- What is sickle cell crisis
- Types of sickle cell crisis
- What causes sickle cell crisis
- Sickle cell crisis triggers
- Sickle cell crisis prevention
- Sickle cell crisis symptoms
- Sickle cell crisis diagnosis
- Sickle cell crisis treatment
What is sickle cell crisis
Sickle cell crisis is a term 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 1). However, the usage of the term ‘sickle cell crisis’ is more commonly associated with sudden pain affecting different parts of the body caused by sickled red blood cells forming clumps in the bloodstream (vaso-occlusive crisis). Other cells also may play a role in this clumping process. These clumps of cells block blood flow through the small blood vessels to your bones and organs. This can cause pain and organ damage. You might have pain in your back, knees, legs, arms, chest or stomach. The pain can be throbbing, sharp, dull or stabbing. How often and how bad the pain gets varies a lot from person to person and from crisis to crisis. Other acute complications include pneumonia, meningitis, sepsis and osteomyelitis, stroke, avascular necrosis, priapism, and venous thromboembolism 2).
The pain from sickle cell crisis can be acute (sudden) or chronic (long-lasting), but acute pain is more common. Acute pain comes suddenly and can range from mild to very severe. The pain usually lasts from hours to a few days. Chronic pain often lasts for weeks to months. Chronic pain can be hard to bear and mentally draining. This pain may severely limit daily activities, work and education.
Almost all people who have sickle cell disease have painful crises at some point in their lives. Some have these crises less than once a year. Others may have 15 or more pain crises in a year. Epidemiologic data indicate that 5.2 percent of patients with sickle cell disease have three to 10 episodes of severe pain every year 3). In most patients, a pain crisis resolves within five to seven days. A severe crisis may cause pain that persists for weeks to months 4).
The frequency, severity, location and duration of pain crises can vary considerably, even within a specific disease subtype 5). Patients with homozygous sickle cell and sickle cell–β°-thalassemia have a higher frequency of vaso-occlusive pain crises than patients with hemoglobin SC and sickle cell–β+-thalassemia genotype 6). Disease severity is thought to depend on a complex interaction of genetic, rheologic and hematologic factors, as well as microvascular and endothelial factors 7).
Severe blockages cause episodes of acute pain or ‘sickle cell crisis’, which may be triggered by a range of physical and psychological stresses, including but not limited to infection, pregnancy, surgery, anxiety, or depression. If not treated promptly, sickle cell crisis can result in internal organ and tissue damage, particularly to the lungs, kidneys, liver and bones. The frequent recurrence of sickle cell crisis can lead to chronic complications such as leg ulcers, blindness, and stroke 8). Acute chest syndrome or chest crisis, is a common and particularly dangerous complication that is currently the leading cause of death among sickle cell disease patients 9). Ambulatory care strategies such as nutritional counseling, folic acid supplementation, pain medication protocols, vaccinations and antibiotics for the prevention and treatment of infection, are essential to sickle cell disease management 10).
A sickle cell crisis pain can begin suddenly and last several hours to several days. You might be able to treat your pain crisis at home with medicines that you take by mouth. If these medicines don’t control your pain, you can’t keep fluids down or you know that you’re having severe pain, you might need to be treated in the emergency department. If your pain still isn’t controlled or you have other problems, you might need to be treated in the hospital.
What medicines can I use at home to control my pain?
Some over-the-counter medicines might help relieve mild pain. Taking acetaminophen (brand name: Tylenol) or aspirin might help. Medicines like ibuprofen (brand names: Advil or Motrin) or naproxen sodium (brand name: Aleve) might help if you can safely take these medicines. However, talk to your doctor before you take any medicine for your pain.
If you have moderate to severe pain, your doctor might prescribe a mild narcotic like codeine. This medicine is often given with aspirin or acetaminophen. You take this medicine regularly, around the clock, rather than waiting for the pain to return before taking your next dose.
What else can I do to control the pain?
A heating pad, hot bath, rest or massage might help. Physical therapy to relax and strengthen your muscles and joints might lessen your pain. Individual counseling, self-hypnosis and activities to keep you from thinking about your pain (such as watching television or talking on the telephone) might also help.
It’s important for you to have a positive attitude, create a supportive environment, and develop coping skills to help you deal with your disease. Strong family relationships and close personal friends can be helpful. A support group might help you cope with your disease.
Work with your family doctor to set goals for the management of your pain. Becoming more actively involved in your treatment will help you better manage your disease.
What is sickle cell disease
Sickle cell disease is a rare blood disorder that is inherited in an autosomal recessive manner, affecting about 1 in 500 African American children and 1 in 36,000 Hispanic American children 11). As of 2015, about 4.4 million people have sickle cell disease, and 43 million are estimated to have sickle cell trait 12). Prevalence of sickle cell disease is high among the people of sub-Saharan Africa, South Asia, the Middle East, and the Mediterranean. Sickle cell disease has several recognized forms including sickle cell anemia, sickle cell hemoglobin C disease, and sickle cell / beta-thalassemia disease.
