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.
Patient ≥ 18 years old
Known homozygous sickle cell disease SS, SC, S-beta+, or S-beta0
Admitted in an intensive care unit
Clinical diagnosis of vaso-occlusive crisis and/or acute chest syndrome
Patient previously included in the study during a previous stay
Injection of iodinated contrast medium outside the scope of the study within 24 hours prior to inclusion, or scheduled within 9 hours following the scheduled time of iohexol injection
Contraindication to iohexol: known or suspected immediate or delayed hypersensitivity, thyrotoxicosis.
Patient undergoing morphine treatment or substitution treatment such as methadone or buprenorphine prior to hospitalization (having received morphine or a derivative regardless of the route of administration in the week prior to hospitalization).
Single group
Injection of iohexol for glomerular filtration rate (GFR) measurement
DrugAll patients will receive the same intervention. In included patients, 5 mL of iohexol will be injected, followed by blood sampling 5min, 1hr and 9hrs after iohexol injection for GFR measurement (as iohexol is known to be an exogenous maker for GFR measurement). Analgesia will be protocolized, based in particular on self-administered morphine (patient-controlled-analgesia). Morphine clearance will be measured thanks to 4 blood samples. Blood sampling for morphine and iohexol dosages will be synchronized in order to reduce the number of vascular punctures. Moreover, the first blood sample (5 minutes after iohexol injection) and the 4th blood sample for morphine dosage will be performed at the time of the daily biological analysis, still in order to reduce the number of vascular punctures. Thus, iohexol will be injected 5 minutes before the daily blood sampling for routine biological analysis.
Therapeutic failure
Prediction of therapeutic failure based on glomerular filtration rate according to the CKD-EPI formula (area under roc curve). Therapeutic failure is defined as a percentage of relief assessed by the verbal numerical scale not reaching 30% within 24 hours.
Glomerular filtration rate according to the CKD-EPI formula
Glomerular filtration rate according to the CKD-EPI formula
Clearance of morphine and its metabolites M3G and M6G
Correlation between clearance of morphine (and its metabolites M3G and M6G) and glomerular filtration rate according to the CKD-EPI formula.
Morphine dose administered
Total dose of morphine administered during the day
Morphine dose administred
Total dose of morphine administered each day
Pain progression using the Visual Analog Scale
Pain intensity will be assessed using the Visual Analog Scale (VAS), a 100-mm horizontal line ranging from 0 mm (no pain) to 100 mm (worst imaginable pain). Participants will indicate their pain level by marking a point on the line. Higher scores represent more severe pain. The change from baseline will be measured to assess pain progression.
Age of participant at inclusion
Age of the participant in years at the time of study inclusion. This variable will be analyzed to assess its correlation with therapeutic failure at 24 hours.
Socioeconomic Status According to EPICES (Evaluation de la précarité et des inégalités de santé dans les Centres d'examens de santé) Questionnaire
Socioeconomic status will be assessed using the EPICES questionnaire, a validated tool to evaluate social deprivation. The score ranges from 0 (no deprivation) to 100 (maximum deprivation). This variable will be analyzed to assess its correlation with therapeutic failure at 24 hours.
Presence of chronic medical conditions at inclusion
Documentation of chronic pathologies or comorbidities present at the time of inclusion, based on medical history and patient records. This variable will be analyzed to assess its correlation with therapeutic failure at 24 hours.
Number of vaso-occlusive crises or acute chest syndrome episodes requiring hospitalization in the previous year
The number of hospitalizations due to vaso-occlusive crises or acute chest syndrome during the 12 months prior to inclusion. This variable will be analyzed to assess its correlation with therapeutic failure at 24 hours.
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