MANAGEMENT AND THERAPY OF SICKLE CELL DISEASE

NIH Publication No. 95-2117, Revised December 1995 (Third Edition) National Institutes of Health, National Heart, Lung, and Blood Institute

(While we have attempted to improve the maneuverability and appearance of this document, we have not knowingly altered any of the text.)

Preface

We are pleased to offer the third edition of Management and Therapy of Sickle Cell Disease. According to all reports, previous editions have served both the lay and professional communities extremely well in sorting out various approaches to health maintenance and complications of patients with sickle cell disease. As in the past, this edition serves as a guide for the health care worker involved in the management of patients with sickle cell disease. It represents a collective summary of experiences with therapeutic regimens rather than the by-product of controlled clinical trials. Some users have referred to this booklet as the Bible and others a "cookbook," and while neither is an accurate descriptor, the contributors hope that the real use is somewhere in between. During this past 5-year interval, progress in clinical management of sickle cell disease has been incredible. Most of the chapters in this edition have been totally rewritten or updated to reflect these advances and modifications in practices and to describe the published results of clinical research. These include findings from the Preoperative Transfusion Study, the Prophylactic Penicillin Trial II, the Multicenter Hydroxyurea Study, as well as epidemiological data derived from the Cooperative Study of Sickle Cell Disease (CSSCD).

The forum for developing this booklet was unchanged from that used in producing previous editions. After accepting assignments to review the specific topics, a small group of pediatricians, nurses, hematologists, and internists met in Bethesda and, at the end of 1 day, had hammered out positions that could be agreed upon by most of the participants. Each 5-year period sees fewer and fewer areas of disagreement, although it is unlikely that everyone present will proceed exactly along the same pathway. We encourage you to use this booklet as you see fit and to share it with your students, house staff, and clinical colleagues. We invite questions and comments and hope that you will feel free to contact the contributors who have made their telephone numbers and addresses available.

Clarice D. Reid, M.D.

Contributors

Rita Bellevue, M.D. New York Methodist Hospital 506 Sixth Street Brooklyn, NY 11215-9008 718/780-5643 718/780-3529 FAX

Lennette J. Benjamin, M.D. Montefiore Medical Center 111 East 210th Street Central Building #221 Bronx, NY 10467 718/920-7373 718/798-5095 FAX

Oswaldo Castro, M.D. Howard University 2121 Georgia Avenue, N.W. Washington, D.C. 20059 202/806-7930 202/806-4517 FAX

Samuel Charache, M.D. The Johns Hopkins University Department of Laboratory Medicine 2006 Sulgrave Avenue Baltimore, MD 21209 410/466-6405 410/466-4330 FAX

Wesley Covitz, M.D. Bowman Gray School of Medicine Department of Pediatrics/Cardiology 300 South Hawthorne Road Winston-Salem, NC 27103 919/748-4627 919/748-4204 FAX

Ann Earles, R.N., P.N.P. Children's Hospital Oakland Department of Hematology/Oncology 747 52nd Street Oakland, CA 94609 510/428-3453 510/450-5647 FAX

Stephen Embury, M.D. San Francisco General Hospital Building 100, Room 263 1001 Potrero Avenue San Francisco, CA 94110 415/206-8574 415/206-3332 FAX

Cage Johnson, M.D. University of Southern California 2025 Zonal Avenue - RMR 304 Los Angeles, CA 90033 213/342-1259 213/342-1255 FAX

Thomas Kinney, M.D. Duke University Medical Center Erwin Road - 5417 Duke North Durham, NC 27710 919/681-3395 919/681-2714 FAX

Mabel Koshy, M.D. University of Illinois at Chicago Room 1420 CSB 840 South Wood Street (M/C 787) Chicago, IL 60612 312/996-5680 312/996-5984 FAX

Lawrence Lessin, M.D. Washington Hospital Center The Cancer Institute 110 Irving Street, N.W. Washington, D.C. 20010 202/877-8112 202/877-8113 FAX

Bertram Lubin, M.D. Children's Hospital Medical Center of Northern California Department of Hematology/Oncology 747 52nd Street Oakland, CA 94609 510/428-3502 510/528-3608 FAX

