Rivers Trial

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Rivers E, et al. "Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock". The New England Journal of Medicine. 2001. 345(19):1368-1377.
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Clinical Question

Among patients with severe sepsis or septic shock, what is the efficacy of early goal-directed therapy (EGDT) in decreasing the risk of mortality?

Bottom Line

Among patients with severe sepsis or septic shock, early goal-directed therapy decreases the risk of mortality.

Major Points

The Rivers trial randomized 263 patients with severe sepsis or septic shock at a single urban Detroit ED to a protocol of early goal-directed therapy (EGDT) vs. standard therapy. In the EGDT arm, patients received an arterial line and a central line with continuous central venous oxygen saturation (ScvO2) monitoring. The EGDT group consisted of several sequential goals in the ER prior to ICU admission:

  1. CVP 8-12mmHg, achieved with fluid boluses
  2. MAP >65mmHg, achieved with vasopressors if necessary
  3. ScvO2 >70%, achieved with packed RBC transfusions and dobutamine if necessary
  4. UOP >0.5mL/kg/hr

While there was no difference in the total volume of administered fluid or percentage of patients receiving dobutamine at 72 hours, patients in the EGDT received more of both therapies in the first 6 hours. This correlated with improved physiologic parameters from 7 to 72 hours (ie, higher ScvO2, lower lactate, higher pH, lower base deficit, and lower mean APACHE II scores). Most importantly, the EGDT arm had a 16% absolute risk reduction in mortality, which correlates with a number needed to treat of 6 patients in order to prevent one in-hospital death. Mortality reduction with EGDT has successfully been replicated several other institutions[1][2] with a NNT of 5 for outcomes similar to the primary outcome of the Rivers trial.[2]

It is impossible to tease out which interventions in the protocol made the most significant impact on mortality. Furthermore, the components of EGDT have been a matter of controversy. Transfusion of packed RBCs to a goal hematocrit of 30 when ScvO2 is <70% is in contrast to the results of the TRICC trial (1999), which demonstrated mortality reduction with restrictive strategy in a similar population. CVP has been known to be a poor surrogate for blood volume in critically ill patients as far back as 1984.[3] Additionally, lactate -- often used to delineate severity of sepsis -- was not included in the protocol in directing care though a more recent trial, EMShockNet[4] (2010), did not demonstrate reduction in mortality when lactate monitoring was compared to ScvO2. To address these controversies, the 2014 ProCESS trial randomized patients one of three protocols: An EGDT-like protocol, a protocol driven by SBP and shock index goals that resuscitated with fluids and vasopressors, or a "standard care" arm that was non-protocol driven. There was no differences in mortality between the interventions. This finding was confirmed in the 2014 ARISE and 2015 ProMISe trials.[5]

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[6]

  • 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

  • Single center, parallel-group, randomized, controlled trial
  • N=263 patients with severe sepsis or septic shock
    • Early-goal directed therapy (n=130)
    • Standard therapy (n=133)
  • Setting: Single, tertiary center in Detroit
  • Enrollment: 1997-2000
  • Analysis: Intention-to-treat
  • Primary outcome: In-hospital mortality

Population

Inclusion Criteria

Patients presenting to the ED with signs of sepsis, severe sepsis, or septic shock (SIRS plus SBP <90mmHg despite 20-30ml/kg crystalloid challenge over 300 minutes or blood lactate >4mmol/L)

Exclusion Criteria

  • Age <18 years
  • Pregnancy
  • Acute cardiovascular event (ie, ACS, acute pulmonary edema)
  • Arrhythmias
  • Status asthmaticus
  • Active GI hemorrhage
  • Seizures
  • Drug overdose
  • Burn or trauma
  • Incurable malignancy
  • Contraindication to central venous catheterization
  • Requires surgery
  • On immunosuppression for transplant or disease
  • DNR advanced directive

Baseline Characteristics

From the EGDT group.

  • Demographics: Age 67.1 years, female 49.2%
  • Laboratory data: Anion gap 21.7 mmol/L, creatinine 2.6 mg/dL, BUN 47.1 mg/dL, total bilirubin 1.3 mg/dL, GGT 117 U/L, Albumin 2.8 g/dL
  • PMH: Alcohol use 38.5%, HF 36.7%, CAD 26.5%, COPD 18.0%, DM 30.8%, HIV 4.3%, HTN 68.4%, Liver disease 23.1%, cancer 12.8%, neurologic disease 34.2%, renal insufficiency 21.4%, smoking 29.9%
  • Time from arrival in ED until enrollment: 1.3 hours
  • Criteria for entry:
    • Temp: 35.9oC
    • HR: 117 BPM
    • SBP: 106 mmHg
    • RR: 31.8 breaths/min
    • Partial pressure of CO2 31.5 mmHg
    • WBC: 13,600/mm3
    • Lactate: 7.7 mmol/L
  • Acute medical condition: Pneumonia 38.5%, urosepsis 25.6%, peritonitis 3.4%
  • Acute surgical condition: Intraabdominal process 7.7%, abscess of arms or legs 1.7%
  • Sepsis-specific:
    • Severe sepsis: 45.3%
    • Septic shock: 54.7%
    • Sepsis syndrome: 75.2%
    • Culture positive: 76.1%
      • Blood cultures positive: 34.2%
    • Culture negative: 23.9%
  • Antibiotic-specific:
    • Given in first six hours: 86.3%
    • Adequate antibiotics: 96.7%
    • Antibiotic duration: 11.7 days

