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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
100
All 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.
CHRU de Tours
Tours, France, France
Henri-Mondor
Créteil, France
CH Le Mans
Le Mans, France
CHU de Nantes
Nantes, France
CHU d'Orléans
Orléans, France
CHU de Rennes
Rennes, France
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.
Time frame: 24 hours
Glomerular filtration rate according to the CKD-EPI formula
Glomerular filtration rate according to the CKD-EPI formula
Time frame: 5 minutes
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.
Time frame: 24 hours
Morphine dose administered
Total dose of morphine administered during the day
Time frame: 24 hours
Morphine dose administred
Total dose of morphine administered each day
Time frame: Day 7
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.
Time frame: Every 4 hours for the first 7 days
Pain progression using a Numeric Rating Scale
Pain intensity will be assessed using the Numeric Rating Scale (NRS), which ranges from 0 (no pain) to 10 (worst imaginable pain). Participants verbally rate their pain on this numeric scale. Higher scores indicate worse pain.
Time frame: Every 4 hours for the first 7 days
Patient Global Impression of Change (PGIC) Over the First 7 Days
The Patient Global Impression of Change (PGIC) scale is a patient-reported outcome measure that assesses the patient's perception of change in their overall health status since the beginning of treatment. It is a 7-point Likert scale ranging from 1 (very much improved) to 7 (very much worse). Lower scores indicate a better outcome (improvement), while higher scores indicate worsening condition. PGIC will be assessed daily every 24 hours during the first 7 days of treatment.
Time frame: Daily, every 24 hours, from Day 1 to Day 7
Number of patients receiving paracetamol, nefopam, ketamine, NSAIDs, or nitrous oxide (MEOPA) within 24 hours
The therapeutic regimen will be recorded by counting the number of patients who receive each of the following analgesics within the first 24 hours: paracetamol, nefopam, ketamine, non-steroidal anti-inflammatory drugs (NSAIDs), and nitrous oxide (MEOPA).
Time frame: 24 hours
Adverse effects of morphine
Adverse effects of morphine include impaired alertness, bradypnea, hypercapnia, pruritus, constipation, bloating, nausea, vomiting, and acute urinary retention.
Time frame: Day 7
Glomerular filtration rate according to the CKD-EPI formula
Basal glomerular filtration rate according to the CKD-EPI formula and crisis glomerular filtration rate according to the CKD-EPI formula (5 minutes)
Time frame: 5 minutes
Plasma clearance of iohexol
Sample collection for iohexol dosage
Time frame: 5 minutes, 1 hour et 9 hours
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