Scott Miller, M.D. SUNY-Brooklyn 450 Clarkson Avenue - Box 49 Brooklyn, NY 11203 718/270-1692 718/270-1985 FAX

Paul F. Milner, M.D. Medical College of Georgia Sickle Cell Clinic - FK 100 Augusta, GA 30912 706/721-2171 706/721-4575 FAX

Kwaku Ohene-Frempong, M.D. The Children's Hospital of Philadelphia Comprehensive Sickle Cell Center 324 South 34th Street Philadelphia, PA 19104 215/590-3423 215/590-2499 FAX

Orah Platt, M.D. Children's Hospital Medical Center, Boston Division of Hematology/Oncology Enders Research Building - Room 761 320 Longwood Avenue Boston, MA 02115 617/355-6347 617/355-6081 FAX

Darlene Powars, M.D. University of Southern California Medical Center Division of Hematology/Oncology 1129 North State Street Los Angeles, CA 90033 213/226-3853 213/226-5049 FAX

Clarice D. Reid, M.D. National Institutes of Health National Heart, Lung, and Blood Institute Division of Blood Diseases and Resources Two Rockledge Centre MSC 7950 - Room 10160 6701 Rockledge Drive Bethesda, MD 20892-7950 301/435-0080 301/480-0867 FAX

Wendell Rosse, M.D. Duke University Medical Center Department of Medicine Hematology/Oncology Post Office Box 3934 Durham, NC 27710 919/684-3724 919/681-8477 FAX

Jeanne A. Smith, M.D. Comprehensive Sickle Cell Center Harlem Hospital - Columbia University 506 Lenox Avenue - Suite 6146 New York, NY 10037 212/939-1701 212/939-1692 FAX

Gwendolyn Swinson, R.N. Bronx Comprehensive Sickle Cell Center Montefiore Medical Center 111 East 210th Street Bronx, NY 10467 718/920-7373 718/798-5095 FAX

Elliott Vichinsky, M.D. Children's Hospital Oakland 747 52nd Street Oakland, CA 94609 510/428-3651 510/450-5647 FAX

Winfred Wang, M.D. St. Jude Children's Research Hospital Department of Hematology/Oncology 332 North Lauderdale Memphis, TN 38101 901/495-3497 901/521-9005 FAX

Doris Wethers, M.D. St. Luke's Roosevelt Hospital Center Sickle Cell Program 1111 Amsterdam Avenue New York, NY 10025 212/523-3103 212/523-1839 FAX

Introduction

Sickle cell disease is a generic term for a group of genetic disorders characterized by the predominance of hemoglobin S (Hb S). These disorders include sickle cell anemia, the sickle beta thalassemia syndromes, and hemoglobinopathies in which Hb S is in association with another abnormal hemoglobin that not only can participate in the formation of hemoglobin polymers but also is present in sufficient concentration to enable the red cells to sickle. Examples of the latter disorders include hemoglobin SC disease, hemoglobin SD disease, and hemoglobin S O Arab disease. The sickle cell disorders are found in people of African, Mediterranean, Indian, and Middle Eastern heritage. In the United States, these disorders are most commonly observed in African Americans and Hispanics from the Caribbean, Central America, and parts of South America.

Sickle cell disorders are best classified by genotype. The type of hemoglobin produced is determined by the two beta globin genes located on chromosome 11 and the four alpha globin genes located on chromosome 16. Individuals who are homozygous for the sickle beta globin gene (beta S) have sickle cell anemia (SS disease). Individuals with sickle beta thalassemia have a beta S gene and a gene for beta thalassemia. If no beta globin is produced by the beta thalassemia gene, the individual has S beta o thalassemia (S beta o thal). If some normal beta globin is produced by the thalassemia gene, the individual has S beta + thalassemia (S beta + thal). In the case of hemoglobin (SC disease), the individual has two abnormal beta globin genes, beta S and beta C, and makes two abnormal hemoglobins, Hb S and Hb C. Because the alpha globin genes are located on a different chromosome from the beta genes, a patient with sickle cell anemia can independently inherit an alpha globin gene abnormality. A common condition in people of African descent that has clinical significance for patients with a sickle cell disorder is the deletion of two of the four alpha globin genes, resulting in alpha thalassemia trait.