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. Sickle cell disease is characterized by abnormal, crescent-moon shaped red blood cells. These so called ‘sickled’ cells are stiff and sticky and interact with other cells and the blood clotting system to block blood flow in the very tiny blood vessels (capillaries) of the peripheral blood system (blood vessels outside of the heart). This prevents the normal flow of nutrition and oxygen (as red blood cells are responsible for carrying oxygen throughout the body). This process triggers a vicious cycle of increased HbS (hemoglobin S) 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 proinflammatory state, causing further complications of vaso-occlusion.
Types of sickle cell crisis
The vaso-occlusive crisis or sickle cell crisis, is the most common presentation of sickle cell disease. The vaso-occlusive crisis is initiated and sustained by interactions among sickle cells, endothelial cells and plasma constituents 13). Microvascular occlusion (the cardinal pathophysiologic cause of acute pain) is responsible for a wide variety of clinical complications of sickle cell disease, including pain syndromes, stroke, leg ulcers, spontaneous abortion and renal insufficiency. Reperfusion intensifies the inflammation and resultant pain. Patients complain of severe debilitating pain, which has variable intensity and frequency, in any part of the body but typically in the long bones, back, pelvis, chest and the abdomen. Symptoms may start as early as six months of age with pain and swelling in both hands and feet (dactylitis). In most instances, there are no reliable signs or tests to indicate the presence or absence of pain associated with vaso-occlusive crisis.
Most patients with sickle cell disease 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 sickle cell disease is likely to be due to vaso-occlusive crisis, it is prudent to perform a thorough evaluation for other life-threatening causes that can be misattributed to sickle cell pain 14). There is no objective measure or lab test to determine the quality and severity of pain in sickle cell disease, and therefore, patient report is the only available guide.
Acute pain in patients with sickle cell disease is caused by ischemic tissue injury resulting from the occlusion of microvascular beds by sickled erythrocytes during an acute crisis. Chronic pain occurs because of the destruction of bones, joints and visceral organs as a result of recurrent crises. The effect of unpredictable recurrences of acute crises on chronic pain creates a unique pain syndrome 15).
Acute bone pain from microvascular occlusion is a common reason for emergency department visits and hospitalizations in patients with sickle cell disease 16). Obstruction of blood flow results in regional hypoxemia and acidosis, creating a recurrent pattern of further sickling, tissue injury and pain. The severe pain is believed to be caused by increased intra-medullary pressure, especially within the juxta-articular areas of long bones, secondary to an acute inflammatory response to vascular necrosis of the bone marrow by sickled eythrocytes 17). The pain may also occur because of involvement of the periosteum or periarticular soft tissue of the joints.
When a vaso-occlusive crisis lasts longer than seven days, it is important to search for other causes of bone pain, such as osteomyelitis, avascular necrosis and compression deformities 18). When a recurrent bone crisis lasts for weeks, an exchange transfusion may be required to abort the cycle 19).
The approach to pain control must include measures to treat acute pain crises, prevent future vaso-occlusive crises and manage the long-term sequelae of chronic pain that can result from multiple recurrent bony infarctions.
Splenic sequestration crisis
Patients with sickle cell disease 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 20).
Aplastic crisis presents 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 red blood cell production, but it can also be caused by other viral infections. The shortened lifespan of red blood cell in sickle cell disease 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 21).
Acute chest syndrome
This complication of sickle cell disease accounts for 25% of deaths and can follow vaso-occlusive crises. Acute chest syndrome is defined as the appearance of a new pulmonary infiltrate on chest radiography accompanied by a fever and respiratory symptoms, including a cough, tachypnea, and chest pain 22). It is hypothesized that acute chest syndrome is the result of hypoxia and an inflammatory mediator-induced increase in adhesion of the pulmonary microvasculature to sickled red blood cells. This process is coupled with a reduction in nitric oxide (NO), which would normally counteract it. The most common symptoms in patients with acute chest syndrome are fever, cough, chest pain, dyspnea, and lung exam may show reduced air entry, rales and sometimes wheeze. acute chest syndrome can progress rapidly to hypoxemia and respiratory failure if not treated promptly. When possible to identify infectious organisms, chlamydia, Streptococcus pneumonia, and Mycoplasma predominate.
Acute chest syndrome could also occur as a result of fat embolism originating from the distal bone in vaso-occlusive crisis. The hypoxia leads to adhesion of sickled erythrocytes to pulmonary microvasculature, setting up local hypoxia in the lungs and causing sickling of more red blood cells; this sets up a vicious cycle. Any pulmonary infiltrate on chest radiography accompanied by abnormal lung findings should raise the suspicion of acute chest syndrome. Affected patients can rapidly progress to worsening respiratory failure and death if not aggressively treated and monitored 23).
