Continuing Education Activity

Sickle cell disease (SCD) is a group of inherited red blood cell disorders affecting about 1 in 500 African American children and 1 in 36,000 Hispanic American children. SCD results in anemia and "sickle cell crisis" (SCC). The main clinical feature of sickle cell disease is the ''acute painful crisis,’’ which often requires hospitalization. The term "sickle cell crisis" is used to describe several acute conditions such as the vaso-occlusive crisis (acute painful crisis), aplastic crisis, splenic sequestration crisis, hyperhemolytic crisis, hepatic crisis, dactylitis, and acute chest syndrome. Other acute complications include pneumonia, meningitis, sepsis and osteomyelitis, stroke, avascular necrosis, priapism, and venous thromboembolism. This activity reviews the evaluation and treatment of sickle cell crisis and discusses the role of the interprofessional team in evaluating and treating this condition.

Objectives:

• Outline the pathophysiology of sickle cell crisis.
• Review the complications of sickle cell disease.
• Outline the treatment and management options available for sickle cell crisis.
• Summarize interprofessional team strategies for improving care coordination and communication to manage sickle cell crises and improve outcomes.

Introduction

Sickle cell disease (SCD) is a group of inherited red blood cell disorders affecting about 1 in 500 African American children and 1 in 36,000 Hispanic American children.[1] SCD results in anemia and "sickle cell crisis" (SCC). The main clinical feature of sickle cell disease is the ''acute painful crisis,’’ which often requires hospitalization.[2] The term "sickle cell crisis" is used to describe several acute conditions such as the vaso-occlusive crisis (acute painful crisis), aplastic crisis, splenic sequestration crisis, hyperhemolytic crisis, hepatic crisis, dactylitis, and acute chest syndrome. Other acute complications include pneumonia, meningitis, sepsis and osteomyelitis, stroke, avascular necrosis, priapism, and venous thromboembolism.[3]

Etiology

Sickle cell disease is an autosomal recessive disorder of a gene mutation. On chromosome 11, nucleotide mutation leads to substitution of glutamic acid to valine at position six on the beta-globin subunit. This leads to changes in the physical properties of the globin chain. Many inciting factors lead to this physical property change of red blood cells. Hypoxia, dehydration, exposure to cold or weather changes, stress, and infections are a few of these risk factors. [3]

Epidemiology

As of 2015, about 4.4 million people have sickle cell disease, and 43 million are estimated to have sickle cell trait. Prevalence of the disease is high among the people of sub-Saharan Africa, South Asia, the Middle East, and the Mediterranean. The most common genotype is homozygous hemoglobin SS (HbSS). [2]

Pathophysiology

In the homozygous form of sickle cell disease, the above-mentioned triggers cause polymerization of hemoglobin, resulting in sickling of erythrocytes. Red blood cells become more rigid. There is a release of adhesion molecules, causing interaction of this deformed, sickled RBC to the endothelium.[2]  This increased adhesion of erythrocytes followed by the formation of heterocellular aggregates physically causes small vessel occlusion and resultant local hypoxia. This process triggers a vicious cycle of increased HbS formation and the release of inflammatory mediators and free radicals that contribute to reperfusion injury. Hemoglobin also binds to nitric oxide (NO), a potent vasodilator, and releases oxygen. Other associated pathological events include increased neutrophil adhesiveness, nitric oxide binding, increased platelet activation, and hypercoagulability. Further microvascular occlusion occurs due to activated neutrophils. Inflammatory mediators such as plasma cytokines, lead to a pro-inflammatory state, causing further complications of vaso-occlusion. It is postulated that the intestinal microbiome may be a potential trigger for vaso-occlusive crisis. [4] While some triggers (cold temperature, dehydration, low humidity, stress) for pain are identifiable, most episodes do not have an identifiable cause.[5]

History and Physical

Vaso-occlusive Crisis (VOC)

Patients present with moderate to severe pain, which has variable intensity and frequency. Young children can have severe pain and swelling of both hands and feet (dactylitis). Most patients with SCD experience pain by the age of 6 years. Pain can begin from any part of the body but frequently affects the extremities and back and chest areas. Fever can accompany vaso-occlusive crisis in some patients. Although pain in patients with SCD is likely to be due to VOC, it is prudent to perform a thorough evaluation for other life-threatening causes that can be misattributed to sickle cell pain.[6]. There is no objective measure or lab test to determine the quality and severity of pain in SCD, and therefore, patient report is the only available guide.

Splenic Sequestration Crisis

Patients with SCD have spleen infarction before the end of childhood. The spleen is affected due to its narrow vessels and its role as a key player in the lymphoreticular system. Splenic sequestration crisis causes acute, painful enlargement of the spleen due to intrasplenic trapping of red cells. Patients with splenic sequestration crisis may have a sudden drop in hemoglobin levels, and one should be vigilant about hypovolemic shock. If not treated promptly, this can be a life-threatening situation. [6]

Aplastic Crisis

SCpresentsts with sudden pallor and weakness confirmed by rapidly dropping hemoglobin levels that are accompanied by reticulocytopenia. The usual trigger for aplastic crisis is parvovirus B19 that directly suppresses the bone marrow affecting RBC production, but it can also be caused by other viral infections. The shortened lifespan of RBC in SCD results in worsening of the patient's baseline anemia, which can dip to dangerously low levels. The infection is self-limited, typically lasting 7 to 10 days. [6]

