Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis

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• Sepsis 1,887

Keywords

• Fluid management
• Sepsis-induced hypotension
• vasopressors

Study arms

• Other
  Restrictive Fluids

  The general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used.

  Drug: Early Vasopressors

• Other
  Liberal Fluids

  The general approach is to use fluid boluses to treat hypotension.

  Other: Early Fluids

Interventions

• DrugEarly Vasopressors

  Norepinephrine will be used as preferred vasopressor and titrated to achieve mean arterial pressure (MAP) between 65 mmHg and 75 mmHg. "Rescue fluids" may be administered as 500ml boluses if predefined rescue criteria are met.

  Also known as: Norepinephrine

• OtherEarly Fluids

  Additional 2 liter intravenous fluid infusion upon enrollment (may forego second liter if MAP/SBP and heart rate are normalized and clinical assessment if patient is fluid replete after the first liter). Administer 500ml fluid boluses for fluid triggers until 5 liters administered or development of clinical signs of acute volume overload develop. "Rescue vasopressors" may be administered after 5 liters of fluid, for development of acute volume overload, or if other predefined rescue criteria are met. Any type of isotonic crystalloid (normal saline, ringers lactate, balanced solution such as plasmalyte) is permitted.

  Also known as: Balanced crystalloid solution

Primary outcomes

1. Death Before Discharge Home by Day 90

   The primary outcome was death from any cause before discharge home by day 90. Point estimates were from Kaplan-Meier curves. There were 109 deaths and 5 patients with censored data the restrictive fluid group and 116 deaths and 4 patients with censored data in the liberal group. We defined home as the same setting or a setting similar to the one where the patient resided before becoming ill. Thus, if a patient originated from a private residence and was discharged from the hospital to a rehabilitation setting, we assessed for vital status until return to the private residence.Vital status was determined using any of the following methods: medical record review, phone calls to patient, proxy or healthcare facility, review of obituaries, or information from the Centers for Disease Control and Prevention's National Death Index (NDI).

   Time frame: From randomization to discharge home up to and including day 90.

Secondary outcomes

1. Organ Support Free Days

   Defined as a patient being alive and without assisted breathing, new renal replacement therapy, or vasopressors (excluding vasopressor use prior to 48 hours). Any day that a patient is alive and without organ support will represent days alive and free of organ support.

   Time frame: 28 days after randomization

2. Ventilator Free Days (VFD)

   Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.

   Time frame: 28 days after randomization

3. Renal Replacement Free Days

   The number of calendar days between randomization and 28 days later that the patient is alive and without renal replacement therapy. Patients who died prior to day 28 are assigned zero renal replacement free days.

   Time frame: 28 days after randomization

4. Vasopressor Free Days

   The number of calendar days between day 2 (eligibility starting 48 hours post randomization) and 26 days later that the patient is alive and without the use of vasopressor therapy. Patients who died prior to day 28 are assigned zero vasopressor free days.

   Time frame: From study day 2 through day 28

5. ICU Free Days

   Defined as the number of days spent alive out of the ICU to day 28.

   Time frame: 28 days after randomization

6. Hospital Free Days to Discharge Home

   Days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days.

   Time frame: 28 days after randomization

7. New Intubation With Invasive Mechanical Ventilation by 28 Days

   Patients who receive invasive mechanical ventilation via endotracheal or tracheostomy tube, except those intubated solely for a procedure and extubated within 24 hours, through to study day 28 meet this endpoint. Non-invasive mechanical ventilation will not be included as an outcome. This is a binary outcome.

   Time frame: 28 days after randomization

8. Initiation of Renal Replacement Therapy

   Patients receiving (new) renal replacement therapy through day 28. Patients with chronic renal replacement therapy initiated prior to the current sepsis illness were not eligible to meet this endpoint.

   Time frame: 28 days after randomization

9. Kidney Disease: Change in Creatinine-based Global Outcomes (KIDGO) Score Between Baseline and 72 Hours

   Assessment of renal function using the KDIGO staging system (using serum creatinine criteria only) between baseline and 72 hours post randomization to assess for de novo acute kidney injury (AKI) (e.g., meeting criteria for AKI by KDIGO criteria) or worsening AKI (e.g., increasing severity). Patients on chronic renal replacement therapy were not eligible for this endpoint determination. Scoring of 1-3 (using serum creatinine levels; a higher score indicates worsening kidney function): 1. creatinine level 1.5-1.9 times baseline OR \>/= 0.3 mg/dl (\>/= 25.5 umol/l) increase 2. creatinine level 2.0-2.9 times baseline 3. creatinine level 3.0 times baseline OR increase in serum creatinine to \>/=4.0mg/dl (\>/= 353 umol/l) OR initiation of renal replacement therapy

   Time frame: 72 hours after randomization

10. Change in SOFA (Sepsis Related Organ Failure Assessment) Score

    SOFA score was calculated at enrollment and at 72 hours using clinically available data.Total score: 0-4 points; 4 = worst outcome. Values not available at baseline were assumed normal. 72 hours assessment: Closest previously known value was carried forward for missing values. SOFA Scoring Breakout (lower scores mean a better outcome; clinically significant organ failure for CLOVERS was defined as a SOFA score 2 or more points higher than baseline): * Coagulation( Platelets, ×10³/µL): Score = 0: \>150; 1: \</= 150; 2: \</= 100; 3: \</= 50; 4: \</= 2 * Liver (Bilirubin, mg/dL): Score: 0: \<1.2; 1: 1.2-1.9; 2: 2.0-5.9; 3: 6.0-11.9; 4: \>11.9 * Cardiovascular(Hypotension): Score: 0: no hypotension; 1: Mean arterial pressure \<70 mmHg; 2: Dopamine\</=5 OR any dobutamine; 3: Dopanime \>5, epinephrine \</=0, or Norepi \</=0.1; 4: Dop \>15, epi \>0.1, or norepi \>0.1 * Renal (Creatinine, mg/dL or urine output, ml/d): Score: 0: \<1.2; 1: 1.2-1.9; 3: 2.0-3.4; 3: 3.5-4.9 or \<500; 4: \>4.9 or \<200

    Time frame: 72 hours after randomization

11. Development of ARDS

    Presence and severity of ARDS is determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio and confirmation of ARDS through chest x-ray reviews.

    Time frame: 7 days after randomization

12. New Onset Atrial or Ventricular Arrhythmia

    The occurrence of one or more episodes (sustained for more than 1 minute for SVT and AF, \> 15 seconds for VT) during through day 28 will be recorded.

    Time frame: 28 days after randomization

13. Death From Any Cause at Any Location by Day 90

    Subjects were contacted at day 90 to ascertain their survival status via telephone contact with the patient or family members or by a review of medical records and publicly available data sources.

    Time frame: From randomization to and including day 90

Baseline characteristics

3 further baseline measures are reported on the registry.

Publications

• Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, Ginde AA, Grissom CK, Janz DR, Jones AE, Liu KD, Macdonald SPJ, Miller CD, Park PK, Reineck LA, Rice TW, Steingrub JS, Talmor D, Yealy DM, Douglas IS, Shapiro NI; CLOVERS Protocol Committee and NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators. Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Ann Emerg Med. 2018 Oct;72(4):457-466. doi: 10.1016/j.annemergmed.2018.03.039. Epub 2018 May 10. PubMed 29753517 ↗

Study documents

• Study protocol · Feb 17, 2021
• Statistical analysis plan · Jul 12, 2019
• Informed consent form · Jan 24, 2019

Documents are hosted by the registry — open the source record to download them.