An acute drop in hemoglobin level marks this crisis. It is common in patients with coexistent G6PD deficiency 24).
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.
What causes sickle cell crisis
Most of the time, you won’t know what caused your sickle cell crisis. A crisis usually has more than one cause. However, you can do several things that might keep a crisis from occurring 25):
- Don’t drink a lot of alcohol.
- Don’t smoke. If you do smoke, quit.
- Exercise regularly but not so much that you become really tired. When you exercise, drink lots of fluids.
- Drink at least eight 12-ounce glasses of water a day during warm weather.
- Reduce or avoid stress. Talk to your doctor if you’re depressed or have problems with your family or job.
- Treat any infection as soon as it occurs. When in doubt, see your doctor.
- Wear warm clothes outside in cold weather and inside in air-conditioned rooms during hot weather. Also, don’t swim in cold water.
- Try to be positive about yourself.
- Tell your doctor if you think you might have a sleep problem, such as snoring or if you sometimes stop breathing during sleep.
- If you have another medical condition, like diabetes, get treatment and control the condition.
- If you are pregnant or plan to become pregnant, get early prenatal care.
- Only travel in commercial airplanes. If you have to travel in an unpressurized aircraft, talk to your doctor about extra precautions.
Sickle cell crisis triggers
While some triggers (cold temperature, dehydration, low humidity, stress, infection) for pain are identifiable, most sickle cell crisis episodes do not have an identifiable cause 26). It is postulated that the intestinal microbiome may be a potential trigger for vaso-occlusive crisis 27).
Factors that can trigger sickle cell crises:
- Low oxygen tension
- Concomitant medical conditions (e.g., sarcoidosis, diabetes mellitus, herpes)
- Extreme physical exercise
- Physical or psychologic stress
- Cold weather
Sickle cell crisis prevention
People with sickle cell disease need to be aware of the factors that can trigger vaso-occlusive crises. People with sickle cell disease are particularly susceptible to dehydration because of a reduced ability to conserve water secondary to a defect in renal concentrating ability. You should wear warm clothes in cold weather, drink adequate amounts of fluids in hot weather and avoid exercising to the point of fatigue and dehydration.
- Drink plenty of water. Dehydration can increase your risk of a sickle cell crisis. Drink water throughout your day, aiming for about eight glasses a day. Increase the amount of water you drink if you exercise or spend time in a hot, dry climate.
- Avoid temperature extremes. Exposure to extreme heat or cold can increase your risk of a sickle cell crisis.
- Avoiding mountain climbing or air flights in an unpressurized cabin (noncommercial flights) above 10,000 feet.
- Avoiding exposure to extreme cold, exercising to exhaustion or using drugs that can lead to acidosis (e.g., acetazolamide [Diamox]).
- Genetic screening and vocational counseling about working (e.g., roofing) or taking part in extreme physical activity (e.g., military training) in the heat.
- Avoiding hypoxemia in the perioperative period when general anesthesia is used or when a procedure involves hypertonic radiographic dyes
Sickle cell crisis symptoms
Common symptoms associated with sickle cell disease include excruciating bone pain, chest pain, severe infections (primarily in children), low levels of circulating red blood cells (anemia) and yellowing of the skin (jaundice). The blocked blood flow can also cause severe organ damage including stroke.
A vaso-occlusive crisis most commonly involves the back, legs, knees, arms, chest and abdomen 28). The pain generally affects two or more sites. Bone pain tends to be bilateral and symmetric. Recurrent crises in an individual patient usually have the same distribution 29). It has been postulated that the symmetry of bone marrow necrosis can be accounted for by centrally mediated reflexes that direct blood away from the marrow in response to the cooler skin temperature 30). If a patient’s pain has a different than usual pattern, other causes for the pain should be sought.
An acute abdominal pain crisis often resembles an intra-abdominal process such as cholecystitis or appendicitis. Diagnoses that may require surgery and suggest a process other than vaso-occlusive crisis include pain in the absence of a precipitating event, pain that differs from the pain experienced in previous vaso-occlusive crises, and lack of pain relief within 48 hours despite hydration and oxygen therapy 31).
Sickle cell crisis diagnosis
The work-up of the patient with a vaso-occlusive crisis should include a complete history, a physical examination, selected laboratory tests and a search for reversible conditions known to precipitate pain crises. The physician should look for clinical evidence of dehydration and infection. The extent of bone and soft tissue involvement should also be assessed. Routine laboratory testing is unnecessary in patients with uncomplicated vaso-occlusive crises 32).
