High-flow Oxygen for Vaso-occlusive Pain Crisis

Official title

A Multicentre, Prospective, Randomized, Multi-arm, Multi-stage Clinical Trial of High-flow Oxygen for Vaso-occlusive Pain Crisis in Adult Patients With Sickle Cell Disease;

Overview

Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive pain crisis (VOC), which may evolve to acute chest syndrome (ACS), the most common cause of death among adult patients with SCD. Currently, there is no safe and effective treatment to abort VOC or prevent secondary ACS. Management of VOC mostly involve a symptomatic approach including hydration, analgesics, transfusion, and incentive spirometry, which was investigated in a very limited number of patients (\<30). The polymerisation of HbS is one major feature in the pathogenesis of vaso-occlusion. Among factors determining the rate and extent of HbS polymer formation, the hypoxic stimulus is one of the most potent and readily alterable. Current guidelines recommend oxygen therapy in patients with VOC in order to maintain a target oxygen saturation of 95%. Low-flow nasal oxygen (LFNO) is routinely used to achieve this normoxia approach, particularly in patients at risk of secondary ACS because they may experience acute desaturation. In contrast, various case series suggest a potential beneficial role of intensified oxygen therapy targeting hyperoxia for the management of VOC, particularly with the use of hyperbaric oxygen, but the latter is difficult to implement in routine clinical practice. A recent high-flow nasal oxygen (HFNO) technology allows the delivery of humidified gas at high fraction of inspired oxygen (FiO2) through nasal cannula. The FiO2 can be adjusted up to 100% (allowing hyperoxia that may reverse sickling) and the flow can be increased up to 60 L/min (which generates positive airway pressure and dead space flushing, that may prevent evolution of VOC towards ACS by alleviating atelectasis and opioid-induced hypercapnia). In patients with acute respiratory failure, HFNO has been shown to improve patient's comfort, oxygenation, and survival as compared to standard oxygen or non-invasive ventilation. The aim of the present study is to test the efficacy and safety of HFNO for the management of VOC and prevention of secondary ACS. The investigators will use a multi-arm multi-stage (MAMS) design to achieve these goals. HFNO will be delivered through AIRVO 2 (Fisher and Paykel Healthcare, New Zealand), a device that incorporates a turbine allowing its use in hospital wards.

Interventions

• Device Stadard low-flow oxygen
  In the control group, standard low-flow oxygen will be delivered via nasal prongs (LFNO), up to hospital discharge or secondary ACS onset, in order to achieve normoxia (target pulse oxymetry saturation of 95%). This strategy is in accordance with current recommendations and usual care
• Device HFNO with low FiO2 (21%-30%)
  HFNO with low FiO2 (21%-30%) targeting normoxia: to test the effect of improved pulmonary function
• Device HFNO with intermediate FiO2 (50%)
  In this group, FiO2 will be set at 50% during the first 24 hours of intervention to target moderate hyperoxia, then reduced to 21-3025% during the following 48 hours to target normoxia
• Device HFNO with high FiO2 (100%)
  In this group, FiO2 will be set at 100% during the first 24 hours of intervention to target intense hyperoxia, then reduced to 21-3025% during the following 48 hours to target normoxia

Primary outcome measures

• Rate of cardiac and neurologic related events (Pilot Stage) [Time frame: At the end end of the "pilot stage" and up to 28 days]
• Rate of vaso-occlusive pain crisis (VOC) resolution without complication (Activity stage) [Time frame: Day 5]
• Rate of secondary acute chest syndrome (ACS)(Efficacy Stage) [Time frame: Day 14]

Secondary outcome measures (12)

• Volume of transfused red blood cells and volume of exsanguinated blood [Time frame: Between day-1 (randomization) and day-14]
• Pain intensity evaluated by categorical pain score [Time frame: Between day-1 (randomization) and day-14]
• Pain intensity evaluated by visual analogue scale [Time frame: Between day-1 (randomization) and day-14]
• VOC duration [Time frame: Day-14]
• VOC-free days [Time frame: Day-14]
• Reticulocyte count [Time frame: Day-2 and Day-5]
• Arterial blood gas [Time frame: Up to 24 hours]
• Cumulative doses of intravenous and subcutaneous opioids [Time frame: Between day-1 (randomization) and day-14]
• Number of complicated VOC [Time frame: Day-14]
• Duration of hospital stay [Time frame: Day-28]
• Number of re-hospitalizations or emergency department consultations for VOC or ACS [Time frame: Up to 28 days]
• Number of death (Mortality) [Time frame: Day-28]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years;
• Patient with major sickle cell disease syndrome (SS, SC, Sβ0 or Sβ+);
• VOC as defined by acute pain or tenderness, affecting at least one part of the body, including limbs, ribs, sternum, head (skull), spine, and/or pelvis, that requires opioids and is not attributable to other causes;
• Intermediate-to-high risk for secondary ACS derived from the PRESEV score (Bartolucci et al, EBioMedicine 2016) as follows: a reticulocyte count >216 G/L OR at least two of the followings : i) spine and/or pelvis CPS >1; ii) leucocyte count >11G/L; iii) hemoglobin ≤ 9 g/dL; in case of long-term treatment by hydroxyurea, only one of the above mentioned criteria will be needed, given its effects on hemoglobin, leucocyte and reticulocytes counts;
• Informed consent;
• Patient affiliated to social security

Exclusion criteria

The presence at inclusion of a primary ACS. Primary ACS is defined by the combination at time of randomization of a clinical sign \[chest pain or auscultatory abnormality (crepitants and/or bronchial breathing)\] with a new pulmonary infiltrate (on chest film, thoracic scan, or lung ultrasound);

• VOC with need of parenteral opioids lasting longer than 72 hours at time of inclusion;
• Known pregnancy or current lactation; Women of child bearing potential will be tested for pregnancy before inclusion;
• Known cerebral vasculopathy or past medical history of stroke, due to Moya Moya or persisting visible macrovessel stenosis/occlusion;
• Known ischemic heart disease or typical chest angina;
• Patient who is currently enrolled in other investigational drug study;
• Known legal incapacity,
• Prisoners or subjects who are involuntarily incarcerated
• Anatomical factors precluding placement of a nasal cannula

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

Other

Study locations

France · 1 center

• Henri Mondor — Créteil

Publications

• Mekontso Dessap A, Habibi A, Guillaud C, Kassasseya C, Larrat C, Agbakou M, Tchoubou T, Candille C, Carpentier B, Landais M, Arlet JB, Fartoukh M, Desclaux A, Masseau A, Oziel J, Bouharaoua S, Affo C, Viglino D, Boukari L, Martin LE, Ngo S, Anguel N, Chantalat C, Bourgarit-Durand A, Genty I, Makowski C, Guillet S, Melica G, Lionnet F, Le Jeune S, Joseph L, Lanternier F, Cougoul P, Bertchansky I, B PMID 40967654

Identifiers

NCT: NCT03976180 · P180303J

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