EMShockNet

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Clinical Question

In patients in severe sepsis and septic shock undergoing resuscitative efforts targeting central venous pressure (CVP) and mean arterial pressure (MAP), is there a difference in in-hospital mortality, ICU length of stay, hospital length of stay, ventilator-free days, or new onset multiple organ failure when lactate clearance is used as a resuscitation goal instead of continuous central venous oxygen saturation (ScvO2) monitoring.

Bottom Line

There appears to be no mortality increase when using lactate clearance as a resuscitation goal instead of continuous ScvO2 monitoring in addition to CVP and MAP in this noninferiority study evaluating patients with severe sepsis and septic shock.

Major Points

In the 2001 Rivers Trial, hemodynamic goals for resuscitation were shown to dramatically improve in-hospital mortality in septic patients. These goals specifically target goal CVP, MAP, ScvO2, and UOP. The results of this study were implemented into the Surviving Sepsis Campaign guidelines[1]. ScvO2 was intended to be a measure of tissue oxygen delivery and consumption, and requires invasive and expensive equipment in the form of a specialized central venous catheter. ScvO2 monitoring has been controversial for this reason, and lactate measurement may represent an alternative goal that correlates to tissue oxygen delivery and consumption.

The 2010 RCT for the EMShockNet investigators is a non-inferiority trial performed in 3 US large urban medical centers which randomized 300 patients to either an ScvO2 group or a lactate clearance group. Each group also underwent sequentially provided therapy to meet CVP, MAP, and then ScvO2/lactate clearance goals. No statistically significant differences in in-hospital mortality (17% Lactate vs. 23% ScvO2), length of ICU or hospital stay, or hospital complications were appreciated. This trial was limited by an overall small number of patients requiring blood transfusions/inotropes (the planned intervention in response to lactate or ScvO2 outside of the goal ranges), lack of blinding, conducted at institutions that already had ED-based quantitative resuscitation programs for sepsis, which may limit how generalizable the study is. Mortality in this study was lower than expected, which may also limit how generalizable the results are.

The outcome of this study suggests that invasive ScvO2 measurements may not be necessary to improve mortality in septic patient who are otherwise undergoing quantitative goal directed therapy. The study failed to show inferiority of lactic acid clearance when compared to ScvO2 as a resuscitation goal behaving as a proxy for the balance of oxygen delivery and oxygen consumption in the tissue.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[2]

  • Begin treatment and resuscitation immediately (best practice statement [BPS] are ungraded, strong recommendations)
  • For sepsis-induced hypoperfusion, give ≥30 mL/kg IV crystalloid fluid in the first 3 hours (strong recommendation, low quality evidence)
  • After initial resuscitation, given additional fluids guided by frequent reassessment of status of hemodynamics like HR, BP, PaO2, RR, temp, UOP, noninvasive, and/or invasive monitoring (BPS)
  • Target MAP of 65 mm Hg in patients requiring vasopressors (strong recommendation, moderate quality of evidence
    • Norepinephrine as first line vasopressor (strong recommendation, moderate quality of evidence)
      • Add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to raise MAP to target
      • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, moderate quality of evidence)
  • Suggested guiding resuscitation to normalize lactate in those with lactate elevations (weak recommendation, low quality of evidence)
  • Recommend administration of IV antimicrobials as soon as possible, preferably within 1 hour of recognition (strong recommendation, moderate quality of evidence)

Design

  • Multicenter, prospective, nonblinded, parallel-group, randomized, controlled trial
  • N=297 (452 screened)
    • ScvO2(n=150)
    • Lactate Clearance (n=150)
  • Setting: Emergency departments of 3 large US urban medical centers
  • Enrollment: January 2007 - January 2009
  • Analysis: Intention-to-treat as well as per-protocol analysis
  • Primary outcome: Absolute in-hospital mortality rate
  • Secondary outcomes: ICU length of stay, hospital length of stay, ventilator-free days, new onset multiple organ failure, number of resuscitative goals achieved, administered treatments, pre-defined protocol-related serious adverse events

Population

Inclusion Criteria

  • Age > 17 years
  • Confirmed or presumed infection
  • 2 or more systemic inflammatory response criteria [3]
  • Hypoperfusion
    • Systolic blood pressure < 90 mmHg after a minimum 20 mL/kg rapid volume challenge or
    • Blood lactate concentration of at least 36 mg/dL (4 mmol/L)