In contrast to these diseases is sickle cell trait. Individuals with sickle cell trait (Hb AS) have a normal beta globin gene (beta A) and a beta S globin gene, resulting in the production of both normal hemoglobin A and hemoglobin S, with a predominance of Hb A. Their red blood cells sickle only under unusual circumstances such as marked hypoxia and the hyperosmolar environment of the renal medulla (resulting in hyposthenuria).

There are two cardinal pathophysiologic features of sickle cell disorders: chronic hemolytic anemia and vaso-occlusion (which results in ischemic tissue injury). Hemolytic anemia may be related to repeated cycles of sickling and unsickling, which interact to produce irreversible red cell membrane changes, red cell dehydration, and erythrocyte destruction. Tissue injury is usually produced by hypoxia secondary to the obstruction of blood vessels by an accumulation of sickled erythrocytes. The organs at greatest risk are those with venous sinuses where blood flow is slow and oxygen tension and pH are low (spleen and bone marrow) or those with a limited terminal arterial blood supply (eye, head of the femur and humerus). The lung, as the recipient of deoxygenated sickle cells that escape from the spleen or bone marrow, may be at special risk for vaso-occlusion and infarction. No tissue or organ is spared from this injury. Symptoms of the hypoxic injury may be either acute (e.g., painful events, acute chest syndrome) or insidious in onset (e.g., aseptic necrosis of the hips, sickle cell retinopathy). The effects of acute and chronic tissue injury may ultimately result in failure of organs like the kidney, particularly as the patient ages.

An additional and less recognized problem is that sickle cell patients live under considerable psychosocial stress. Not only do they experience stresses common to other painful chronic illnesses, but they must also cope with the unpredictable nature of their illness. The recurrent and unpredictable nature of the disease can adversely affect both school and work attendance and has the potential of reducing the patient's sense of self-esteem.

Appropriate counseling and management requires definitive diagnosis. The diagnosis of sickle cell disease is primarily based on hemoglobin electrophoresis. In those instances where Hb S is found in association with another abnormal hemoglobin such as Hb C, the diagnosis can be made by electrophoresis alone. In those instances, however, when the electrophoresis reveals only Hb S, Hb F (fetal hemoglobin), and Hb A2, there can be difficulty in distinguishing between sickle cell anemia and some of the sickle beta thalassemia syndromes, including S beta o thal and sickle cell trait, in association with hereditary persistence of fetal hemoglobin (S HPFH). It is important that distinctions be made because these disorders differ markedly in their clinical expression. For example, symptoms of patients with Hb S beta o thal are similar to those of Hb SS; patients with Hb S beta + thal have less associated symptoms, and those with Hb S HPFH are asymptomatic and not anemic.

Patients with SS or S beta o thal disease or S HPFH all have similar electrophoretic patterns. Mean corpuscular volume (MCV) is definitely decreased in thalassemia syndromes and is somewhat decreased in S HPFH. Measurement of Hb A2 and Hb F may help in distinguishing between these conditions. In general, Hb A2 levels are elevated above 3.5 percent in S beta o thal and are low in patients with S HPFH. Hb F levels are generally higher in the sickle beta thalassemic disorders than in SS disease, although there is considerable overlap between these diagnostic groups. In those instances where S HPFH is suspected, measurement of Hb F in the parents and/or siblings can be valuable.

The diagnosis of sickle cell disease cannot and must not be made from either a sickle cell preparation or solubility test because neither of these tests will reliably distinguish sickle cell trait from sickle cell disease. The diagnosis of a specific sickle cell disorder can be readily established through an analysis of the alpha and beta globin gene complex by using techniques of molecular biology; however, these are not usually required. The clinician should rely on the clinical history, blood counts, peripheral blood smear, hemoglobin electrophoresis with measurement of the minor hemoglobins A2 and F, and, when available, family studies that include hemoglobin electrophoresis and measurement of Hb A2 and Hb F.