However, if a sickle cell crisis patient has symptoms that are severe enough to warrant hospitalization, routine laboratory examination such as complete blood count (CBC) with differential, a reticulocyte count, and a complete metabolic panel including liver function tests are needed. Type and screen blood for possible transfusion if needed. Inflammatory markers include CRP (C-reactive protein), 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 acute chest syndrome and in the case of fever. Urine, sputum and blood should be cultured for a possible source of infection. Fever is common in patients with an uncomplicated vaso-occlusive crisis and does not necessarily indicate the presence of an underlying infection 33). An abdominal ultrasound may be considered for concerns of cholelithiasis. Arterial blood gas (ABG) can be obtained for hypoxemia and respiratory failure 34). CT head and MRI brain would be indicated if there is suspicion of stroke.
Sickle cell crisis treatment
Acute sickle cell crises are managed primarily with drug therapy. Psychologic supportive care is also important. The standard treatment approach for sickle cell crisis includes opioid analgesics, adequate hydration, rest, and cognitive and behavioral therapies 35). The management of acute pain in sickle cell crises is summarized in Table 1. In addition, the American Pain Society recently released a comprehensive guideline on pain management in sickle cell disease 36).
Optimal management requires a multidisciplinary team that includes a family physician, a hematologist, nurses, a psychiatrist, a physical therapist, a pain specialist and social workers. These team members work together to provide empathetic, consistent, longitudinal care in a trustworthy environment 37). Discussions of coping mechanisms, reassurance about pain management and the presence of a cohesive family unit are all important in preventing psychologic instability and the development of a chronic pain syndrome.
Therapeutic red cell exchange transfusion is advised as an adjuvant, for the management of sickle cell crisis, and it is mainly practiced in the pediatric population. Red blood cell transfusion is recommended as the first line of management, for sickle cell disease to keep the HbS levels below 30% 38).
Table 1. Treatment Principles for Acute Pain Management in Patients with Sickle Cell Crises
If possible, identify and treat underlying precipitating factors.
If needed, administer fluids orally, or intravenously as 5 percent dextrose in water or in a 25 percent normal saline solution.
Use oxygen therapy only if hypoxemia is present.
Acute pain management
Avoid delays in administering analgesia.
Administer an opioid analgesic parenterally (preferably intravenously) on a regular basis in a full therapeutic dosage or by patient-controlled analgesia. Avoid “as-needed” dosing.
Reassess the patient every 30 minutes for pain severity, sedation, vital signs and respiratory rate.
Use pain measurement scales as an objective guide to titrate the maintenance dosage of an analgesic and to determine treatment effects.
For breakthrough pain, administer one fourth to one half of the maintenance dosage, depending on the degree of sedation.
If three or more rescue doses are needed within a 24-hour period, increase the maintenance dosage by 25 to 50 percent, and repeat the same steps until analgesia is achieved.
Pain management after an acute crisis
Begin tapering the parenterally administered analgesic when the pain severity score is less than 5 on the visual analog scale or verbal pain scale and the patient’s mood improves. Reduce the maintenance dosage by 25 percent every 24 hours, and replace the parenterally administered drug with an equianalgesic oral agent given in divided doses.
Consider hospital discharge when the patient’s pain is controlled with an orally administered analgesic or no analgesia is needed.
If the patient still has pain at the time of hospital discharge, provide a prescription for a sufficient quantify of analgesic drug to treat resolving or relapsing pain until the patient’s next office appointment.
Pain from a vaso-occlusive crisis is often undertreated because of concerns about narcotic addiction and tolerance, perceived drug-seeking behavior, excessive sedation, respiratory depression and lack of specific findings on the physical examination 40).
Physicians often fail to prescribe narcotics appropriately and tend to overestimate opioid dependence in patients with pain crises. Yet the incidence of opioid analgesic addiction in patients with sickle cell disease has been reported to be no higher than 3 percent 41).
Many drug regimens have been effective in the treatment of acute pain in sickle cell disease. Pain management should follow the three-step “analgesic ladder” recommended by the World Health Organization for the treatment of cancer-related pain 42). The choice of analgesic and the dosage used should be based on the severity of pain in the individual patient.
Patients with mild pain can often be treated at home with oral fluids and nonnarcotic analgesics (Table 2). Patients can also be started on acetaminophen with or without codeine or oxycodone (Roxicodone), depending on pain severity. Nonsteroidal anti-inflammatory drugs can be used unless they are specifically contraindicated because of peptic ulcer disease, renal disease or hepatic dysfunction.
