Sickle Cell Information Center - Problem Oriented Clinical Guidelines by James Eckman, M.D. and Allan Platt, PA-C These guidelines are updated copies from the book: "Problem Oriented Management of Sickle Cell Syndromes", originally published in 1991 using grant support from the Genetic Services Branch of the Maternal and Child Health Bureau, U.S. Department of Health and Human Services (Grant MJC-131003-04), The Southeastern Regional Genetics Group (Grant MCJ 131002-08) and a legislative grant from the State of Georgia Department of Human Resources (DHR Contract 427-93-10593) Sickle Cell Disease In Children And Adolescents: Diagnosis, Guidelines For Comprehensive Care, And Care Paths And Protocols For Management Of Acute And Chronic Complications CLICK HERE To go to a palm friendly menu page CLICK HERE

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Notice: These protocols are guidelines in use at the Sickle Cell Center at Grady Health System, and they are intended for use by heath care providers treating patient with sickle cell syndromes. These guidelines are supplements to current text in general medicine, surgery and pediatrics. The recommendations for use and dosages of all medications is based on a review of current medical literature and 10 years of sickle cell acute care experience. The use of any drug should be preceded by a careful review of the package insert, which provides indications and dosages as approved by the United States Food and Drug Administration.

Introduction - Sickle cell syndromes are caused by inheritance of homozygous hemoglobin S or compound heterozygosity for hemoglobin S and hemoglobin C or a beta thalassemia. Clinical manifestations, primarily caused by the altered solubility characteristics of the hemoglobin, include chronic hemolysis, heightened susceptibility to serious infection, and episodic vascular occlusions with ischemic tissue damage causing pain episodes and ultimately organ failure.

Pathophysiology and Principles of Treatment -The biochemistry of hemoglobin S and the hypothesized pathophysiologic mechanisms of complications provide principles for treatment of complications in sickle cell syndromes. These principles must be applied in preventing and treating almost every complication observed during the clinical course of patients. The pathophysiology of pain and principles of pain management are also reviewed to provide a rational basis for the use of analgesics to treat pain associated with complications.

Health Maintenance - Those with sickle cell disease should be evaluated periodically to establish a normal baseline for the patient, identify impending problems, to update immunizations and maintain nutrition support, and to provide patient and parent education and support. A schedule table provides broad guidelines for the frequency of visits and interventions to be stressed throughout life. There is wide variation in the severity of the disease between individuals and these guidelines provide suggested minimum health maintenance activities.

Emergency Room, Ambulance, and Triage Guidelines - Sickle cell patients are frequently seen in emergency rooms for evaluation of new symptoms and for pain management. These patients are high risk for life threatening events and their triage level should be high. Patients level of pain should be assessed and believed. Ambulance staff should transport the patient to a emergency facility with knowledgeable staff. Time should not be used in the field obtaining an IV unless there is a long transport. Nasal oxygen can be administered if the patient is dyspneic. Emergency room staff performing triage and evaluation should be aware high priority problems:

Specific Problems In Management

Abdominal Pain - Sickle pain episodes may present with pain in the abdomen and intra-abdominal pathology can precipitate pain crisis. This population has the usual problems which can present with abdominal pain, however, the incidence of gall stones with cholecystitis, peptic ulcer disease, and pyelonephritis is increased. Complications such as splenic or hepatic sequestration are almost unique problems in patients with these diseases. This protocol will address some of the more common problems and is not meant to be encyclopedic. When in doubt, the advice of a surgical consult is invaluable and admission for observation almost mandatory.

Allergic Reaction - The manifestations of allergic reactions vary in severity from mild fever, rash, pruritus, urticaria (hives), to life threatening problems or angioneurotic edema, respiratory failure, and anaphylaxis with shock. Such reactions can occur after exposure to drugs, contrast material, serums, vaccines, local anesthetic agents, cosmetics, insect bites, and foods.

