Vaso-Occlusive Crises

The purpose of this research is to see if ketamine is effective and safe in treating children and young adults with sickle cell disease experiencing sickle cell related pain. In this study, we will compare the outcomes (such as pain scores) in persons who receive standard of care pain medicine (an opioid such as morphine) plus a low dose (amount) of ketamine to those who receive only standard of care pain medicine.

Introduction Sickle cell disease is the most common inherited genetic disorder in France and worldwide. Its main acute manifestation is vaso-occlusive crisis, a frequent reason for emergency department visits. Acute chest syndrome is the leading complication and cause of death during vaso-occlusive crisis, occurring in approximately 15-20% of hospitalized episodes, often within the first few days after symptom onset. Early identification of patients at risk of developing acute chest syndrome remains a major clinical challenge. Although predictive clinical and biological scores exist, their ability to identify high-risk patients remains limited in daily practice. Chest X-ray has traditionally been used to support the diagnosis of acute chest syndrome, but its diagnostic performance and repeated radiation exposure are increasingly questioned. Lung ultrasound is a non-invasive bedside imaging tool that has shown good performance for detecting pleural effusion, alveolar consolidation and interstitial syndrome, and is increasingly used by emergency physicians. However, its diagnostic performance when systematically performed by emergency physicians in adult sickle cell patients presenting with vaso-occlusive crisis has not yet been specifically assessed. Hypothesis / Objective We hypothesize that systematic pleuropulmonary ultrasound performed early after emergency department admission may help identify patients with vaso-occlusive crisis who are at risk of developing acute chest syndrome, and may allow earlier diagnostic assessment. The primary objective of the ECHODREP study is to evaluate the diagnostic performance of systematic pleuropulmonary ultrasound, performed by an emergency physician within six hours of admission, for the diagnosis of acute chest syndrome during hospitalization in adult sickle cell patients presenting with vaso-occlusive crisis. Secondary objectives are to assess the association between ultrasound findings and the final diagnosis of acute chest syndrome, to describe patient outcomes according to ultrasound results, including hospitalization, admission to intermediate care, emergency department revisits and mortality at day 3, day 7 and day 28, and to compare ultrasound performance according to the operator's level of experience. Method ECHODREP is a prospective, observational, single-arm, monocentric diagnostic performance study conducted in the Emergency Department of Henri-Mondor University Hospital. The study will include 200 adult patients with sickle cell disease - SS, SC or S-beta-thalassemia - presenting to the emergency department for vaso-occlusive crisis. Patients with a diagnosis of acute chest syndrome already established on arrival, patients previously included in the study, protected adults, and patients refusing participation will not be included. After informed consent, a pleuropulmonary ultrasound will be performed within six hours of emergency department admission by an emergency physician investigator who is not involved in the patient's clinical care. The examination will assess twelve predefined lung zones. In order to avoid influencing standard care and to preserve the objectivity of the study, ultrasound findings obtained for research purposes will not be communicated to the treating medical team and will not be used for diagnostic or therapeutic decisions. Patients will receive standard care for vaso-occlusive crisis according to local practice. A telephone follow-up will be performed at day 28 to collect vital status, emergency department revisits, hospitalizations and any secondary diagnosis of acute chest syndrome. At the end of follow-up, an independent adjudication committee, blinded to the research ultrasound findings, will determine the final diagnosis: uncomplicated vaso-occlusive crisis or acute chest syndrome. The primary endpoint will be the diagnosis of acute chest syndrome within seven days after emergency department admission or before hospital discharge, based on the medical record. Diagnostic performance will be assessed by calculating sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the ROC curve, with 95% confidence intervals. Additional analyses will compare outcomes according to ultrasound findings and operator experience. Conclusion This exploratory study will provide original data on the diagnostic performance of early pleuropulmonary ultrasound performed by emergency physicians in adult sickle cell patients presenting with vaso-occlusive crisis. If ultrasound demonstrates adequate diagnostic accuracy, it could contribute to earlier identification of acute chest syndrome, improve risk stratification in the emergency department and help optimize the management pathway of these patients. By evaluating both diagnostic performance and patient outcomes, ECHODREP may support the integration of lung ultrasound into future diagnostic strategies for acute chest syndrome in sickle cell disease.