Table 2. Nonnarcotic Analgesics for Mild Pain in Sickle Cell Disease
|Drug||Usual starting dosage in adults|
500 to 1,000 mg every 4 to 6 hours (maximum < 4,000 mg per day)
Acetylsalicylic acid (aspirin)
650 to 1,000 mg every 4 to 6 hours (maximum < 4,000 mg per day)
1,000 mg initially, then 500 mg every 8 to 12 hours
Choline magnesium trisalicylate (Trilisate)
1,000 to 1,500 mg every 12 hours
200 to 400 mg every 4 to 6 hours
500 mg initially, then 250 mg every 6 to 8 hours
200 mg every 4 to 6 hours
25 to 75 mg, then 250 mg every 6 to 8 hours (maximum < 300 mg per day)
Narcotic analgesics can be used in patients with moderate to severe pain. The dosage of the selected narcotic should be titrated to achieve effective pain control. Because of the dose-limiting side effects of weak opioids (codeine and oxycodone), which include sedation, nausea and vomiting, these drugs are best used to manage moderate pain (Table 3). Pain that is sufficiently severe to require an emergency department visit or hospitalization should be treated with stronger opioids (Table 4).
If a patient has poor venous access and is unable to take enteral narcotics because of vomiting, the subcutaneous route can be employed, using morphine or its equivalent. It is important to remember that subcutaneous administration may result in prolonged absorption if a patient is dehydrated.
Adjuvant nonopioid agents such as antihistamines and antiemetics can be helpful for preventing or relieving opioid-related side effects 44). The use of adjuvant analgesics such as tricyclic antidepressants should be considered in patients with a chronic pain syndrome resulting from recurrent acute pain crises 45).
Nonpharmacologic techniques can also be tried. These measures include physical therapy, rest, heat application, transcutaneous electrical nerve stimulation (TENS), self-hypnosis and diversional techniques 46).
Table 3. Common Opioids Used to Treat Mild to Moderate Pain in Sickle Cell Disease
|Drug||Usual oral starting dosage in adults||Comments and precautions|
30 to 60 mg Every 3 or 4 hours
Available in liquid or tablet form, alone or in combination with acetaminophen
Side effects: impaired ventilation (histamine release possibly triggering bronchospasm) and increased intracranial pressure as a result of carbon dioxide retention
10 to 30 mg every 4 hours
Often used in combination with acetaminophen, which limits safe dosage to 12 tablets per day (about 4 g of acetaminophen)
Side effects: similar to those of codeine
Table 4. Opioids Used to Treat Severe Pain in Sickle Cell Disease
|Drug||Oral/IM potency||Equianalgesic dosages||Usual starting dosage in adults|
15 to 30 mg every 4 hours
0.1 to 0.15 mg per kg every 3 or 4 hours
2 to 4 mg every 4 to 6 hours
1 to 2 mg every 4 to 6 hours
50 to 150 mg every 3 or 4 hours
75 to 100 mg every 3 or 4 hours
2 to 4 mg every 6 to 8 hours
Up to 1 mg IV every 3 to 6 hours; 1 to 2 mg IM or SC every 6 to 8 hours
Footnote: *—Single-dose studies determined that the relative potency is 6:1; with repetitive doses, this ratio changes to 3:1.
Abbreviations: IM = intramuscular; IV = intravenous; SC = subcutaneous.[Source 48) ]
Meperidine vs. morphine
In the past, moderate to severe pain in sickle cell disease was usually treated with meperidine (Demerol) administered parenterally or, more commonly, intramuscularly. Compared with morphine, however, meperidine has a number of properties that make it a poor opioid analgesic for repeated use in most patients with sickle cell disease.
Meperidine is a weak opioid analgesic with a short half-life (two to three hours). Thus, frequent dosing is required to maintain a sustained analgesic effect. In addition, normeperidine, a metabolite of meperidine, has been associated with seizures, particularly in patients with impaired renal function who are being given high doses at frequent intervals 49). Repeated injections of meperidine can lead to fibrosis, infection and sterile abscess formation at the injection site.
For these reasons, parenterally administered morphine should be considered the treatment of choice for moderate to severe pain in vaso-occlusive crises. Morphine’s side effects include pruritus, nausea, vomiting and rash. In addition, dosage adjustments are necessary in patients with liver dysfunction 50).
Some patients prefer meperidine for the treatment of pain crises and may be reluctant to change to morphine. Analgesia should be discussed when patients are not in pain.
Regardless of the type of opioid analgesic used, respiratory rate and oxygen saturation must be closely monitored because of the potential for respiratory depression. If the respiratory rate is less than 10 per minute or excessive sedation occurs, the opiate should be discontinued, the dosage should be reduced or the dosing frequency should be lengthened 51).
Methods of narcotic analgesics delivery
With parenteral administration, narcotic analgesics can be given using a fixed schedule (with rescue doses administered for breakthrough pain), continuous infusion or patient-controlled administration. Dosing on an “as-needed” basis should be avoided because it does not confer an adequate sustained level of analgesia.