Anemia - Aplastic and Hyperhemolytic Crisis- Anemia is lifelong, starting in the first year of life as the fetal hemoglobin level falls. The average red cell survival is reduced from a normal of 120 days down to an average of 10 to 20 days in sickle cell anemia. This produces anemia, a high reticulocyte count, and a striking proliferation of red cell precursors in the bone marrow to compensate for the hemolysis. Other problems related to the anemia are jaundice (elevated indirect bilirubin), changes in bone structure, and a high lactic dehydrogenase. Increase in the severity of anemia can be a sign of developing life-threatening complications such as aplastic crisis and splenic sequestration. Both of these important complications will be discussed in this chapter. Many infectious complications will cause partial suppression of erythrocyte production increasing the anemia in patients with sickle syndromes. Acute anemia can be caused by an aplastic episode, sequestration, G6PD, acute chest syndrome, an allo-antibody, renal failure, or folate deficiency

Anesthesia an Preoperative Management -A recent cooperative study of preoperative transfusion demonstrates that sickle cell patients should have simple transfusions to raise the patient's hemoglobin to 10 gm/dl before surgery. These simple transfusions are safer and as effective in preventing postoperative complications as are exchange or aggressive transfusions to decrease the hemoglobin S level below 30%. Postoperative complications such as chest syndrome, fever, and alloimmunization with delayed transfusion reactions are common. Alloimmunization can be minimized by giving antigen matched blood (matched for K, C, E, S, Fy, and Jk antigens). All patients should receive incentive spirometry, given adequate hydration and oxygenation.

Aplastic Crisis - Aplastic episode occurs in highest frequency during early childhood, however, can occur at any age. The complication is characterized by very rapid onset of life-threatening anemia caused by the absence in production of new erythrocytes. The reticulocyte count is low and erythroid precursors are absent or markedly reduced in the bone marrow. The syndrome is now known to be caused by infection with the parvo virus B19. Many viral and bacterial infection.

Back Pain - Back pain is extremely common during pain episodes in patients with sickle syndromes. In children and young adults one must always consider renal pathology or musculoskeletal pain unrelated to the sickle syndrome. In older adults, disk disease, tumors and infection. Gynecologic disease is a consideration in sexually active females at any age.

Bone Pain - More prolonged and constant pain can be seen with bone infarction, sickle arthritis, and aseptic necrosis of the femur or humerus. With chronic pain, non-steroidal anti-inflammatory medications with renal sparing properties should be administered continuously to maintain analgesic blood levels during these episodes. TENS units, relaxation techniques, occupational and physical therapy approaches may be useful in reducing pain and maintaining a functional lifestyle. Education and support are often required to prevent the inappropriate continuous use of opiate analgesics for these chronic pain states.

Chelation Therapy and Iron Overload  Iron overload occurs in people with sickle cell syndromes who have required numerous red cell transfusions. The body’s iron stores become saturated after receiving approximately 500 mg Fe/kg, or 20-30 transfusions. Progressive iron accumulation beyond this point will lead to organ toxicity, particularly to the heart, liver, endocrine organs. The toxicity of iron is believed to be due to free radical damage to tissues induced by iron that is circulating unbound to plasma proteins such as transferrin. The human body does not excrete a significant amount of iron. Phlebotomy, the treatment of choice for iron overload due to hereditary hemachromatosis, is not an option for chronically anemic individuals.

Chest Pain and Chest Syndrome - Chest pain in patients with sickle syndromes can occur from pulmonary infarction, pneumonia, myocardial ischemia, chest wall pain from bone infarction, or as part of the diffuse pain of pain crisis. Esophageal disease, peptic ulcer disease, and gall bladder disease can occasionally cause chest pain. The symptom complex of acute pleuritic chest pain, fever, prostration, leukocytosis, and infiltrates on chest x-ray is termed the acute chest syndrome. This medical emergency, a common cause of hospitalization, is usually caused by pulmonary infarction from sickling in adults and infection in children.

Congestive Heart Failure - Patients with sickle syndromes most commonly develop heart failure from high output secondary to anemia. Symptoms of dyspnea on exertion, palpitations, and weakness and physical findings of murmurs, third heart sounds, and enlarged heart, which occur because of the anemia, may be mistaken for intrinsic cardiac disease. Older patients and those who receive frequent transfusion may develop cardiac disease which may lead to heart failure.