Table 1 summarizes the relationships between the clinical severity, blood counts, peripheral smear, Hb A2 levels, and Hb S levels for the more common sickle cell disorders.

Chapter 1--Child and Adolescent Health Care Maintenance

During the past several decades, there have been substantial advances in the management of patients with sickle cell disease. For example, infant morbidity and mortality from overwhelming pneumococcal infection have been reduced by the administration of prophylactic antibiotics, and some individuals have been cured of their disease by bone marrow transplantation. Enhanced testing of blood products for infectious agents and more careful attention to crossmatching for minor red blood cell antigens have reduced complications from blood transfusion. Comprehensive sickle cell programs can reduce morbidity and mortality by providing easily accessible health care services administered by individuals knowledgeable about the disease and its complications. As a result of these advances, children with sickle cell anemia have about an 85 percent probability of reaching 20 years of age.

At the crux of effective health care maintenance is a strong patient-provider relationship built on trust, respect, open communication, and mutual understanding. The child and family should be encouraged to be active participants in the health care program, to be candid in expressing their concerns, and to work closely with the provider in all areas. In turn, the provider must be sensitive to the child's development and be willing to offer counseling and education that is age appropriate, realizing that the child's need for information will change with age. Providers who speak only to the parents and fail to incorporate the child or adolescent into the management plan will foster dependency in the child, ultimately hindering the transition to adulthood. The provider also must be knowledgeable about existing medical and psychosocial resources within the community and assist the patient in accessing these services when appropriate.

DEFINITIVE DIAGNOSIS

When a newborn's screening test indicates "sickle cell disease," it is the primary physician's responsibility to either establish a definitive diagnosis or to refer the patient to a pediatric hematologist for this purpose. As discussed in Chapters 1 and 5, establishing a definitive diagnosis requires accurate characterization of the hemoglobin phenotype and correlation of the phenotype with the clinical history, blood counts, and red blood cell morphology. Recent advances in molecular biology techniques have identified many variations in the beta globin gene area (beta globin gene haplotype) that may modify the clinical expression of sickle cell disease. Studies of the child's parents are useful in establishing a definitive diagnosis but must be undertaken with caution as the tests may disclose mistaken paternity. As in all inherited disorders, thorough counseling of the mother is recommended before performing extensive family testing, and family testing should not be performed if the mother objects.

Once the definitive diagnosis is established, the parents should be provided with appropriate education and counseling about the specific form of sickle cell disease affecting their child. Providers must explain things carefully, avoiding medical jargon and allowing ample time for questions. Practitioners should not "overload" parents by providing them with too much detail during initial visits. More than one counseling/education session is required to ensure that parents adequately understand the information. A practitioner should not hesitate to refer the patient and family to a specialist for counseling. Many community-based sickle cell organizations are available to help with patient education and the acquisition of social services.

The definitive diagnosis should be recorded on the child's immunization record and in other key medical records. A copy of the diagnostic information also should be given to the parents so that information can be shared with other health professionals involved with the infant's care.

MAINTENANCE HEALTH CARE SERVICES

General Issues

Health care maintenance services for children and adolescents with sickle cell disease include those services provided to healthy children and services specifically provided for sickle cell disease. Routine services include immunizations and dietary counseling as well as education about preventive health measures. The frequency of visits should depend on the needs of the child and family. During the first 2 years of life, health care maintenance visits should be scheduled concurrently with needed immunizations. Older patients who are doing well can be seen semi-annually. Children also should be seen within a short time after a hospitalization or emergency room visit so the physician can review the situations that may have precipitated the event and make any necessary changes in the treatment plan.

Immunizations should be administered according to schedules recommended by either the American Academy of Pediatrics or the American Academy of Family Practice. In addition, all children with sickle cell disease should be immunized against hepatitis B virus and should receive the polyvalent pneumococcal vaccine at age 2 years, with a booster at age 5 years. Seasonal influenza vaccines are recommended.