Patient-controlled analgesia offers several unique advantages in the treatment of severe pain occurring in a vaso-occlusive crisis 52). One study 53) found that the intermittent fixed schedule and the patient-controlled method were equally efficacious in providing adequate analgesia. Patient-controlled analgesia prevents fluctuation in blood drug levels and may reduce the time between the perception of pain and the administration of the analgesic. This approach reduces overmedication and excessive sedation. It also provides patient autonomy and decreases the nursing time required for analgesic administration.
Oxygen therapy is often used routinely in the management of vaso-occlusive crises, despite lack of evidence supporting the effectiveness of these measures in all patients.25,26 Oxygen therapy has not been shown to affect the duration of a pain crisis or to be useful in patients with acute chest syndrome whose partial pressure of arterial oxygen (PaO2) is in the normal range. Hence, oxygen should be administered only if hypoxemia is present 54). Oxygen may also suppress erythrocyte production, depress reticulocytosis and cause rebound sickle cell crises on discontinuation of therapy when the arterial oxygen tension is raised above the normal range 55).
Pulse oximetry may not be a reliable method of determining the PaO2 in patients with sickle cell disease.28 One reason may be the differences in the oxygen dissociation curve between normal hemoglobin and sickle cell hemoglobin (hemoglobin S) 56). Sickle cell erythrocytes have decreased oxygen affinity and increased unsaturated hemoglobin in the arterial blood. All low pulse-oximetry saturation values should be compared with values obtained at steady state, if available, or should be confirmed by measuring the PaO2 directly with an arterial blood gas determination 57).
Most patients with sickle cell anemia have hemoglobin values of 6 to 10 g per dL (60 to 100 g per L). The hemoglobin S molecule has a low affinity for oxygen (which allows for adequate tissue oxygenation). During a vaso-occlusive crisis, a patient’s hemoglobin level often declines by at least 1 g per dL (10 g per L).
A hemoglobin value of 5 g per dL (50 g per L) or less or a decline in the hemoglobin value of greater than 2 g per dL (20 g per L) from the patient’s baseline level has been used as a guide for considering simple transfusion therapy 58). Patients should be transfused to their baseline hemoglobin level. A higher hematocrit may make the blood more viscous and further increase sickling.
Other indications for transfusion include acute chest syndrome with hypoxia and the need for surgery using general anesthesia.
Exchange transfusions should be considered only in patients who have a prolonged refractory vaso-occlusive crisis with a stable baseline hemoglobin concentration. The goal is to reduce sickling by reducing the hemoglobin S level to below 20 percent 59).
Increased plasma osmolarity from a reduced plasma volume can worsen a vaso-occlusive crisis by causing intracellular dehydration, hemoglobin polymerization and further sickling. During hyponatremia, the affinity of hemoglobin S for oxygen is increased. Therefore, at any given PaO2, less oxygen is in the deoxygenated state, which is the form most susceptible to polymerization. Patients with sickle cell disease have isosthenuria, which leads to difficulty in excreting a sodium load 60).
Fluids should be administered in a quantity sufficient to correct existing deficits and replace ongoing losses in order to maintain a euvolemic state. Large fluid volumes may decrease plasma oncotic pressure and increase hydrostatic pressure. This can lead to pulmonary edema, especially in patients with impaired renal function, cardiac failure or pulmonary vascular injury.
If tolerated, oral rehydration should be used in patients with milder vaso-occlusive crises. The parenteral route of rehydration is indicated in patients with severe pain, vomiting or volume depletion. After existing volume deficits have been corrected with normal saline, fluid replacement should consist of 5 percent dextrose in water or in a 25 percent normal saline solution 61).
Hydroxyurea (Hydrea) increases the production of hemoglobin F and thereby reduces the severity of sickle cell disease by preventing the formation of hemoglobin S polymers 62). At present, hydroxyurea should be used in patients who have severe complications and who can reliably follow the regimen.
Hydroxyurea is initiated in a dosage of 500 mg per day. The dosage is increased to 1,000 mg per day after six to eight weeks, with the patient monitored for a decline in granulocyte or platelet counts. The maintenance dosage is between 1,000 and 2,000 mg per day, depending on the balance between hematologic toxicity and increases in hemoglobin F values 63). Blood counts should be followed every four to six weeks to detect longer term hematologic toxicities.
A rising mean corpuscular volume is a good surrogate marker for rising hemoglobin F levels. Treatment should be stopped if a patient does not respond after several months of hydroxyurea therapy.
The long-term effects of hydroxyurea maintenance therapy are not well known. More studies are needed to better determine negative effects such as carcinogenicity and positive effects such as the prevention of organ damage and reduced mortality.