Cough - Pneumonias, acute chest syndrome caused by sickling in pulmonary arteries, and fat embolization, are acute complications seen with increased frequency in patients with sickle syndromes. They present difficult differential diagnostic problems because manifestations of chest pain, cough, fever, pulmonary infiltrates, and severe hypoxia are common to all. Treatment includes hospitalization with careful monitoring of hemoglobin and blood gasses, oxygen for hypoxia, judicious hydration and pain treatment, antibiotics, and exchange transfusion in episodes with severe hypoxia, rapid progression, or diffuse pulmonary involvement. Older patients may develop chronic restrictive lung disease, pulmonary hypertension and cor pulmonale.

Depression - Persons diagnosed with chronic medical illnesses, such as the sickle syndromes, may be at risk for depression. The day to day stresses associated with the illness may contribute to feelings of helplessness, a feeling of not being in control, and create a vulnerability to develop depressive symptoms.

Diarrhea - Diarrheal illnesses in patients with sickle syndromes require special attention in terms of therapeutic considerations. Dehydration that can occur, especially in children can precipitate pain episodes and other complications. Salmonella infections must be excluded because of the tendency of these to disseminate causing sepsis, septic arthritis, or osteomyelitis.

Dysmenorrhea - Pain before and during the menstrual period is common in sickle cell patients. This can be problematic in that patients often confuse this pain with sickle pain episodes and may expect relief with narcotic analgesics. Young patients and those approaching menopause may also have pain episodes that appear to be precipitated by menstruation or the premenstrual syndrome. Secondary dysmenorrhea must be excluded.

Earaches and Hearing Loss - Earaches are common causes of fever, irritability, failure to feed, and vomiting in young children. Patients with sickle cell syndromes may be predisposed to serious complications such as meningitis so early, appropriate treatment is important. Sensorineural hearing loss (SNHL) has been associated with sickle cell disease (SCD) in older children and adults and may affect up to 40% of the population. Desferrioxamine used for chelation therapy for transfusion related iron overload can cause ototoxicity.

Edema - Edema is included as a separate problem not because it is specific to sickle cell syndromes, but because it occurs frequently. If not managed aggressively, edema in the low extremity predisposes the patient to leg ulcers and other complications. Edema is most often benign, however, it can also be the first manifestation of serious complications.

Eye Inflammation and Retinopathy - Peripheral arterial occlusions, beginning in childhood, may lead to neovascularization with risk of vitreous hemorrhage, retinal detachment, and blindness. Patients with Hb SC disease, and perhaps sickle thalassemias, are at increased risk for retinal complications. Yearly eye examination by an ophthalmologist with appropriate use of laser photocoagulation and surgery may reduce the severity of these complications.

Fever and Infections - Infections are a major cause of morbidity and mortality in patients with sickle cell disease. Bacterial infections are the major cause of death in children during the first five years of life. Those under three are at greatest risk for fatal sepsis, however, overwhelming infections can be seen at any age. The increased susceptibility to overwhelming infection from encapsulated organisms is likely the result of splenic function early in life. Organisms which are particularly virulent in these patients include Streptococcus pneumoniae, salmonella, Hemophilus influenza, and meningococcus. Serious infections such as sepsis, meningitis, and pneumonia caused by these organisms are common and life-threatening. There is also an increased incidence of infections of the bones and joints which may be related to ischemic damage with secondary infection. Infections of the urinary system are more common and may be more severe than in individuals without a sickle syndrome. Reduction in morbidity and mortality from these complications requires prevention, early recognition, and aggressive treatment with appropriate antibiotics. Preventive measures include initiation of prophylactic penicillin at birth, administration of pneumococcal and hemophilus b polysaccharide vaccine at age 2, and routine immunization for childhood diseases. Treatment includes early recognition, aggressive diagnostic evaluation, judicious use of empiric antibiotics in patients with significant fever, and adequate treatment of documented infection with appropriate antibiotics.

Headaches - Headaches in sickle cell anemia patients may be caused by any of the common etiologies or may be early symptoms of several life-threatening disorders, which are more common in sickle cell anemia patients. These include meningitis, subarachnoid hemorrhage, or osteomyelitis of the jaw or skull. Patients presenting with headache need complete and thoughtful evaluation.