Acute Chest Syndrome (ACS)

This complication of SCD accounts for 25% of deaths and can follow vaso-occlusive crises. The trigger for ACS is frequently hypoxia due to hypoventilation of the chest caused by VOC crisis. It could also occur as a result of fat embolism originating from the distal bone in VOC. The hypoxia leads to adhesion of sickled erythrocytes to pulmonary microvasculature, setting up local hypoxia in the lungs and causing sickling of more RBCs; this sets up a vicious cycle. The presenting symptoms and signs include fever, cough, tachypnea, chest pain, hypoxia, wheeze, respiratory distress, and even failure. Any pulmonary infiltrate on chest radiography accompanied by abnormal lung findings should raise the suspicion of ACS. Affected patients can rapidly progress to worsening respiratory failure and death if not aggressively treated and monitored. [7]

Hemolytic Crisis

An acute drop in hemoglobin level marks this crisis. It is common in patients with coexistent G6PD deficiency. [6]

Others

Femoral/humeral head osteonecrosis due to vaso-occlusion along with increased pressure from increased erythrocyte marrow, priapism, proliferative retinopathy, and renal complications are often due to vaso-occlusion.

Evaluation

Sickle cell crisis patient evaluation warrants routine laboratory examination such as CBC with differential, a reticulocyte count, and a complete metabolic panel including liver function tests. Type and screen blood for possible transfusion if needed. Inflammatory markers include CRP, procalcitonin, and pancultures may be considered for fever and identification of the source of infection. There should be a low threshold to obtain chest X-rays to facilitate early identification of ACS. An abdominal ultrasound may be considered for concerns of cholelithiasis. ABG can be obtained for hypoxemia and respiratory failure.[8] CT head and MRI brain would be indicated if there is suspicion of stroke.

Treatment / Management

Vaso-occlusive Crisis Management 

Rapid pain assessment and initiation of analgesia should be undertaken promptly. Depending on the degree and severity of pain, analgesic administration can be given intravenously (IV) or intranasally. For patients who are not in severe pain and can tolerate oral medications, oral analgesics can be used. Generally, the type, route, and dose of the analgesic should be individualized to the patient. Most guidelines recommend early initiation of parenteral opioid analgesics, usually with morphine at 0.1 mg/kg IV or subcutaneously (SC) every 20 minutes, and maintaining this analgesia with morphine at doses of 0.05 to 0.1 mg/ kg every 2 to 4 hrs (SC/IV or PO). Those with persistent pain benefit from a PCA pump. Close monitoring of vital signs including oxygen saturation should be maintained with frequent reassessments of pain severity or resolution.[8] If the pain is controlled, the patient may be ready for discharge with a home care plan and oral analgesia.[9] If the pain is uncontrolled despite the above treatment plan, consider hospitalization and the use of stronger forms of analgesia or higher doses titrated to the patient's needs. Simple or exchange transfusion may be warranted.[10] LMWH tinzaparin has been found to shorten the course of pain. A randomized, controlled, double-blind study has suggested that the clinical effects of tinzaparin are due to its effect on cellular factors. No special monitoring is needed for once-daily dosing.[10] Adjuvant therapy includes hydroxyurea, antihistamines, anxiolytics, and antiemetics.[10] It is prudent to maintain adequate hydration and be vigilant in identifying other causes of pain that may need additional treatment.

For other complications like acute chest syndrome, splenic sequestration-supportive care with oxygen, judicious fluid administration, and transfusion therapy is needed. Close monitoring of oxygen saturation and respiratory status, with particular attention to excessive sedation, is also necessary.[11] For acute chest syndrome, empiric antibiotics, adequate analgesics, simple or exchange transfusion, may be considered. Incentive spirometry, oral hydration, and comfort measures are recommended. Patients with splenic sequestration crisis resulting in hypovolemic shock, if not treated aggressively, have higher mortality. Management requires aggressive supportive care and blood transfusion.[8] Aplastic crisis is treated with supportive care and simple transfusions as needed.

Differential Diagnosis

Vaso-occlusive crisis presents with severe pain with a relative paucity of objective clinical signs. Differential diagnosis should include conditions specific to the site of the pain and not be blindly attributed to sickle cell disease. As an example, patients presenting with an abdominal painful crisis can mimic acute abdomen and the differential should include conditions that give acute abdominal pain such as, Acute Appendicitis, acute Pancreatitis, acute pyelonephritis, Pelvic inflammatory disease, and hepatobiliary disease. Avascular necrosis and acute osteomyelitis are a consideration when there is persistent local bone pain.

Consultations

When available, consultation with a hematologist may be helpful.

Pearls and Other Issues

Early detection and rapid initiation of appropriate treatment for several acute conditions including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, and hemolytic crisis is needed. These crises, if not treated early, can result in mortality.

Enhancing Healthcare Team Outcomes

Patients with sickle cell crises are best managed by an interprofessional team that also includes ICU nurses. The key is rapid hydration and pain control. In addition, oxygenation should be monitored. It is important to find and treat the trigger of the crisis to prevent a recurrent crisis.

Despite optimal treatment, the quality of life of most patients with sickle cell is poor, marked by repeated admissions. The pharmacist should ensure that the patient is compliant with hydroxyurea because it has been shown to reduce the adverse effects of the disease.