Exclusion Criteria

  • Pregnancy
  • Primary diagnosis other than sepsis
  • Suspected requirement for immediate surgery within 6 hours of diagnosis
  • Absolute contraindication to either chest or neck central venous catheterization
  • CPR
  • Transfer form another institution with a sepsis-specific resuscitative therapy underway
  • Advanced directive orders that would restrict the study procedure

Baseline Characteristics

From the Lactate Clearance Group

  • Mean age: 59.8 years
  • Race: 59% white, 31% Black
  • Sex: 55% men
  • Comorbidities
    • Diabetes Mellitus: 30%
    • COPD: 17%
    • HIV Positive: 8%
    • End-stage renal disease: 10%
    • Active malignancy: 28%
    • Organ transplant: 3%
    • Indwelling vascular line: 4%
    • Nursing home resident: 19%
  • Disease Severity: Mean (SD)
    • SAPS II score: 44.8 (18.4)
    • SOFA score: 6.7 (3.6)
    • MEDS score: 10.9 (3.9)
  • Suspected infection source
    • Pulmonary: 32%
    • Urinary tract: 27%
    • Intra-abdominal: 23%
    • Skin/soft tissue: 13%
    • Blood: 5%
    • Unknown: 9%
  • Features of sepsis
    • Lactate ≥ 41%
    • Shock: 81%
    • Culture positive: 82%
    • Blood culture positive: 41%
    • Gram positive: 22%
    • Gram negative: 19%

Interventions

  • Randomized to ScvO2 group or Lactate clearance group
    • ScvO2 group
      • Central venous catheter connected to computerized spectrophotometer that displayed continuous ScvO2
      • First, isotonic crystalloid administered in boluses to achieve CVP ≥ 8 mmHg
      • Second, MAP goal of ≥65 mmHg, if not achieved with fluids, targeted by initiation/titration dopamine or norepinephrine
      • Third, ScvO2 goal of ≥70% achieved by transfusion of pRBCs if Hct < 30%, or dobutamine initiation/titration if Hct > 30%
    • Lactate clearance group
      • Received identical central venous catheter as ScvO2 group, but was not connected to computerized spectrophotometer, preventing display of ScvO2
      • CVP and MAP goals as per the ScvO2 group
      • Lactate clearance ≥ 10% (or if both lactate concentrations were not elevated)
        • Lactate clearance calculated by [(Initial Lactate - Delayed Lactate) / Initial lactate] x 100%
        • Initial lactate measured at the start of resuscitation
        • Delayed lactate measured at least 2 hours after resuscitation was initiated.
        • If lactate clearance < 10% and Hct < 30%, prBCs administered, else if Hct > 30%, dobutamine initiated and titrated
        • While lactate clearance was less than 10%, lactate measurements were performed at minimum 1 hour intervals

Outcomes

Comparisons are lactate clearance monitoring vs. ScvO2 monitoring.

Primary Outcomes

In-hospital mortality rate (Intent-to-treat)
17% vs. 23% (Mortality difference = 6%; 95% CI -3% to 15%)

Secondary Outcomes

ICU length of stay, mean (SD), d
5.9(8.46) vs. 5.6(7.39) (p = 0.75)
Hospital length of stay, mean (SD), d
11.4(10.89) vs. 12.1(11.68) (p = 0.60)
Hospital complications - Ventilator-free days, mean (SD)
9.3(10.31) vs. 9.9(11.09) (p = 0.67)
Hospital complications - Multiple organ failure, No.(%)
37(25) vs. 33(22) (p = 0.68)
Hospital complications - Care withdrawn, No. (%)
14(9) vs. 23(15) (p = 0.15)
 
Administered treatments and resuscitation goals
Crystalloid volume, mean (SD), L
0-<6 hrs: 4.5(2.36) vs. 4.3(2.21) (p=0.55)
6-72 hrs: 12.4(6.15) vs. 11.8(6.41) (p=0.44)
Vasopressor administration, No. (%)
0-<6 hrs: 108(72) vs. 113(74) (p=0.60)
6-72 hrs: 100(67) vs. 108(72) (p=0.45)
Dobutamine administration, No. (%)
0-<6 hrs: 5(3) vs. 8(5) (p=0.57)
6-72 hrs: 10(7) vs. 13(9) (p=0.66)
PRBC transfusion, No. (%)
0-<6 hrs: 11(7) vs. 5(3) (p=0.20)
6-72 hrs: 35(23) vs. 31(21) (p=0.78)
Mechanical Ventilation, No. (%)
0-<6 hrs: 40(27) vs. 39(26) (p=0.99)
6-72 hrs: 69(46) vs. 75(50) (p=0.56)
Activated protein C, No. (%)
0-<6 hrs: 0 vs. 0
6-72 hrs: 3(2) vs. 2(1) (p=0.68)
Parenteral corticosteroids, No. (%)
0-<6 hrs: 18(12) vs. 26(17) (p=0.25)
6-72 hrs: 59(39) vs. 51(34) (p=0.40)

No significant differences in SBP, HR, CVP, ScvO2, Lactate, SOFA score, SAPS II score, MEDS score, or GCS when obtained at times 0, 24, 48, or 72 hours (or when available).