Hematuria and Nephropathy - Kidney damage starts very early and progresses throughout life causing major complications in many individuals with sickle syndromes. Hyposthenuria, which starts in the first ten years of life, causes nocturia and enuresis, predisposes to dehydration, and reduces resistance to urosepsis. Hematuria and papillary necrosis are common. With advancing age, Proteinuria, renal tubular acidosis, nephrotic syndrome, glomerulosclerosis, and renal insufficiency occur.

Hepatitis, Increased Jaundice - Patients with hemolytic anemia will have an elevated indirect bilirubin from the increased breakdown of heme and lactic dehydrogenase for increased breakdown of erythrocytes. The level of indirect bilirubin seldom is > 4 mg.% unless there is some problem in hepatic clearance. Elevations in direct bilirubin, SGOT, or alkaline phosphatase suggest liver disease or increased release from cells other than erythrocytes. Liver problems encountered in hemoglobinopathy patients include passive congestion from sickling and right heart failure, cholelithiasis, viral or alcoholic hepatitis, hepatic fibrosis/ cirrhosis, liver infiltration, and hemosiderosis/hemachromatosis. Changes in symptoms or laboratory values require evaluation.

Hydroxyurea (Hydrea) Therapy - Daily administration of oral hydroxyurea (Hydrea) is the first effective pharmacological intervention documented to provide clinically significantly prevention of complications in sickle cell disease. Treatment with Hydrea has recently been shown to reduce pain events, hospital admissions and the need for blood transfusions by 50%.. Hydroxyrea Patient Consent - Information Form -click here

Hypertension - Patients with sickle syndromes have blood pressure lower than normal compared to age and sex matched controls. Those with high values relative to this population have an increased risk of stroke and death. Blood pressure should be monitored and values must be assessed understanding the lower values expected for patients with sickle cell anemia. Those with blood pressure values above 140/90 mm Hg should be evaluated for secondary causes and considered for treatment. Except in cases of extreme BP elevation (systolic BP greater than 200 mm Hg, diastolic BP greater than 110 mm Hg, or both) or elevated BP with evidence of ongoing target-organ damage, hypertension should not be diagnosed on the basis of measurements made on a single occasion. Hypertension is diagnosed when at least two separate readings, obtained at least 1 to 2 weeks apart, average 140/90 mm Hg. Patients should abstain from tobacco use and caffeine ingestion for at least 30 minutes before the BP measurement is taken. Use of an appropriately sized cuff, in which the bladder encircles at least 80% of the arm, is essential because a cuff that is too large or too small will result in falsely low or falsely high readings, respectively.

Leg Ulcers - Leg ulcers cause chronic disability in 10 to 15% of older children and adults with sickle cell anemia. They are likely related to vascular stasis explaining the chronicity and recurrence. Treatment includes saline wet-to-dry debridement, Unna’s boots, hydroscopic dressings, and antibiotics for cellulitis. Transfusion and skin graphs may be of benefit in recalcitrant cases.

Lymphadenopathy - Generalized lymphadenopathy is seen in a large number of systemic illnesses of all etiologies. In patients with sickle syndromes, it can occur secondary to extramedullary hematopoiesis, however, this is always a diagnosis of exclusion even if node biopsy shows some histologic evidence of marrow elements. Localized lymphadenopathy is more often with local infection or malignancy.

Multi-organ System Failure - Acute multiorgan failure syndrome is a severe, life-threatening complication of pain episodes that may occur in patients with otherwise mild sickle cell disease. The syndrome appears to be reversed with prompt, aggressive transfusion therapy. The onset of organ failure was associated with fever,rapid fall in hemoglobin level and platelet count, nonfocal encephalopathy, and rhabdomyolysis. Bacterial cultures are negative in most cases. Aggressive transfusion therapy is associated with survival and with rapid recovery of organ function in most episodes. The syndrome may develop in patients with previously exhibited relatively mild disease with little evidence of chronic organ damage and may be recurrent. High baseline hemoglobin levels may represent a predisposing factor.

Nasal Congestion and Bleeding - The most important preventive consideration when a child or adult with a sickle syndrome presents with upper respiratory infection is to always consider central nervous system involvement or sepsis. Early use of antibiotics for purulent discharge is indicated to prevent move severe infections in this population. Recurrent rhinitis, frequent "colds", or epistaxis requires complete evaluation. This includes a careful allergy history, environmental evaluation, and exclusion of other medical or physical causes.

