Clinical trial NCT03549923: Evaluation of Early CRRT InTerventions in Patients With ECMO(ELITE)
Official title: Impact of Early CRRT Intervention in Patients Receiving VA-ECMO Support on 30-day Mortality: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cardiogenic Shock
Keywords: extracorporeal membrane oxygenation
renal replacement therapy
beta-blocker
Lead sponsor: Beijing Anzhen Hospital
Sponsor class: OTHER
Collaborators: name: The First Affiliated Hospital of Zhengzhou University
First posted: 2018-06-08
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: Extracorporeal membrane oxygenation (ECMO) is of great value in supporting patients with cardiac shock. More than 80% ECMO patients will develop renal catastrophe that continuous renal replacement therapy (CRRT) is required. The evidence is conflict as to whether early CRRT improves outcomes. Early CRRT before a definite indication developed may prevent side effects of toxicity and fluid overload and therefore, bring survival benefit for the patient. This hypothesis need to be tested in RCT.

Plasma catecholamine levels can be very high in patients under VA-ECMO, which maybe toxic to the cardiac myocardium. Beta-blockers can antagonize the effects of catecholamine. In patients with VA-ECMO, the protective effect of beta-blocker may improve the patients' outcome. This hypothesis also need to be tested in RCT.

ELITE (Evaluation of Early CRRT and Beta-blocker InTerventions in Patients with ECMO) study is a factorial designed RCT with the purpose to test the benefit of early CRRT and beta-blocker in patients treated with V-A ECMO. In the CRRT arm, patients will be randomized to simultaneous CRRT (not late than 24 hours after the initiation of ECMO) or routine therapy (CRRT when indicated). In the beta-blocker arm, patients will be randomized to beta-blocker treatment with a heart rate target of 75±5 bpm or routine therapy. The primary outcome is all-cause mortality at 30 days. Patients discharged alive will be followed for 1 year. Data of mortality and quality of life which are secondary outcomes of this study, will be collected.

Detailed description: Background:

Extracorporeal membrane oxygenation (ECMO) is of great value in supporting patients with severe cardiopulmonary failure, but the mortality rate is still high.

Acute kidney injury (AKI) and fluid overload (FO) are the leading causes of death in patients under Veno-arterial (VA) ECMO. Continuous renal replacement therapy (CRRT) is an effective way to remove toxic substances and provide fluid management. According to current guidelines, CRRT is withhold until at least one of the following criteria is met: severe hyperkalemia (\> 6.5 mmol/L), metabolic acidosis (pH \< 7.2), pulmonary edema, blood urea nitrogen level \> 112 mg/dL, or oliguria (urine output \< 200 mL/12h) for more than 72 hours. However, fluid overload and metabolic disorders may cause irreversible damage to the patient and therefore increase mortality. The hypothesis of ELITE study is that simultaneous CRRT may provide better fluid management and avoid metabolic disorders, and bring survival benefit in VA-ECMO patients.

Patients under VA-ECMO are critically ill with high plasma catecholamine levels and treatment of various inotropic agents, which are toxic to the failed myocardium. Beta-blockers can antagonize the effects of endogenous and exogenous catecholamines. The hypothesis of ELITE study is that beta-blocker may protect the failing heart function and reduce 30-day mortality.

Study design:

ELITE study is a prospective, multi-centered, open, 2×2 factorial randomized controlled clinical trial.

In the simultaneous CRRT versus conventional-indication CRRT arm, patients under VA-ECMO will be randomized to the following 2 groups:

1. Simultaneous CRRT group: CRRT is initiated simultaneously (not late than 24 hours from the initiation of ECMO treatment), regardless of presentation of conventional indication of CRRT. CRRT lasts for 12 hours or more is recommended.The physician can decide when to withdraw CRRT based on the patient's condition.
2. Conventional-indication CRRT group: CRRT is not initiated unless conventional indication of CRRT is presented. The conventional indication of CRRT is as follow: KDIGO stage 3 AKI and one of the following criteria is met: severe hyperkalemia (\> 6.5 mmol/L), metabolic acidosis (pH \< 7.2), pulmonary edema, blood urea nitrogen level \>112 mg/dL, or oliguria (urine output \< 200 mL/12 h) for more than 72 hours.