Sickle cell disease is a severe monogenic genetic disorder caused by an autosomal recessive mutation of the β-globin gene, leading to production of abnormal hemoglobin (HbS). It primarily affects individuals from Africa or the French overseas territories. In France, approximately 26,000 patients are affected. Improved care has significantly increased life expectancy. Vaso-occlusive crises (VOC) are the main clinical complication. They result from polymerization of HbS, deforming red blood cells and causing capillary occlusion, tissue hypoxia, intense bone pain, and frequent hospitalizations. In France in 2015, 25,150 hospitalizations were recorded, 61% of which were for VOC. Iloprost is a prostacyclin (PGI2) analogue with vasodilatory, anti-platelet, anti-inflammatory, and antioxidant properties. It is used to treat severe limb ischemia and Raynaud's phenomenon, administered by IV infusion for 5 to 28 days. It is well tolerated and has shown efficacy for bone pain related to bone marrow edema. Its rapid and sustained action makes it an interesting candidate for VOC, which are comparable to ischemic-origin pain. To date, only one reported case of iloprost use for a VOC exists, showing rapid and lasting improvement. This randomized, multicenter, double-blind, placebo-controlled clinical trial aims to evaluate the efficacy of iloprost in patients hospitalized for VOC, with the objective of reducing pain and opioid consumption. This comprehensive approach could significantly improve VOC management.

Background: Sickle cell disease is a genetic disorder of haemoglobin (which carries oxygen in red blood cells). The shape of sickle cell-patients' red blood cells is abnormal. Thus, red blood cells can be blocked in small vessels, responsible for painful crises due to a lack of downstream circulation. These crisis (acute vaso-occlusive crisis) require strong treatment based on morphine, and often require intensive care.However, treatment is often insufficiently effective. Patient can also experiment acute chest syndrome, a complication of vaso-occlusive crisis, which can be responsible for respiratory failure. In addition, patients with sickle cell disease frequently have kidney damage called sickle cell nephropathy, which in the early stages of the disease is responsible for renal hyperfiltration, meaning that the kidneys filter the blood more than necessary, with faster elimination of drugs. For example, it is known that higher doses of antibiotics must be used in these patients than in the general population for the same effectiveness. The hypothesis of the study is that morphine, a drug eliminated by kidneys, is underdosed in patients with sickle cell disease, which is responsible for the difficulties in achieving sufficient analgesia. Objective: To determine the glomerular filtration rate threshold for which it is necessary to prescribe higher doses of morphine in sickle cell patients with vaso-occlusive crisis. Methods: inclusion of 100 patients admitted to intensive care for an acute vaso-occlusive crisis or acute chest syndrome and receiving morphine. Within 24 hours of study inclusion, four morphine dosages will be performed, in parallel with a precise determination of the glomerular filtration rate by measuring the elimination rate of a tracer, 100% eliminated by the kidneys and injected at the start of the study. This tracer is iohexol, a contrast agent commonly used in radiology. Morphine underdosage will be interpretated regarding glomerular filtration rate. The effectiveness of analgesia and the amount of analgesics required will be also be analyzed. Outlook: At the end of this study, the investigators will be able to offer adapted doses of morphine for sickle cell patients in crisis, adapted to glomerular filtration rate, in the aim of personalizing analgesia.

Sickle cell disease is a chronic disease characterized by multiple vaso-occlusive complications. The basic treatment for patients with a vaso-occlusive crisis (VOC) is based on adequate hydration, oxygen therapy and pain control. Loco Regional Anesthesia (LRA) is one of the major treatments in resuscitation anesthesia for both anesthesia and analgesia. LRA allows effective and almost immediate pain control by blocking nerve afferents in a given area. LRA could decrease the inflammatory response during crises and accelerate resolution of the crisis.