Vaso-occlusive crisis management
Vaso-occlusion is an emergency condition requiring intensive care admission and carries a high mortality 64). Rapid pain assessment and initiation of analgesia should be undertaken promptly. Depending on the degree and severity of pain, an 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) 65). Those with persistent pain benefit from a patient-controlled analgesia pump. Close monitoring of vital signs including oxygen saturation should be maintained with frequent reassessments of pain severity or resolution 66). If the pain is controlled, the patient may be ready for discharge with a home care plan and oral analgesia 67). 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 68). Low molecular weight heparin 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 69). Adjuvant therapy includes hydroxyurea, antihistamines, anxiolytics, and antiemetics 70). 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 71). 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 72). Aplastic crisis is treated with supportive care and simple transfusions as needed.
Management after hospital discharge
Most patients have residual pain at the time they are discharged from the hospital. Therefore, they should be given an oral narcotic analgesic in a dosage equivalent to the dosage that was necessary to control their pain while they were hospitalized. They should be given enough of the narcotic analgesic to last until the next scheduled outpatient follow-up visit 73).
Patients should be instructed to use the visual analog scale or the verbal categorical scale as a guide for self-tapering of the analgesic dosage based on their level of pain.
References [ + ]
|1, 12, 65.||↵||Borhade MB, Kondamudi NP. Sickle Cell Crisis. [Updated 2018 Oct 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526064|
|2.||↵||Hiran S. Multiorgan dysfunction syndrome in sickle cell disease. J Assoc Physicians India. 2005 Jan;53:19-22.|
|3.||↵||Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325:11–6.|
|4.||↵||Shapiro BS. The management of pain in sickle cell disease. Pediatr Clin North Am. 1989;36:1029–45.|
|5, 16, 28, 35, 37, 40, 46, 49.||↵||Ballis SK, Carlos TM, Dampier C, and Guidelines Committee. Guidelines for standard of care of acute painful episodes in patients with sickle cell disease. Harrisburg, Pa.: Commonwealth of Pennsylvania Department of Health, 1996.|
|6.||↵||Nagel RL. Sickle cell anemia is a multigene disease: sickle cell painful crises, a case in point. Am J Hematol. 1993;42:96–101.|
|7.||↵||Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med. 1997;337:1584–90.|
|8.||↵||Green SA, Aljuburi G, Majeed A, et al. Characterizing emergency admissions of patients with sickle cell crisis in NHS brent: observational study. JRSM Short Rep. 2012;3(6):37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386659/|
|9.||↵||Moore F, Mortimer P, Wooller J Updated Sickle Cell Crisis Guidelines. Joint Royal Colleges Ambulance Liaison Committee. 2009|
|10.||↵||Sickle-cell disease and other haemoglobin disorders. Fact sheet N°308. WHO, January 2011|
|11.||↵||Jeremiah ZA. Abnormal haemoglobin variants, ABO and Rh blood groups among student of African descent in Port Harcourt, Nigeria. Afr Health Sci. 2006;6(3):177-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1831888/|
|13, 62, 63.||↵||Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999;340:1021–30.|
|14, 20, 21, 24.||↵||Hebbel RP, Boogaerts MA, Eaton JW, Steinberg MH. Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity. N. Engl. J. Med. 1980 May 01;302(18):992-5. https://www.ncbi.nlm.nih.gov/pubmed/7366623|
|15.||↵||Payne R. Pain management in sickle cell disease. Ann N Y Acad Sci. 1989;565:189–206.|
|17, 29, 33.||↵||Serjeant GR, Ceulaer CD, Lethbridge R, Morris J, Singhal A, Thomas PW. The painful crisis of homozygous sickle cell disease: clinical features. Br J Haematol. 1994;87:586–91.|
|18, 19, 32, 39, 43, 47, 48.||↵||Approach to the Vaso-occlusive Crisis in Adults with Sickle Cell Disease. Am Fam Physician. 2000 Mar 1;61(5):1349-1356. https://www.aafp.org/afp/2000/0301/p1349.html|
|22.||↵||Sedrak A, Kondamudi NP. Sickle Cell Disease. [Updated 2018 Oct 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482384|
|23.||↵||Simon E, Long B, Koyfman A. Emergency Medicine Management of Sickle Cell Disease Complications: An Evidence-Based Update. J Emerg Med. 2016 Oct;51(4):370-381. https://www.ncbi.nlm.nih.gov/pubmed/27553919|