In the Beta-blocker versus routine therapy arm, patients with a maintaining dosage of dopamine/dobutamine \<5 μg/kg/min, and with neither epinephrine nor norepinephrine will be randomized to the following 2 groups:

1. Esmolol group: Patients will receive a continuous esmolol infusion in addition to routine management. The esmolol infusion commences at 25 mg/h and increases by 25 mg/h every 20-minute until the maximal tolerate dosage is reached or the heart rate reduced to 75±5 bpm, or an upper dose limit of 2000 mg/h is reached. Continue infusing esmolol to maintain the heart rate threshold or at the discretion of the physician until either ICU discharge or death. Oral beta-blockers should be considered before the withdrawal of esmolol.
2. Control group: All beta-blockers, including esmolol, should not be used during ICU treatment, unless the doctor thinks there's a strong indication.

Primary outcome: All-cause mortality at 30 days.

Secondary outcomes:

1. All-cause mortality at 365 days
2. Proportion of patients with long-term RRT indicated
3. Success rate of weaning from ECMO: defined as survive \> 24 hours after weaning
4. Any serious adverse events (SAEs), including bleeding, severe arrhythmias, ventilator associated pneumonia, hemorrhagic infection, surgical site infection, any reason induced limb ischemia, stroke and any adverse events that the physician regards as serious.
5. EQ-5D score at 365 days
6. Duration stay at ICU and hospital.
7. Unplanned readmission to hospital.
8. Cause-specific mortality

Sample size consideration:

The sample size calculations are based on the following hypothesis: (a) an estimate 30-day mortality of 70% in the control group; (b) a 20% relative risk reduction for each intervention alone (simultaneous CRRT and beta-blocker); (c) no loss to follow-up; (d) no interaction of the two interventions.

For each intervention, we calculated that a sample size of 496 patients would be required, 248 patients for the treatment group and 248 patients for the control group. In the 2 × 2 factorial design, patients will be randomized to one of four arms, the sample size of each would be 124 patients. With a crossover rate of 10%, the study will randomize 548 patients, 137 patients per arm.

Eligibility criteria: Inclusion Criteria for CRRT Study:

1. Patients receiving VA-ECMO support for any reason no longer than 24 hours
2. Provision of informed consent

Exclusion Criteria for CRRT Study:

1. Age \< 18 years
2. Patients with convention indication of CRRT: AKI prior to enrollment caused by any reason, at least one of the following criteria is met: severe hyperkalemia (\> 6.5 mmol/L), metabolic acidosis (pH \< 7.2), pulmonary edema, blood urea nitrogen level \> 112 mg/dL, or oliguria (urine output \< 200 mL/12h) for more than 72 hours.
3. CKD with estimated GFR\<30 mL/min
4. Have already initiated CRRT
5. Active hemorrhage/thrombotic thrombocytopenic purpura
6. Respiratory failure has already initiated VV-ECMO or extracorporeal carbon dioxide removal device before the initiation of VA-ECMO of this time.
7. Prepared for heart transplant or patients received heart transplant.

Inclusion Criteria for Beta-blocker Study:

1. Patients receiving VA-ECMO support for any reason.
2. Dopamine/dobutamine \<5 μg/kg/min, no administration of adrenaline or norepinephrine.
3. Within 7 days after initiation of VA-ECMO

Exclusion Criteria for Beta-blocker Study:

1. Age \< 18 years
2. Contraindications or intolerance to beta-blockers

   * Moderate or severe bronchial asthma attack or history of bronchial asthma
   * Sinus bradycardia (heart rate \< 60 bpm)
   * Type II second-degree or third-degree AVB
   * Allergy to esmolol
3. For women at child bearing age, pregnant or positive pregnancy test.
4. Respiratory failure has already initiated VV-ECMO or extracorporeal carbon dioxide removal device before the initiation of VA-ECMO of this time
5. Have been on beta-blocker treatment after initiation of ECMO
6. Prepared for heart transplant or patients received heart transplant.

Primary outcomes:
measure: All-cause mortality
timeFrame: 30 days
Secondary outcomes:
measure: All-cause mortality
timeFrame: 365 days
measure: Proportion of patients receiving long-term RRT
timeFrame: 365 days/when patient dies
measure: Success rate of weaning from ECMO
timeFrame: 30 days
measure: Any serious adverse events (SAEs)
timeFrame: 30 days
measure: EQ-5D score
timeFrame: 365 days
measure: Duration stay at ICU and hospital
timeFrame: 365 days
measure: Unplanned readmission to hospital
timeFrame: 30 days
measure: Cause-specific mortality
timeFrame: 365 days
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Anzhen Hospital
Study officials:
affiliation: Beijing Anzhen Hospital
name: Jianzeng Dong, PhD., Md.
role: PRINCIPAL_INVESTIGATOR
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