Subgroup Analysis

No subgroup analysis was performed.

Adverse Events

Protocol-related serious adverse events No., (%, CI)
Lactate clearance group
9/150 (6%, 95% CI, 3%-11%)
ScvO2 group
11/150 (7%, 95%CI, 4%-13%)

Criticisms

  • Rivers counter-point [4]
    • There are hemodynamic phases of shock, and the Jones trial patients were not in the same stage as the Rivers trial patients
      • The Jones trial, unlike the Rivers trial, gave fluid as a resuscitative effort prior to randomization
    • Jones et al and Rivers et al patients had different characteristics, with the Rivers et al patients appearing sicker based on baseline hemodynamics. The Jones et all patients overall received less blood, more pressors, and less mechanical ventilation for some reason
    • Lactate may indicate a stress response/increased endogenous catecholamine production, and should not be taken as a indicator of the balance between oxygen delivery and consumption
      • Also note exogenous lactate sources: Ringer's lactate, pRBC transfusions
    • Jones trial is a noninferiority study, which can show false equivalency without careful study design
  • Jones counter-counter-point to Dr. Rivers [5]
    • Rivers trial may have had selection bias as the Jones trial study population appears to be more consistent with other recent sepsis trials (this may be due to resuscitation in Jones trial prior to randomization)
    • The "phases of shock" argument is argued against by the Jones trial and Rivers trial sharing identical inclusion criteria
    • Noninferiority trials, when carefully designed, can be effective, they show noninferiority (as good as or better), rather than equivalency (as good as)
    • Jones et al is a better trial than the Rivers trial methodologically in that Rivers et al did not perform intention-to-treat analysis
  • Rivers counterpoint to Jones counterpoint [6]
    • Lactate clearance of >10% is associated with decreased mortality [7] but this was a different study population (not all were septic), and the lactate clearance did not seem to be associated with more aggressive resuscitation
    • Below critical levels of systemic oxygen delivery, we do not always see lactate elevations
    • Complex interventions like the specialized CVC's should not be avoided if they have a true mortality benefit just because they are complex
    • A 10% lactate clearance would be perceived differently at various initial lactate levels, so it could represent a dangerous goal (i.e. drop from 10 to 9 less clinically relevant vs. 3 to 2.7).
  • Elevated lactate in sepsis is not due to tissue hypoxia but more likely due to beta-adrenergic effects of endogenous catecholamines. May be beneficial to have elevated lactate (compared to occult shock without lactate elevations), and except in rare cases, the concept of titrating sepsis treatment towards a lactate goal does not make sense physiologically [8]
    • Furthermore, ProCESS, ARISE, and ProMISe each show no evidence that ScvO2 monitoring has a mortality benefit. This implies that lactate measurements may have no survival benefit (other than acting as a proxy for overall higher level of care).

Funding

Funded by grants from the NIH as well as the National Institute of General Medical Sciences

Further Reading

  1. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  2. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  3. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644‐1655. doi:10.1378/chest.101.6.1644
  4. Rivers EP et al. Counterpoint: should lactate clearance be substituted for central venous oxygen saturation as goals of early severe sepsis and septic shock therapy? No. Chest 2011. 140:1408-1413.
  5. Jones AE. Rebuttal From Dr Jones. Chest. 2011;140(6):1413‐1415. doi:10.1378/chest.11-2597
  6. Rivers EP, Elkin R, Cannon CM. Rebuttal From Dr Rivers et al. Chest. 2011;140(6):1415‐1419. doi:10.1378/chest.11-2599
  7. Jansen TC et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am. J. Respir. Crit. Care Med. 2010. 182:752-61.
  8. https://emcrit.org/pulmcrit/understanding-lactate-in-sepsis-using-it-to-our-advantage/
Rivers Trial
ProCESS
ARISE
ProMISe