a higher risk of stroke and of death [1. JAMA. 2011;306(20):2248-2254]

Vasopressin even at the 0.4 u/hr dose may impair gastric perfusion [1. Anesthesiology.  2011; 114(6):1396-402]

Classification of what sepsis, severe sepsis, and septic shock varies amongst different studies and affects predicted mortality [2. Intensive Care Med (2012) 38:811–819]

PRBCs in one article do not improve ScvO2 or Organ Function, but not clear that these pts should have received transfusion by EGDT criteria [1. JEM;2012:43(4):593]

The CV and MicroCirc effects of dobutamine. Use if echo evidence of systolic dysfunction [1. Journal of Critical Care, Volume 27, Issue 6, December 2012, Pages 630–638]

EGDT safe and effective in ESRD patients and they got intubated less [1. Critical Care 2004, 8(Suppl 1):P163 (DOI 10.1186/cc2630)]

CRP seems just as good as Procalcitonin for when to stop ABX (23921272 )

Excellent Reviews

Marik’s take on what to do with severe sepsis [1. Annals of Intensive Care 2011;1:17]

Point/Counterpoint on Resuscitation Goals from Rivers and Jones

Proof of my contention of Denominator Shift Bias

[1. JAMA. 2012 Apr 4;307(13):1405-13.]

Regulatory Crap

Many septic patients do not meet criteria within 3 hours (24680548)




  1. Brian Wieczorek says


    I am interested in any feedback you may have on the use of ketamine drips for sedation in the setting of severe sepsis. I have been using fentanyl drips for sedation in a variety of settings with success. I would think that ketamine would be an ideal sedative adjunct with severe sepsis. Any information or feedback to support the use of ketamine in this setting is appreciated.

    Brian Wieczorek MD

  2. ed says

    scott you said sepsis protocol result in 12 percent mortality reduction. Do the patients who die of sepsis in your protocol suffer longer. For example do they stay longer in ICU. Do they end up receiving more invasive interventions?

    If more people are cured AND those that die do so more humanely, than your protocol should be adapted widely. I will cast my net wide.

    If those that die survive weeks in ICU instead of hours; the protocol might benefit from some exclusion criteria. I will cast the net more selectively.

  3. John says

    The triage screening tool seems very liberal. During a bad flu season there are days when it seems as if everyone meets SIRS criteria. Several otherwise healthy people with the flu or URI would might be getting an invasive and unnecessary screening work-up. Then what to do with the young person, mildly malaised but non-toxic, flu positive with a white count of 18k, creatinine/BUN of 1.4/30 and a lactate of 3.0?

    • says

      That was our intent. All a positive screen gets you is a lactate sent; there is no reason not to be liberal on the screen. In your pt you mention with a lactate of 3, what do you do? You do exactly what you would have done without a lactate. Flu does cause severe sepsis though and a patient with a lactate of 5 is probably staying in-house b/c they might be one of the many who will decompensate like the ones we have been seeing this flu season.

  4. chris hartman says

    i’m getting lots of grumblings about initiating a sepsis triage screening tool without a formal wbc count because i suspect it doesn’t identically match sirs criteria. clearly it fails to become a triage screening tool if laboratory data is included. any true evidence based on excluding the wbc count beyond what i would describe as obvious logic. thanks. anyone’s thoughts would be appreciated. thanks. cjh

    • says

      I think the grumblers are missing the point, the GNYHA screen is more sensitive not less. We haven’t published yet, but we have >15,000 patients now and the screen has found the severe sepsis patients at our participating hospitals. What I would tell these folks is do the triage screen, and then if a patient screens negative, the docs or PAs or NPs will get back the white count and they can reeval if they want to send a lactate.

  5. Harry Peled says

    There are 3 major RCT’s questioning the whole Rivers Protocol. One is ARISE trial from the ANZICS group and Process trial funded by NIH from University of Pittsburgh as well as one in the UK. There is evidence that excess fluid titrated to CVP increases mortality and if one is Rivers purist one should aim for Hgb of >10 in some of these situations (not 7-10). though major RCT shows no benefit from tx >7.0 hgb in most cases. Also some studies have shown dobutamine increases mortality in sepsis. No one argues with early aggressive fluids and keeping MAP. The value of the protocol and interventions is questioned by many reputable physicians. I am happy to send reference list if desired.

    • says

      You may want to listen to some of the recent casts on the subject. I am not a proponent of classic EGDT, but that being said:
      There is NO evidence that fluid titrated to CVP increases mortality
      There is no evidence that a Hb trigger of 10 has no benefit IN THESE PATIENTS.
      No study shows dobutamine increases mortality when titrated to non-supranormal goals.
      We may want to separate out the associations from causative evidence when we make this case.

  6. Harry Peled says

    Agee with dobutamine as harm only shown for supranormal. However if titrtae to mixed venous alone one may overshoot. Agree that not clear if harm in this subset by hgb 10 but the only RCT has not shown benefit. There is a retrospective study showing better mortaility with CVP<8 as opposed to 8-12 based on VASST study admittedly it is not an RCT- Crit care Med 2011 Vol 39 #2 p259-265. Thanks and do overall like the modfied rivers approach yu have on the site. Thanks

  7. A. Wohl, MD says

    Apologies that this comment is late in the game..Hopefully you’ll see it and can give some advice.
    We are just now (better late than never..) implementing system wide protocols for early screening and treatment protocols for sepsis. I’ve been tasked with the staff education part and have relied heavily on your work with the NY collaborative. We are advocating simultaneous antibiotic administration for our ED nurses. However, the some of the nursing staff appear to be suffering from “paradigm paralysis” as sequential antibiotic administration has been a dogma long taught in nursing school “in order to know which antibiotic might cause a reaction”. Is there literature that discusses the actual percentage of antibiotic reactions so I can help shift their paradigm? Do you have any other practical advice to help with this barrier?
    Thanks so much Scott,

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