Morphine Clearance and Glomerular Filtration in Sickle Cell Patients in Crisis in Intensive Care

Overview

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.

Interventions

• Drug Injection of iohexol for glomerular filtration rate (GFR) measurement
  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 syn

Primary outcome measures

• Therapeutic failure [Time frame: 24 hours]
• Glomerular filtration rate according to the CKD-EPI formula [Time frame: 5 minutes]

Secondary outcome measures (10)

• Clearance of morphine and its metabolites M3G and M6G [Time frame: 24 hours]
• Morphine dose administered [Time frame: 24 hours]
• Morphine dose administred [Time frame: Day 7]
• Pain progression using the Visual Analog Scale [Time frame: Every 4 hours for the first 7 days]
• Pain progression using a Numeric Rating Scale [Time frame: Every 4 hours for the first 7 days]
• Patient Global Impression of Change (PGIC) Over the First 7 Days [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 [Time frame: 24 hours]
• Adverse effects of morphine [Time frame: Day 7]
• Glomerular filtration rate according to the CKD-EPI formula [Time frame: 5 minutes]
• Plasma clearance of iohexol [Time frame: 5 minutes, 1 hour et 9 hours]

Eligibility criteria

Inclusion criteria

• 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
• Receiving PCA treatment with morphine
• Patient's consent for study participation and/or from a relative if case of patient's incapacity
• Affiliation to social protection

Exclusion criteria

• 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).
• Chronic liver disease likely to interfere with morphine metabolism (cirrhosis )
• Any condition that contraindicates the use of morphine according to the summary of product characteristics
• Patients under legal protection
• Pregnant or breastfeeding women

Exclusion criteria

• Need for extrarenal epuration within 24 hours of inclusion

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

France · 6 centers

• CHRU de Tours — Tours
• Henri-Mondor — Créteil
• CH Le Mans — Le Mans
• CHU de Nantes — Nantes
• CHU d'Orléans — Orléans
• CHU de Rennes — Rennes

Identifiers

NCT: NCT07246265 · DR230314 · 2024-511985-34-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