Efficacy of Liberal Versus Restricted IV Fluid Approach in the Management of Sickle Cell Vaso-Occlusive Crisis

Official title

Fluid Management in Sickle Cell Disease Vaso-occlusive Crisis: Restrictive Versus Liberal Strategies: A Randomized Controlled Trial (FLASC Trial)

Overview

Sickle cell disease (SCD) is a prevalent inherited blood disorder characterized by vaso-occlusive crises (VOCs), which lead to severe pain and complications. Despite hydration being a cornerstone of VOC management, the optimal fluid strategy remains uncertain. This study evaluates restrictive versus liberal fluid management strategies in patients with acute VOC. This multi-center, open-label, non-inferiority RCT will enroll patients with SCD presenting with acute VOC. Participants will be randomized to either a restrictive or liberal intravenous fluid management protocol. Primary outcome is pain score reduction. Secondary outcomes include time to pain resolution, ED length of stay, hospital admission rate, cumulative opioid dose, adverse events (incidence of fluid overload, pulmonary congestion), acute chest syndrome, incidence of acute kidney injury, revisit rates within 72 hours of ED discharge, need for intensive care or high-dependency unit admission, need for additional interventions, and 28 days overall mortality. Data will be analyzed using intention-to-treat principles. We hypothesize that a restrictive fluid strategy will achieve non-inferior pain control compared to a liberal strategy, while minimizing fluid-related complications. This study will provide evidence to inform clinical guidelines for fluid management in SCD patients experiencing VOCs.

Detailed description

This study is a prospective, non-inferiority, open-label, multicenter randomized-controlled trial (RCT) conducted in the emergency departments (EDs) of tertiary care hospitals in Saudi Arabia. The primary objective is to compare two fluid management strategies- restrictive (intervention) vs. liberal (control) in adult sickle cell disease (SCD) patients hospitalized for VOC. The study evaluates whether a restrictive fluid approach is non-inferior to a liberal strategy in terms of pain resolution, hospitalization duration, and other clinical outcomes.

Patients will be randomized upon ED admission, and their assigned fluid regimen will be administered within the first hour. Clinical teams will monitor outcomes throughout hospitalization or up to 28 days post-enrollment.

Study Population

1. Recruitment Screening: All patients admitted to the ED with VOC will be screened for eligibility.

Consent Model: A priori informed written consent will be obtained from conscious, coherent patients or substitute decision-makers. 2. Inclusion Criteria Age \>18 years with confirmed SCD diagnosis.

Presenting with VOC requiring hospitalization.

Numeric Pain Rating Scale (NPRS) \>5

Willingness to participate and provide informed consent. 3. Exclusion Criteria Requiring specialized IVF management per the physician's discretion.

Cardiac/Renal Conditions:

Congestive heart failure (CHF) or symptomatic systolic heart failure.

Patients with ESRD on chronic dialysis.

Hemodynamic Instability:

Shock (SBP \<100 mmHg or MAP \<65) with hypoperfusion signs.

Other Exclusions:

Known/suspected pregnancy.

Prior enrollment in this trial within the last 30 days.

Concurrent enrollment in another trial affecting fluid management.

Inability to obtain IV access.

Trial Intervention

1. Screening \& Randomization Screening occurs upon ED admission; evaluations must precede randomization.

A screening log will track eligible vs. randomized patients. 2. Informed Consent An a priori consent model is used due to the conscious-coherent state of most SCD patients in VOC.

Efforts will be made to obtain consent immediately from the patient or surrogate. 3. Intervention Arms A. Intervention (Restrictive)Keep-vein-open (KVO) rate only (minimal fluids to maintain IV patency). No additional IV fluids administered.

B. Control (Liberal) 20 mL/kg IV bolus (NS or LR over 1 hour) + maintenance fluids (1.5-2 mL/kg/day).

Initiation: Both regimens starts within 1 hour of ED admission and continue until ED discharge.

Hospitalized Patients:

Pain scores (NPRS) recorded at 24, 48, and 72 hours. Total fluid intake documented at hospital discharge.

Interventions

• Drug Sodium Chloride (NaCl) 0.9 %
  Keep vein open rate
• Drug Sodium Chloride (NaCl) 0.9 %
  IV bolus of 20 mL/kg of normal saline over 1 hour, followed by maintenance fluids at 1.5-2 ml/kg times the calculated daily maintenance requirements

Primary outcome measures

• Change in Pain intensity [Time frame: Baseline (within 30 minutes post admission), 1 hour, then hourly until ED discharge or 24- 48- and 72-hours post-admission ( for admitted patients)]

Secondary outcome measures (7)

• Time to pain resolution [Time frame: up to 4 hours]
• ED length of stay [Time frame: at least 4 hours]
• Hospital admission rate [Time frame: within 24 hours of ED admission]
• Cumulative Opioid Dose [Time frame: up to 4 hours]
• Revisit Rates [Time frame: within 72 hours post ED discharge]
• Overall Mortality [Time frame: within 28 days post-enrollment]
• Adverse events [Time frame: up to 7 days]

Eligibility criteria

Inclusion criteria

• Patients >18 years old with a confirmed diagnosis of SCD.
• Presenting with a VOC.
• NPRS >5
• Willingness to participate and provide informed consent.

Exclusion criteria

• Patient requiring specialized IVF management as per the treating physician discretion.
• Patients with congestive heart failure, and /or acute or chronic symptomatic systolic heart failure
• Patients with ESRD on chronic dialysis
• Patients with signs of shock (low SBP <100 or MAP < 65) and signs of hypo perfusion
• Known or suspected pregnancy
• Previously enrolled in this trial within the last 30 days
• Enrolled in another trial study that interfered with fluid management
• Unable to obtain IV access.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Saudi Arabia · 2 centers

• King Fahd Hospital of the University — Dammam
• King Saud University Medical City — Riyadh

Publications

• Puri L, Nottage KA, Hankins JS, Anghelescu DL. State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease. Paediatr Drugs. 2018 Feb;20(1):29-42. doi: 10.1007/s40272-017-0263-z. PMID 28853040
• Rizio AA, Bhor M, Lin X, McCausland KL, White MK, Paulose J, Nandal S, Halloway RI, Bronte-Hall L. The relationship between frequency and severity of vaso-occlusive crises and health-related quality of life and work productivity in adults with sickle cell disease. Qual Life Res. 2020 Jun;29(6):1533-1547. doi: 10.1007/s11136-019-02412-5. Epub 2020 Jan 13. PMID 31933113
• Okomo U, Meremikwu MM. Fluid replacement therapy for acute episodes of pain in people with sickle cell disease. Cochrane Database Syst Rev. 2015 Mar 12;(3):CD005406. doi: 10.1002/14651858.CD005406.pub4. PMID 25764071
• Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, Kutlar A, Seisa M, Stinson J, Strouse JJ, Yusuf F, Zempsky W, Lang E. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020 Jun 23;4(12):2656-2701. doi: 10.1182/bloodadvances.2020001851. PMID 32559294
• Rosa RM, Bierer BE, Thomas R, Stoff JS, Kruskall M, Robinson S, Bunn HF, Epstein FH. A study of induced hyponatremia in the prevention and treatment of sickle-cell crisis. N Engl J Med. 1980 Nov 13;303(20):1138-43. doi: 10.1056/NEJM198011133032002. PMID 6999348
• GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematol. 2023 Aug;10(8):e585-e599. doi: 10.1016/S2352-3026(23)00118-7. Epub 2023 Jun 15. PMID 37331373

Identifiers

NCT: NCT07188766 · 2025-01-0451

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