What are the management strategies for a patient with sickle cell disease?

Management of Sickle Cell Disease

Hydroxyurea is the first-line disease-modifying therapy for most individuals with sickle cell disease, reducing pain crises and improving fetal hemoglobin levels, with additional FDA-approved agents (L-glutamine, crizanlizumab, voxelotor) available as adjunctive or second-line treatments. 1, 2

Disease-Modifying Pharmacotherapy

First-Line Therapy

• Hydroxyurea remains the cornerstone of disease-modifying treatment for individuals with HbSS or HbSβºthalassemia genotypes, increasing fetal hemoglobin production and reducing red blood cell sickling 1, 3
• Hydroxyurea decreases the frequency of pain episodes, reduces acute chest syndrome occurrences, and decreases the need for blood transfusions 3
• The medication probably improves pain crisis frequency, duration, intensity, hospital admissions, and opioid use based on moderate-quality evidence 3
• Evidence is insufficient regarding optimal dosing strategies (standard dose versus dose escalation to maximum tolerated dose) and long-term effects on fertility and reproduction 3

FDA-Approved Adjunctive Therapies

• L-glutamine reduces hospitalization rates by 33% and decreases mean length of stay from 11 to 7 days compared with placebo by reducing red blood cell oxidant injury 1, 4
• Crizanlizumab (a selectin blocker) reduces pain crises from 2.98 to 1.63 per year compared with placebo and is indicated for adults and pediatric patients aged 16 years and older 5, 1
  • Administer 5 mg/kg by intravenous infusion over 30 minutes on Week 0, Week 2, and every 4 weeks thereafter 5
  • Monitor for infusion-related reactions (occurring in 7% of patients), which present most frequently as pain, nausea, vomiting, fatigue, dizziness, pruritus, diarrhea, and pyrexia 5
  • Critical warning: Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., anaphylaxis treatment), as corticosteroids may increase the risk of acute chest syndrome and fat embolism 5
• Voxelotor increases hemoglobin by at least 1 g/dL in 51% of patients versus 7% with placebo by improving hemoglobin oxygen-binding capacity 1, 2

Acute Pain Crisis Management

Immediate Assessment and Treatment

• Pain is diagnosed based solely on the patient's self-report—if the patient states they are in pain, initiate aggressive treatment immediately without waiting for objective findings 6
• Delays in addressing and undertreatment of sickle cell pain are common pitfalls that must be actively avoided 6
• Continue baseline long-acting opioid medications throughout the crisis and implement multimodal analgesia 7, 8
• Patient-controlled analgesia (PCA) is superior to continuous infusion, showing lower overall morphine consumption 8, 6
• Use scheduled around-the-clock dosing or PCA rather than "as needed" dosing for severe pain requiring parenteral opioids 8
• Critical principle: Opioid dependency is rare in sickle cell disease; opioid sensitivity is more common—never assume addiction 7, 6

Hydration Protocol

• Administer 5% dextrose solution or 5% dextrose in 25% normal saline rather than normal saline alone, as patients with sickle cell disease have impaired sodium excretion due to hyposthenuria 9
• Oral hydration is preferred when possible, but start IV fluids if oral intake is inadequate 7, 9
• Meticulous fluid management with accurate measurement and replacement of fluid losses is essential 7, 8
• Avoid normal saline alone—this is a critical error due to impaired urinary concentrating ability 9

Oxygen Management

• Document baseline oxygen saturation and maintain SpO2 above baseline or 96% (whichever is higher) with continuous monitoring 7, 9, 8
• Do not give continuous oxygen therapy unless necessary—only administer to maintain target saturation 7
• Postoperatively or during severe crisis, administer oxygen continuously for 24 hours or until the patient can mobilize freely 7
• Hypoxia precipitates sickling and must be avoided 9

Temperature Control

• Maintain normothermia—hypothermia leads to shivering and peripheral stasis, increasing sickling 7
• Use active warming measures including warmed fluids and increased ambient temperature 7
• A spike in temperature may be an early sign of sickling or infection 7, 9