Neurologic Symptoms and Stroke -Hemiplegia secondary to cerebral vascular ischemia occurs with high frequency in children with sickle syndromes. The onset may be in the first year of life and 80% occur before the age of twenty. There is a very high recurrence rate approaching 85% in the three years after the first episode. Other neurological presentations such as seizures, transient ischemic attacks, coma, and sensory loss also occur. Treatment is with chronic transfusion to maintain the Hb S level at less than 30% to prevent recurrences. Present evidence suggests that the need for transfusion may be life-long and complications such as alloimmunization, iron overload, and exposure to infectious disease may be common complications. Bone marrow transplantation may, in the future, offer these children the best chances for a more normal life.

Overdose - Drug overdoses occur in patients with sickle cell syndromes through accidental ingestion, inadvertent intake of excessive medication to control pain, and suicide attempts. Management of drug overdose requires identification of the drugs ingested through history, physical, and analysis of blood, urine and gastric contents; specific intervention based on knowledge of the drug’s pharmacology; and intensive medical support.

Pain Episodes - The most common acute problem and distressing manifestation in the patient with sickle cell disease is the sickle pain episode (also unfortunately termed pain "crisis"). A pain episode is defined as a self-limited episode of diffuse, reversible pain often occurring in the extremities, back, chest, and abdomen. The severity of pain has been reported to range from mild transient attacks of five minutes to excruciating pain lasting days or weeks requiring hospitalization. This intense pain is believed to be caused by the inflammatory response to bone or marrow necrosis, ischemic muscle, and ischemic bowel resulting from the obstruction and sludging of blood flow produced by sickled erythrocytes. The pain episode is almost never a cause of mortality, however, affected individuals often fear serious complications or death. The frequency of pain episode varies with each individual depending upon their hemoglobin phenotype, physical condition, and many other variables. Precipitating factors include alterations which cause increased physical and psychological stress, especially fever, dehydration, overexertion, rapid temperature change, or anger. Episodes, however, frequently occur without apparent antecedent causes.

Pain Management - Management of pain episode begins with a thorough clinical evaluation to exclude correctable precipitants, life threatening complications, and causes of pain unrelated to sickle cell disease. A detailed history and physical examination is important to identify correctable precipitating factors such as infection, dehydration, acidosis from any cause, emotional stress, extreme temperature exposure, or ingestion of other substances such as alcohol or other recreational drugs. There are no characteristic clinical findings which make the diagnosis or define the severity of a pain episode so the patient’s assessment must be accepted. Uncharacteristic pain, new physical findings, or changes in laboratory values suggest complications rather than an uncomplicated pain episode. Treatment of a pain episode includes oral or intravenous hydration, administration of analgesics, bed rest, and treatment of the underlying causes such as infection. Pain should be managed as an acute pain syndrome tailoring the analgesic, route of administration, dosage, and frequency of administration to the level of pain and response to therapy experienced by the patient.

Pharyngitis and Sleep Apnea - Infections of the throat are no more common in sickle cell anemia patients, but prompt treatment may prevent complications such as sepsis, meningitis, pain crisis or aplastic crisis. Since patients have a predisposition to these complications, their occurrence must always be considered especially when evaluating children with upper respiratory symptoms. The incidence of adenotonsillar hypertrophy (ATH) in SCD appears increased and not related to infectious diseases. We suggest that ATH represents a part of the natural course of compensatory lymphoid tissue enlargement in children with SCD. This causes obstructive sleep apnea syndrome with symptoms of snoring. Adenotonsillectomy can correct the of symptoms and improve alveolar hypoventilation. Overnight polysomnography is diagnostic.

Pregnancy - Management of pregnancy in the patient with a sickle syndrome requires coordinated care by obstetricians and hematologists knowledgeable in the disease. There are increased risks for the pregnant patient and spontaneous abortion is more likely. With careful management, there is no reason that women cannot have children. All female patients should receive accurate information about risks of pregnancy, genetic transmission of sickle syndromes, methods of contraception, prenatal diagnosis, prevention of sexually transmitted disease and the increased responsibility of raising children at puberty and periodically throughout their reproductive lives.