Dietary counseling is an important part of routine health care. Mothers should be encouraged to breastfeed their infants, although iron-fortified formulas are an alternative. Supplemental iron should not be prescribed unless the patient is documented to have reduced iron stores by specific assessments of the serum ferritin level or measurement of serum iron and iron-binding capacity. Children with hemoglobin SC disease are often microcytic in the absence of iron deficiency or concomitant alpha thalassemia. Similarly, the incidence of alpha thalassemia trait is quite high in the African-American population and may produce microcytosis in the absence of iron deficiency. Routine administration of supplementary folic acid may not be necessary unless the dietary history reveals inadequate folate intake. Particular attention should be paid to the diet if education, unmet economic needs, or cultural patterns place the child at risk for dietary deficiencies.

All children, including those with sickle cell disease, need regular dental care. Supplemental fluoride given topically, in vitamins, or in the drinking water, should be provided when indicated. Cleaning and dental fillings do not require special care. Operative procedures such as extractions and root canal therapy should be preceded and followed by standard rheumatic fever antibiotic prophylaxis to lessen the risk of bacteremia/sepsis. If general anesthesia is required, the child should be hospitalized, and preoperative transfusion should be considered if the surgery is extensive (see Chapter 10).

Other health care maintenance services include routine hearing and vision screening and periodic skin tests for tuberculosis. Because of the ocular complications of sickle cell disease, adolescents and adults should be seen annually by an ophthalmologist. Providers must also counsel patients and parents about the adverse health effects of illicit drugs, including tobacco and alcohol. Teenagers should be counseled about safe sex practices, including abstinence. If sexually active, they should be encouraged to use condoms to prevent getting sexually transmitted diseases, including acquired immunodeficiency syndrome (AIDS). Adolescent girls should receive additional counseling on birth control practices and be provided with birth control pills or other effective contraceptives when requested, given that there are no specific contraindications (see Chapter 13, Contraception and Pregnancy).

Sickle Cell-Specific Issues

In addition to the general health maintenance issues, there are health maintenance issues specific for sickle cell disease. These include the need for parents to learn specific physical assessment skills, to administer prophylactic antibiotics, to implement measures that minimize the risk of vaso-occlusive complications, and to use analgesics and comfort measures to minimize pain. During health maintenance visits, providers also should carefully review the history and physical examination for evidence of organ dysfunction.

When performing the physical examination, providers should pay attention to growth parameters and physical development. Physical growth and sexual maturation are delayed in sickle cell anemia patients compared with normal children, but the child eventually will "catch up" during the late teenage years. Common physical findings in children with sickle cell disease include mild generalized lymphadenopathy, functional systolic murmurs, and slight hepatic enlargement. Splenomegaly is often seen in infants and young children but is uncommon in children with SS disease and S beta o thalassemia after age 6 years. Splenomegaly, however, is frequently observed in patients of all ages with Hb SC disease and S beta + thalassemia. Because limitation of motion and pain are common signs of aseptic necrosis, the range of motion of the hips of older children and adolescents should be assessed. Scleral icterus is another common physical finding. Because children and adolescents are often teased about their "yellow eyes," they should be taught the nature of this characteristic and reassured that it will not affect their visual acuity and does not necessarily reflect liver disease.

Blood counts should be done frequently during the first year of life to establish the patient's baseline, but after 12 months of age, the hemoglobin and hematocrit are relatively stable and need to be checked only once or twice a year in uncomplicated patients. For patients who are doing well, an annual urinalysis and measurement of blood urea nitrogen (BUN), serum creatinine, and liver enzymes are adequate for monitoring the patient for evidence of organ damage. Before the administration of the first transfusion, the patient's red blood cell antigens should be determined and recorded in the patient's permanent medical record.

Specific physical assessment skills that should be taught to parents include taking the body temperature and assessing respiratory effort, degree of pallor, and spleen size. Parents of children who have an enlarged spleen should be taught to palpate the spleen and may be given a tongue depressor that indicates the level at which the spleen extends below the left costal margin in the mid-clavicular line. The parent can use this "spleen stick" to determine if the spleen size has changed and can provide the stick to other health care providers who assess the child. The skin around the ankles of adolescents should be examined carefully for ulcers, and patients should be reminded to avoid trauma to the lower extremities because this may precipitate ulcerations. Parents should also be told that the child may have repeated episodes of enuresis or nocturia as a result of the renal concentrating defect and should be provided with suggestions on how to manage this rather difficult problem. Parents should remind school officials that their child will need access to fluids while at school and will also need to be excused periodically from class to use lavatory facilities.

