Clinical trial NCT02802696: Transfusion-Associated Circulatory Overload Best Eliminated With Lasix
Official title: Pre-transfusion Furosemide in Patients at High Risk of Transfusion-associated Circulatory Overload - The Transfusion-Associated Circulatory Overload Best Eliminated With Lasix (TACO-BEL) Study: A Pilot Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Transfusion-associated Circulatory Overload
Keywords: Transfusion
Transfusion Medicine
Diuretic
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
Collaborators: name: University Health Network, Toronto
name: Canadian Blood Services
First posted: 2016-06-16
Enrollment: 80
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a pilot double-blinded placebo-controlled randomized controlled trial (RCT) to evaluate the feasibility of conducting a multicenter, randomized, placebo-controlled trial to assess the efficacy of pre-transfusion furosemide in preventing transfusion-associated circulatory overload (TACO) in hemodynamically stable inpatients aged 65 years or older receiving a single unit red blood cell transfusion. Patients will be randomly allocated to receive either furosemide (20mg intravenous) or placebo (saline) within 60 minutes of starting a red blood cell (RBC) transfusion. Randomization will be stratified by centre and renal dysfunction (creatinine clearance ≥ 60 mL/min or \< 60 mL/min). This is a blinded trial: patients, care-providers (physicians and nurses), data collectors, outcome adjudicators, and data analysts will not be aware of group allocation.

Detailed description: The investigators proposed this pilot study to assist us in determining the feasibility of conducting a definitive multicenter randomized trial across Canada.

Rationale:

The rationale for this study includes: (1) TACO is the leading cause of morbidity and mortality due to transfusion; (2) risk factors for TACO include older age, renal dysfunction and positive fluid balance; (3) furosemide is a diuretic commonly prescribed for fluid overload; (4) furosemide can decrease pulmonary artery pressures; and (5) clinical uncertainty as to the effect of furosemide in preventing TACO. The investigators will enroll 80 patients in this pilot study at two centers.

Hypothesis:

The investigators hypothesize that 80 patients can be enrolled in the trial within a 2-month period

Justification:

If pre-transfusion that furosemide decreases the rate of TACO with red blood cell transfusion, clinical practice worldwide would change. Over 800,000 patients in Canada receive a blood transfusion annually and many are at high risk for TACO and may benefit from this simple, low-cost intervention. This intervention could easily be generalizable worldwide. There are practical challenges related to patient recruitment, adherence to trial protocol and data collection, all of which the TACO-BEL Pilot Trial will seek to measure.

Objectives:

The primary outcome of this trial is to determine the feasibility of performing a large multi-centre, randomized, placebo-controlled trial with concealed allocation and blinded outcome assessment, adequately powered to determine a clinically significant effect of pre-transfusion furosemide on the incidence of transfusion-associated circulatory overload.

Primary outcome measure is the number of patients enrolled within a two-month period

Secondary feasibility outcome measures include:

1. Proportion of patients screened meeting eligibility criteria
2. Proportion of eligible patients consenting to participate
3. Proportion of consenting patients receiving the allocated treatment
4. Proportion of treated patients completing follow-up assessment
5. Proportion of patients in which blinding was maintained throughout study

Research Method:

Patients meeting inclusion criteria will be identified by reviewing transfusion orders received by the blood transfusion laboratory or by referral from ordering physicians; these patients will then be approached by study personnel to obtain pre-transfusion informed consent. Randomization will be performed by pharmacy at the time of drug preparation. The randomization code will be generated in random blocks of 4 to 6, stratified by center, and renal function at time of randomization (creatinine clearance \< 60 and ≥ 60 mL/min) using a computer based randomization program.

Intervention:

Patients will be administered a bolus dose of 20mg furosemide (20mg/2mL) intravenously within 60 minutes prior to the start of the red blood cell transfusion. Patients randomized to placebo will be administered an equal volume of normal saline intravenously immediately within 60 minutes prior to the start of the red blood cell transfusion.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 65 years.
* Receiving a single unit red blood cell transfusion

Exclusion Criteria:

* Active bleeding (active visible bleeding, required 2 or more RBC units in the preceding 24 hours, drop in Hb \> 20 g/L in the preceding 24 hours);
* Hemodynamically unstable (systolic blood pressure \< 90 mmHg or on inotropes);
* Anticipated major surgical procedure within 24 hours of enrolment;
* Presence of hyponatremia (Na \< 130 mmol/L);
* Presence of hypokalemia (K \< 3.5 mmol/L);
* Dialysis or creatinine clearance \< 30 mL/min;
* Order for platelet or plasma transfusion at same time;
* Allergy to furosemide;
* Risk of withholding furosemide felt by attending physician to place patient at excessive risk of harm;
* Previously enrolled in the study;
* Plan for discharge on the day of randomization;
* Unable to provide informed consent.