Priapism -Priapism is the painful erection of the penis caused by sickling in the corpora cavernosa. This complication usually has an onset at age 5 to 35. It often occurs as a severe episode requiring hospitalization following multiple episodes of short duration termed stuttering. Episodes may be precipitated by infection, intercourse, masturbation, or nocturnal erections. Onset in the early morning awaking the patient is common. Treatment includes pain relief, hydration, exchange transfusion, and surgical shunt procedures between the corpora cavernosa and the corpus spongiosum. Impotence is a long-term sequelae of repeated episodes in half to one third of cases.

Proteinuria and Renal Insufficiency - Proteinuria is becoming a common finding in patients with sickle cell anemia, and results from damage to the glomerulus (sickle cell glomerulopathy). It may occur in up to 27% of adults with hemoglobin SS and in 5-8% of adults with other sickle hemoglobinopathies. Despite the paucity of associated clinical findings, it may herald the development of progressive renal insufficiency, and lead to end-stage renal disease and, therefore, should be thoroughly investigated.

Sequestration Splenic and Hepatic- Splenic sequestration episode occurs in highest frequency during the first five years of life in children with sickle cell anemia. Splenic sequestration occurs at any age in individuals with the other sickle syndromes. In all sickle syndromes, sequestration may be seen primarily in the liver in older individuals. This complication is characterized by onset of life-threatening anemia with rapid enlargement of the spleen and/or liver with a high reticulocyte count. In older individuals with primarily hepatic sequestration, there may be rapid deterioration of hepatic function, rhabdomyolysis, and renal insufficiency. Treatment of the acute episode requires early recognition, careful monitoring, aggressive transfusion support, and occasional emergent splenectomy. Episodes tend to be recurrent so many advocate splenectomy or chronic transfusion.

Sickle Cell Trait - Individuals with sickle cell trait are generally asymptomatic and have no abnormal physical findings. Their laboratory evaluation is normal with no anemia, no evidence of hemolysis, and no laboratory abnormalities other than hemoglobin AS on hemoglobin electrophoresis. Many individuals will have decreased ability to concentrate their urine. There may be an increased incidence of urinary tract infection during pregnancy. Painless hematurea does occur in 1 to 4 % of individuals with sickle cell trait . This complication is usually not a significant problem, however, a minority of individuals may have significant problems with recurrent hematurea requiring medical intervention, transfusion, and iron therapy. Complications such as splenic infarction, pain episodes, and sudden death may be induced by severe hypoxia, severe dehydration, and exertion at the limits of human endurance.

Substance Abuse and Addiction- Despite many opinions to the contrary, sickle cell anemia does not predispose to or provide absolute protection from drug addiction. A small number of patients exhibit behavior diagnostic of narcotic addiction. These patients have very frequent contact with health professionals which both compromises their health care and that of other patients with sickle syndromes. Treatment of patients with drug addiction and a sickle cell syndrome poses a number of very difficult management problems. First, drug addiction compromises our ability to diagnose and treat complications in the disease. Pain episodes are less responsive to therapy in drug tolerant patients. Drug seeking behavior may mask symptoms of serious complications. Second, regular use of opiates may make the health of sickle syndrome patients worse. For example, regular meperidine use is associated with seizures. Also, drug withdrawal may precipitate severe acute pain episodes and other more life-threatening complications.

Transfusion Therapy - The treatment goals for transfusion are to relieve symptoms, treat complications and prevent complications. Because of the risks of iron overload, exposure to hepatitis, HIV , and other infectious agents, alloimmunization, induction of hyperviscosity, and limits on the resource, transfusion therapy should be used judiciously.

Urinary Track Symptoms and  Enuresis- Urinary tract infections are more common in individuals with sickle cell syndromes. These are caused by the "usual" organisms seen in the general population. Asymptomatic urinary tract infections may be a precipitating event for a pain crisis.

Vaginitis - Vaginitis is a common problem in all females. Frequent treatment with antibiotics make the problem more common in the female with sickle syndromes. The presence of vaginal discharge or symptoms can indicate serious illness requiring specific therapy.

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Last modified: March 12, 2004