One of the major advances in the care of infants with sickle cell anemia has been the recognition that oral penicillin given twice a day will reduce morbidity and mortality from pneumococcal infections. Prophylactic penicillin is recommended for all patients with SS disease and S beta o thal until they are 5 years of age. For patients who are allergic to penicillin, erythromycin ethyl succinate (20 mg/kg) divided into two daily doses can provide adequate prophylaxis. The importance of administering the prophylactic antibiotics should be addressed at all visits because parents may become lax in dispensing this essential treatment over time. Penicillin may be prescribed in either liquid or tablet form; finely crushed pills may be given to young children. Pills have an important advantage over liquid penicillin preparations because pills are stable for years compared with liquid forms of penicillin that must be discarded after 2 weeks. An alternative to oral penicillin is injections of 1.2 million units of long-acting Bicillin (registered trademark) every 3 weeks. A recently concluded randomized trial demonstrated that penicillin prophylaxis may be safely stopped after the patient's fifth birthday. Concerns regarding the development of penicillin-resistant pneumococcal infections should not prevent the use of prophylactic penicillin, but appropriate measurements of antibiotic sensitivity are required in treating patients who have pneumococcal infections (see Chapter 6).

The role of prophylactic penicillin in SC disease and S beta + thal is less well established. Although these latter two groups of patients are not at the same risk as children with SS disease for overwhelming infection by encapsulated organisms because they have better preservation of splenic function, a significant number of pneumococcal infections have been reported. Regardless of whether a sickle cell patient is receiving prophylactic antibiotics, these patients should be evaluated promptly when they develop a fever greater than 38.5 oC (101 oF) (see Chapter 6, Infection).

Parents and patients should be instructed in the proper use of analgesia. Fear of addiction may prevent parents from administering adequate analgesics to their children. Similarly, older patients may undermedicate themselves for fear of becoming addicted to the analgesic (see Chapter 7, Painful Events). Discussing these issues with the patient and parents and using nonaddictive analgesics where possible should minimize the risk of drug dependency. Providers can explore various ancillary measures with the patient to assist with pain management, including biofeedback and relaxation techniques. The provider can also address health care practices that minimize the risk of painful events such as maintaining adequate hydration, treating infections promptly, and avoiding temperature extremes. Patients can often predict that a painful event is about to happen and can frequently help themselves by implementing treatment before the pain becomes too severe. Deterioration in school performance or changes in behavior may be early signs of cerebrovascular disease and should be evaluated promptly by physicians knowledgeable about sickle cell disease.

Primary care providers should identify physicians with expertise in sickle cell disease to assist them in managing sickle cell patients under their care. Cost-effective care can be provided when there is close collaboration and communication between primary care providers and consultant specialists.

Adolescents

Those who treat adolescents should realize that these individuals are coping with a very difficult time in their life, and the multiplicity of problems confronting healthy adolescents also exists for individuals with sickle cell disease. All health professionals who care for adolescents must be particularly attuned to the range of their problems and to the local resources available for assistance (see Chapter 4). Compliance with medication regimens and clinic visits can be a problem at any age but is a particular problem in this age group. Health care providers should identify ways to motivate such patients, including peer support groups and one-on-one guidance by a knowledgeable staff member.

The transition from a pediatric medical setting to the adult care setting is often difficult for the patient. Ideally, adolescents in the pediatric setting should be given assistance in learning how to use the adult care facility and be introduced to their new providers by those who have cared for them as children (see Chapter 3, Patient Care Coordination). In some hospitals, this transition is greatly eased by holding concurrent pediatric/adolescent/adult sickle cell clinic sessions.