|25.||↵||Practical Tips for Preventing a Sickle Cell Crisis. Am Fam Physician. 2000 Mar 1;61(5):1363-1364. https://www.aafp.org/afp/2000/0301/p1363.html|
|26.||↵||Quinn CT, Lee NJ, Shull EP, Ahmad N, Rogers ZR, Buchanan GR. Prediction of adverse outcomes in children with sickle cell anemia: a study of the Dallas Newborn Cohort. Blood. 2008 Jan 15;111(2):544-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2200853/|
|27.||↵||Mehta SR, Afenyi-Annan A, Byrns PJ, Lottenberg R. Opportunities to improve outcomes in sickle cell disease. Am Fam Physician. 2006 Jul 15;74(2):303-10. https://www.aafp.org/afp/2006/0715/p303.html|
|30.||↵||Serjeant GR, Chalmers RM. Current concepts in haemotology. 1. Is the painful crisis of sickle cell disease a “steal” syndrome. J Clin Pathol. 1990;43:789–91.|
|31.||↵||Baumgartner F, Klein S. The presentation and management of the acute abdomen in the patient with sickle-cell anemia. Am Surg. 1989;55:660–4.|
|34, 66.||↵||Chou ST, Fasano RM. Management of Patients with Sickle Cell Disease Using Transfusion Therapy: Guidelines and Complications. Hematol. Oncol. Clin. North Am. 2016 Jun;30(3):591-608. https://www.ncbi.nlm.nih.gov/pubmed/27112998|
|36.||↵||Preboth M. Management of pain in sickle cell disease. Am Fam Physician. 2000;61:1541–2.|
|38.||↵||Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48. doi: 10.1001/jama.2014.10517. https://jamanetwork.com/journals/jama/article-abstract/1902235|
|41.||↵||Pathophysiology and management of sickle cell pain crisis. Lancet. 1995;346:1408–11.|
|42.||↵||Cancer pain relief. Geneva: World Health Organization, 1986.|
|44, 73.||↵||Ballas SK. Management of sickle pain. Curr Opin Hematol. 1997;4:104–11|
|45.||↵||Pollack CV Jr, Sanders DY, Severance HW Jr. Emergency department analgesia without narcotics for adults with acute sickle cell pain crisis: case reports and review of crisis management. J Emerg Med. 1991;9:445–52.|
|50.||↵||Ballas SK. Management of sickle pain. Curr Opin Hematol. 1997;4:104–11.|
|51.||↵||Ballas SK Complications of sickle cell anemia in adults: guidelines for effective management. Clev Clin J Med. 1999;66:48–58.|
|52.||↵||Shapiro BS, Cohen DE, Howe CJ. Patient-controlled analgesia for sickle-cell-related pain. J Pain Symptom Manage. 1993;8:22–8.|
|53.||↵||Gonzalez ER, Bahal N, Hansen LA, Ware D, Bull DS, Ornato JP, et al. Intermittent injection vs. patient-controlled analgesia for sickle cell crisis pain. Arch Intern Med. 1991;151:1373–8.|
|54.||↵||Zipursky A, Robieux IC, Brown EJ, Shaw D, O’Brodovich H, Kellner JD, et al. Oxygen therapy in sickle cell disease. Am J Pediatr Hematol Oncol. 1992;14:222–8.|
|55.||↵||Embury SH, Garcia JF, Mohandas N, Pennathur-Das R, Clark MR. Effects of oxygen inhalation on endogenous erythropoietin kinetics, erythropoiesis, and properties of blood cells in sickle-cell anemia. N Engl J Med. 1984;311:291–5.|
|56, 60, 61.||↵||Okpala I. The management of crisis in sickle cell disease. Eur J Haematol. 1998;60:1–6.|
|57.||↵||Homi J, Levee L, Higgs D, Thomas P, Serjeant G. Pulse oximetry in a cohort study of sickle cell disease. Clin Lab Haematol. 1997;19:17–22.|
|58, 59.||↵||Brozovic M, Davies S. Management of sickle cell disease. Postgrad Med J. 1987;63:605–9.|
|64.||↵||Mamdapur AB, Sagar MS, Madhusudan R, Samir M. Therapeutic Red Cell Exchange Transfusion as an Adjuvant Therapy for Management of Sickle Cell Crisis in Adults. Indian J Crit Care Med. 2018;22(6):457-459. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020634/|
|67.||↵||Ballas SK. Current issues in sickle cell pain and its management. Hematology Am Soc Hematol Educ Program. 2007:97-105.|
|68, 69, 70.||↵||Robieux IC, Kellner JD, Coppes MJ, Shaw D, Brown E, Good C, O’Brodovich H, Manson D, Olivieri NF, Zipursky A. Analgesia in children with sickle cell crisis: comparison of intermittent opioids vs. continuous intravenous infusion of morphine and placebo-controlled study of oxygen inhalation. Pediatr Hematol Oncol. 1992 Oct-Dec;9(4):317-26.|
|71.||↵||Porter M. Rapid Fire: Sickle Cell Disease. Emerg. Med. Clin. North Am. 2018 Aug;36(3):567-576.|
|72.||↵||Chou ST, Fasano RM. Management of Patients with Sickle Cell Disease Using Transfusion Therapy: Guidelines and Complications. Hematol. Oncol. Clin. North Am. 2016 Jun;30(3):591-608.|