Management of Fever in Sickle Cell Disease

Immediate Actions for Fever ≥38.0°C

• Obtain blood cultures and start broad-spectrum antibiotics immediately without waiting for culture results—functional hyposplenism makes these patients vulnerable to overwhelming sepsis from encapsulated organisms like Streptococcus pneumoniae within hours 9
• Delaying antibiotics while awaiting cultures is a critical error that can lead to death within hours in functionally asplenic patients 9
• Obtain chest radiograph to evaluate for pneumonia or acute chest syndrome 9

Life-Threatening Complications Requiring Urgent Evaluation

Acute Chest Syndrome

• Defined by new segmental infiltrate on chest radiograph plus lower respiratory tract symptoms, chest pain, and/or hypoxemia 9, 8, 6
• Occurs in more than 50% of hospitalized patients with vaso-occlusive crisis 8
• Promote early mobilization, physiotherapy, and incentive spirometry every 2 hours (or blowing bubbles for young children) after moderate or major surgery 7
• Consider bronchodilator therapy for patients with history of small airways obstruction, asthma, or acute chest syndrome 7

Stroke

• Any acute neurologic symptom other than transient mild headache requires urgent evaluation 8
• Common presentations include hemiparesis, aphasia, seizures, severe headache, cranial nerve palsy, stupor, or coma 8
• All children <17 years should have transcranial Doppler results available from within the previous 12 months before elective procedures 8

Splenic Sequestration

• Characterized by rapidly enlarging spleen and hemoglobin decrease >2 g/dL below baseline 8, 6
• Can progress rapidly to shock and death 8
• Requires careful transfusion to avoid acute overtransfusion 8

Peri-operative Management

Pre-operative Planning

• Schedule patients early on the operating list to avoid prolonged starvation 7
• Avoid last-minute cancellations for administrative reasons, particularly if the patient has received a blood transfusion in preparation for surgery 7
• Avoid routine surgery if the patient is febrile or having a painful crisis 7, 8
• Notify the acute pain team in advance if the patient is undergoing major surgery, particularly with a history of chronic pain 7

Transfusion Strategy

• A nominated lead haematologist is responsible for deciding the peri-operative transfusion plan 7
• Avoid unnecessary transfusion to reduce the risk of allo-immunisation 7
• Complications may be reduced by meticulous peri-operative care and appropriate transfusion 7

Post-operative Monitoring

• Maintain a low threshold to admit patients to high dependency or intensive care, as the majority of complications occur postoperatively 7
• Patients are at increased risk of acute chest syndrome, pain, acute renal insufficiency, stroke, sepsis, and venous thromboembolism in the peri-operative period 7
• All post-pubertal patients should receive thromboprophylaxis due to increased risk of deep vein thrombosis 8

Curative Therapy

Hematopoietic Stem Cell Transplant

• Hematopoietic stem cell transplant is the only curative therapy currently available 1
• Best results are seen in children with a matched sibling donor 1
• Limited by donor availability, immunologic transplant rejection, long-term adverse effects, and poor end-organ function (especially problematic for older patients) 4

Gene Therapy

• Gene therapy using CRISPR-Cas9 technology to correct the genetic defect is under investigation 2
• Two gene therapy products (Casgevy and Lyfgenia) have received FDA approval for treatment of sickle cell disease 2

Multidisciplinary Care Coordination

• Clinical teams should work in partnership with patients and their families, keeping them informed of clinical decisions at all times 7
• Planned surgery should ideally be undertaken in centers with experience in caring for sickle cell disease patients 7
• In emergencies, seek advice from specialists with experience in sickle cell disease through haemoglobinopathy network arrangements 7
• Children and their caregivers know their disease best—all management decisions should result from shared decision-making 6
• Foster trust that patients will be heard, particularly when reporting pain, to mitigate effects of systemic racism causing mistrust of the healthcare system 6