COUNSELING

In addition to genetic counseling, sickle cell patients and their families may need counseling in academic and vocational guidance as well as counseling related to recreational activities and travel. The basic premise, however, is that parents should treat their affected child as normally as possible. Parents should encourage activities that foster self-esteem and self-reliance. A positive self- image and a feeling of self-worth will help children and adolescents to cope more effectively with their illness.

Academic and Vocational Counseling

Providers should be prepared to counsel teachers and other school officials as well as patients. Narcotic analgesic usage and repeated absences may impair school performance, necessitating the need for specialized tutoring or the development of an individualized educational plan. Unless impaired by cerebrovascular disease, children with sickle cell disease have the usual range of intelligence and should be encouraged to develop their full potential. With additional tutoring or other assistance to compensate for time lost from school, they can often remain at grade level. Appropriate counseling and anticipatory guidance may minimize academic difficulties.

Vocational counseling is very important for adolescents and adults with sickle cell disease. Gainful employment is possible, despite the unpredictable nature of vaso-occlusive complications. The adoption of flexible work hours is an example of a strategy that will help patients in the workforce. Referral to community resources, including school guidance and vocational rehabilitation counselors, is another way to assist the patient in assessing and obtaining goals. Introducing children and adolescents to adults with sickle cell disease who have successfully coped with their illness has a very positive effect. Health care providers should be familiar with legal protection against discrimination in the workplace, provided by the Americans With Disabilities Act.

Recreation and Travel

There is often a need to provide counseling in the area of recreation and physical activities. Patients should be encouraged to get regular exercise. School-age children should participate in physical education classes, but they should be allowed to rest if they tire, and they should be encouraged to drink fluids after exercise. The potential risks of recreational activities that involve strenuous exertion should be discussed with the patient. Patients with sickle cell disease should dress warmly for cold weather and should avoid direct exposure to cold temperatures, including swimming in cold water. Children and adolescents should engage in competitive athletics with caution because it is difficult to heed the signs of fatigue in the heat of competition, and the team may find it difficult to replace an athlete sidelined by illness.

Children with sickle cell disease may benefit from a summer camping experience, either in an appropriate regular camp or through participation in a special camp for children with sickle cell disease. If the camp staff members are knowledgeable about the disease and comfortable with the care of these children, the camper can learn self-reliance and share experiences with other children about sickle cell disease while having fun. Health care providers and others who attend camp with sickle cell children typically find this a rewarding experience.

Patients and families often seek advice on the best methods of travel. Flying in a pressurized aircraft usually poses no special problems for sickle cell patients, provided that fluids are liberalized and the patient dresses warmly to accommodate for the low humidity and cool temperature of the aircraft. On the other hand, air travel above 15,000 feet in nonpressurized planes can induce vaso-occlusive complications. Land travel by bus or automobile is not associated with any increased risk of sickle cell-related complications, although frequent rest and refreshment stops should be included in the travel plans. Patients should be encouraged to consult their physician before traveling and should be advised to carry with them specific medical information that includes their diagnosis, baseline hematologic values, a list of current medications, and the name and telephone number of their physician. Providers should give their patients the names of physicians or care facilities to contact in the event of problems.

BIBLIOGRAPHY

Brown AK, Sleeper LA, Miller ST, et al. Reference values and hematological changes from birth to five years in patients with sickle cell disease. Arch Pediatr Adolesc Med 1994;148:796-804.

Falletta JM, Woods RM, Verter JI, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia. J Pediatr 1995;127(5):685-90.

Farber M, Koshy M, Kinney TR. Cooperative study of sickle cell disease: demographic and socioeconomic characteristics of patients and families with sickle cell disease. J Chron Dis 1985;36:495-505.

Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314:1593.

Gill F, Sleeper L, Weiner S, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Blood 1995;86(2):776-83.

Leiken SL, Gallagher D, Kinney TR, et al. Mortality in children and adolescents with sickle cell disease. Pediatrics 1989;84:500-8.

Pearson HA, Gallagher D, Chilcote R, et al. Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics 1985;76:392-7.

Platt OS, Rosenstock W, Espeland M. Influence of sickle hemoglobinopathies on growth and development. N Engl J Med 1984;311:7-12.

