• Rate of cardiac and neurologic related events (Pilot Stage) [ Time Frame: At the end end of the "pilot stage" and up to 28 days ]
  This endpoint will be assessed at the end of the "pilot stage" and throughout the entire study for cumulative safety information. Research arms will only continue to recruitment in the next stage if they have been shown to be both safe (<5 cardiac or neurologic related events, in the arm during the pilot phase as defined by one of the following: acute coronary syndrome, acute ischemic stroke, or seizure) and feasible (<8 definitive discontinuations before day-2 due to patient's intolerance), although patient data from all patients and all stages will be included in the final analyses.
• Rate of vaso-occlusive pain crisis (VOC) resolution without complication (Activity stage) [ Time Frame: Day 5 ]
  VOC will be considered terminated when at least 3 of the following 4 criteria are met at two consecutive assessments: i) absence of fever for 8 hours; ii) absence of pain progression and no requirement of intravenous infusion of opioid analgesics for the last 8 hours; iii) the patient is able to walk or move without pain; iv) absence of spontaneous pain with a CPS (categorical pain score) of 1 or less
• Rate of secondary acute chest syndrome (ACS)(Efficacy Stage) [ Time Frame: Day 14 ]
  Defined as the proportion of patients with secondary ACS during the 14 days following randomization. Secondary ACS is defined as the combination after 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).

• 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 with categorical pain score (CPS). Patients will grade their pain (range 0-3 points, with 0, no pain; 1, mild pain, unaffected by mobilization; 2, moderate pain, increased by mobilization; 3, severe pain with disability) in seven body sites (all four limbs, ribs and sternum, head, and spine and pelvis)
• Pain intensity evaluated by visual analogue scale [ Time Frame: Between day-1 (randomization) and day-14 ]
  Pain intensity evaluated with the visual analogue pain scale (VAS) .It is presented as a 10 cm horizontal line on which the patient's pain intensity is represented by a point between the extremes of "no pain at all" and "worst pain imaginable."
• 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 ]
  Arterial blood gas assessed at least once during the first 24 hours of treatment (if available)
• Cumulative doses of intravenous and subcutaneous opioids [ Time Frame: Between day-1 (randomization) and day-14 ]
• Number of complicated VOC [ Time Frame: Day-14 ]
  A complicated VOC is defined as the occurrence of at least one of the following events between randomization and day-14: transfusion, exchange transfusion, mechanical ventilation, shock (catecholamine infusion), intensive care admission or death.
• Duration of hospital stay [ Time Frame: Day-28 ]
  Defined as the time from randomization to hospital discharge; patients still hospitalized at day-28 will be attributed a hospital stay of 28 days)
• 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 ]

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.

• 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
  Other Name: Control group
• Device: HFNO with low FiO2 (21%-30%)
  HFNO with low FiO2 (21%-30%) targeting normoxia: to test the effect of improved pulmonary function
  Other Name: Intervention group
• 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
  Other Name: Intervention group
• 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
  Other Name: Intervention group

• Active Comparator: standard 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;
  Intervention: Device: Stadard low-flow oxygen
• Experimental: HFNO with low FiO2 (21%-30%)
  HFNO with low FiO2 (21%-30%) targeting normoxia: to test the effect of improved pulmonary function;
  Intervention: Device: HFNO with low FiO2 (21%-30%)
• Experimental: HFNO with intermediate FiO2 (50%)
  HFNO with intermediate FiO2 (50%): to test the combined effect of improved pulmonary function and moderate hyperoxia; in this group, FiO2 will be set at 50% during the first 24 hours of intervention to target moderate hyperoxia, then reduced to 21-30% during the following 48 hours to target normoxia
  Intervention: Device: HFNO with intermediate FiO2 (50%)
• Experimental: HFNO with high FiO2 (100%)
  HFNO with high FiO2 (100%): to test the combined effect of improved pulmonary function and intense hyperoxia; in this group, FiO2 will be set at 100% during the first 24 hours of intervention to target intense hyperoxia, then reduced to 21-30% during the following 48 hours to target normoxia
  Intervention: Device: HFNO with high FiO2 (100%)

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;
• 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 inclusion 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 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;
• Chronic transfusion program;
• Known cerebral vasculopathy or past medical history of stroke;
• Known ischemic heart disease or typical chest angina;
• Patient who is currently enrolled in other investigational drug study;
• Previous participation in this study.
• Known legal incapacity,
• Prisoners or subjects who are involuntarily incarcerated
• Anatomical factors precluding placement of a nasal cannula

• Fisher and Paykel Healthcare
• Orkyn'