Interventions

  • Randomized to EGDT vs. standard therapy
  • EGDT protocol consisted of several sequential goals started in the ER 6 hrs prior to ICU admission:
    • CVP 8-12mmHg, achieved with fluid boluses
    • MAP >65mmHg, achieved with vasopressors or vasodilators if necessary
    • ScvO2 >70%, achieved with packed RBC transfusions to maintain Hct >30%, then dobutamine started at 2.5 mcg/kg/min (max 20 mcg/kg/min, HR<120bpm) until ScvO2 >70% if necessary
    • UOP >0.5 mL/kg/hr
  • Standard therapy maintained:
    • CVP 8-12 mmHg
    • UOP >0.5 mL/kg/hr
    • MAP 65-90 mmHg with either vasopressors or vasodilators

Outcomes

Comparisons are EGDT vs. standard therapy.

Primary Outcome

In-hospital mortality
30.5% vs. 46.5% (RR 0.58; 95% CI 0.38-0.87; P=0.009; NNT=6)

Secondary Outcomes

28-day mortality
33.3% vs. 49.2% (RR 0.58; 95% CI 0.39-0.87; P=0.01)
60-day mortality
44.3% vs. 56.9% (RR 0.67; 95% CI 0.46-0.96; P=0.03)
Sudden CV collapse
10.3% vs. 21% (P=0.02)
Multiorgan failure
16.2% vs. 21.8% (P=0.27)

Additional Analyses

Total fluids
0-6 hours: 4.9 L vs. 3.5 L (P<0.001)
7-72 hours: 8.6 L vs. 10.6 L (P=0.01)
0-72 hours: 13.4 L vs. 13.4 L (P=0.73)
RBC transfusion
0-6 hours: 64.1% vs. 18.5% (P<0.001)
7-72 hours: 11.1% vs. 32.8% (P<0.001)
0-72 hours: 68.4% vs. 44.5% (P<0.001)
Vasopressors
0-6 hours: 27.4% v.s 30.3% (P=0.62)
7-72 hours: 29.1% vs. 42.9% (P=0.03)
0-72 hours: 36.8% vs. 51.3% (P=0.02)
Dobutamine
0-6 hours: 13.7% vs. 0.8% (P<0.001)
7-72 hours: 14.5% vs. 8.4% (P=0.14)
0-72 hours: 15.4% vs. 9.2% (P=0.15)
Mechanical ventilation
0-6 hours: 53.0% vs. 53.8% (P=0.90)
7-72 hours: 2.6% vs. 16.8% (P<0.001)
0-72 hours: 55.6% vs. 70.6% (P<0.02)
Pulmonary-catheterization
0-6 hours: 0% vs. 3.4% (P=0.12)
7-72 hours: 18% vs. 28.6% (P=0.04)
0-72 hours: 18% vs. 31.9% (P=0.01)

Criticisms

  • ED staff was not blinded to treatment group [7]
  • It is impossible to determine which interventions were most important. It is unclear if it was the whole EGDT protocol, or one single component, such as the extra 1.5L crystalloid in the EGDT arm administered in the first 6 hours.
  • The use of ScvO2 and pressure monitoring had not been tested in this population prior and is a continued source of controversy.
  • The goal of administering packed RBC transfusions in order to maintain a high oxygen carrying capacity in the EGDT arm has been criticized. It is controversial what effect the oxygen carrying capacity is increased with this therapy. The oxygen carrying capacity is dependent upon the age of the blood product, and the side effect profile of RBC transfusions may outweigh the rise in oxygen carrying capacity.
  • The study was single-center [8]
  • The control group had an above-average mortality.[8][7]
  • Transfusion red blood cells to increase ScvO2 is controversial as it has been associated with increased mortality in the critically ill and may contribute to dystoxia. [7]

Funding

Equipment provided by Edward Lifesciences and Nova Biomedical, with support from the Henry Ford Health Systems Fund for Research.

Further Reading

  1. Sivayoham N, et al. "Outcomes from implementing early goal-directed therapy for severe sepsis and septic shock: a 4-year observational cohort study." European Journal of Emergency Medicine(2012):19;4:235-240
  2. 2.0 2.1 Otero RM et al. "Early Goal-Directed Therapy in Severe Sepsis and Septic Shock Revisited." Chest(2006)130;5:1579-1595
  3. Shippy CR, et al. "Reliability of clinical monitoring to assess blood volume in critically ill patients." Critical Care Medicine. 1984;12(2):107-112.
  4. Jones AE et al. "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial." JAMA 2010; 303(8) 739-746.
  5. Mouncey PR, et al. "Trial of early, goal-directed resuscitation for septic shock." The New England Journal of Medicine. 2015; Published online 2015-03-17. Accessed 2015-03-18.
  6. 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.
  7. 7.0 7.1 7.2 Letters to the editor
  8. 8.0 8.1 Critical Care forum