Primary outcomes:
measure: Number of patients enrolled
timeFrame: 2 months period
Secondary outcomes:
measure: Proportion of patients screened meeting eligibility criteria
timeFrame: 2 months
measure: Proportion of eligible patients consenting to participate
timeFrame: 2 months
measure: Proportion of patient receiving the allocated treatment
timeFrame: 2 months
measure: Proportion of treated patients completing follow-up assessment
timeFrame: 2 months
measure: Proportion of patient in which blinding was maintained throughout study
timeFrame: 2 months
measure: Vital Signs
timeFrame: Baseline and 6 hours post transfusion
measure: Positive end-expiratory pressure
timeFrame: Baseline and 6 hours post transfusion
measure: Inspiratory oxygen
timeFrame: Baseline and 6 hours post transfusion
measure: Incidence of TACO within 6 hours from completion of transfusion
timeFrame: within 6 hours
measure: Severity of TACO-graded as per the Public Health Agency of Canada's Transfusion Transmitted Injuries Surveillance System
timeFrame: within 6 hours
measure: Validation of TACO as per criteria adopted from the US Center for Disease Control
timeFrame: within 6 hours
measure: Change in plasma brain natriuretic peptide(BNP)
timeFrame: Baseline and Day 1
measure: Net fluid balance at 24 hours from start of transfusion- all intravenously-administered fluids (including the transfused blood product and the study intervention)
timeFrame: Within 24 hours
measure: Proportion of patients developing hyponatremia or hypokalemia by Day 1
timeFrame: By Day 1
measure: Proportion of patients developing hypotension
timeFrame: Within 24 hours
measure: Proportion of patients developing acute kidney injury
timeFrame: Within 24 hours
measure: Need for increased supplemental oxygen is defined as any increase in oxygen flow ≥ 1 L/hr or (fraction of inspired oxygen)FiO2 ≥ 5% of 1 hour duration or longer, prompted by either patient symptoms or a fall in oxygen saturation(SpO2) ≥ 5%
timeFrame: Within 24 hours
measure: Need for inotropic support is defined as the initiation of a continuous infusion of dopamine, dobutamine, epinephrine, or norepinephrine
timeFrame: Within 24 hours
measure: Need for additional diuretic or vasodilatory therapy is defined by the prescription of non-study furosemide, hydrochlorothiazide, metolazone, or either transdermal or intravenous nitroglycerin
timeFrame: Within 24 hours
measure: Occurrence of acute coronary syndrome or new arrhythmia
timeFrame: within 7 days
measure: Mortality during hospital stay
timeFrame: Upto 30 days
measure: Length of hospital stay
timeFrame: From date of admission until the date discharge from an acute care hospital or date of death from any cause, whichever came first, assessed up to 30 days.
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Canadian Blood Services
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: Sunny Brook Health Sciences Centre
name: Jeannie Callum, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: AABB (2015) AABB Association Bulletin #15-02: Transfusion Associated Circulatory Overload (12/28/15). Vol. 2016,
citation: Alam A, Lin Y, Lima A, Hansen M, Callum JL. The prevention of transfusion-associated circulatory overload. Transfus Med Rev. 2013 Apr;27(2):105-12. doi: 10.1016/j.tmrv.2013.02.001. Epub 2013 Mar 1.
citation: Lieberman L, Maskens C, Cserti-Gazdewich C, Hansen M, Lin Y, Pendergrast J, Yi QL, Callum J. A retrospective review of patient factors, transfusion practices, and outcomes in patients with transfusion-associated circulatory overload. Transfus Med Rev. 2013 Oct;27(4):206-12. doi: 10.1016/j.tmrv.2013.07.002. Epub 2013 Sep 26.
citation: Sarai M, Tejani AM. Loop diuretics for patients receiving blood transfusions. Cochrane Database Syst Rev. 2015 Feb 16;2015(2):CD010138. doi: 10.1002/14651858.CD010138.pub2.