US Department of Health and Human Services, Public Health Service, Sickle Cell Disease Guideline Panel. Sickle cell disease: screening, diagnosis, management, counseling in newborns and infants. Clinical Practice Guideline Number 6. Rockville, Maryland: Agency for Health Care Policy and Research, 1993; AHCPR publication no. 93-0562.

Zarkowsky HS, Gallagher D, Gill FM, et al. Bacteremia in sickle hemoglobinopathies. J Pediatr 1986;109:579-85.

Sickle Cell Pamphlets for Parents:

1. A Parents' Handbook for Sickle Cell Disease. Part I, Birth to Six Years of Age. By Shelly Lessing, M.S., Elliott Vichinsky, M.D., Editors. Children's Hospital, Oakland Sickle Cell Center. Copyright 1990. State of California, Department of Health Services Genetic Disease Branch, Revised 1991.

2. Sickle Cell Disease in Newborns and Infants. A Guide for Parents. U.S. Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research, 1993.

3. Your Child and Sickle Cell Disease. By Sara Day, R.N. Produced by the Biomedical Communications Department. St. Jude Children's Research Hospital, Memphis, Tennessee. Mid South Sickle Cell Center. P.O. Box Suite 235, 1 Children Plaza, Memphis, Tennessee 38103.

Chapter 2--Adult Health Care Maintenance

Many patients can live for long periods without experiencing acute or severe exacerbations of sickle cell disease. Increased awareness of the disease's complications and improved use and availability of health care are positive contributors to patient longevity and productivity. Contrary to previous estimates that one-half of all sickle cell disease patients die before age 20 years, about 90 percent of patients now survive past that age. Recent studies indicate that the mean age at death for SS patients is 42 years for males and 48 years for females. Most patients with SC and S beta + thalassemia can be expected to reach age 70 years and older. Many patients live a full life, and patients age 50 years now constitute a large segment of the adult population with sickle cell disease.

Common practices and approaches to optimal health care maintenance of adults are reviewed in this chapter, with an emphasis on developing a useful operational strategy for clinicians. Health maintenance includes prevention, early recognition and treatment of complications, and continuing patient education. In contrast to the stress of acute crises, well-patient visits provide a better psychological setting for the development of effective doctor-patient relationships and effective coping skills. The development of such relationships may result in fewer visits to the emergency room and fewer hospitalizations.

INITIAL PATIENT VISIT

During the initial patient visit, a complete medical history should be taken, and a physical examination should be performed. A patient should have a complete blood count, reticulocyte count, and hemoglobin electrophoresis if this information is not already available. Laboratory tests, including urinalysis, liver function, urea, creatinine, electrolytes, and chest x-ray, should also be obtained. Certain laboratory tests, although not routinely performed, may be indicated by the presence of specific complications. These tests include screening for red cell antibodies, measurement of arterial blood gases, pulmonary function tests, electrocardiograms (EKGs), studies to detect the presence of gallstones, and radiographs or magnetic resonance imaging (MRI) scans of the femoral and humeral heads to detect aseptic necrosis. Previous medical records should be requested as well. If the patient has never received the pneumococcal vaccine, immunization should be offered.

Patients with sickle cell disease are at high risk for developing sickle cell retinopathy. Patients should see an ophthalmologist for retinoscopy; the ophthalmologist should conduct followup examinations of patients diagnosed with significant proliferative retinopathy, at regular intervals.

Also during the initial visit, health providers should assess the patient's understanding of the disease and its complications (see "Patient Education" in Chapter 3, Patient Care Coordination). Family planning and genetic counseling services should be discussed, and the availability of prenatal diagnosis should be mentioned when appropriate (see Chapter 13, Contraception and Pregnancy). Asymptomatic patients often have a false feeling of security about their disease. They should be cautious particularly regarding the choice of a profession and jobs requiring strenuous exercise and exposure to high altitudes.

PATIENT FOLLOWUP VISITS

Most patients with sickle cell disease should have regular medical evaluations approximately every 3 to 6 months; certain patients need to be seen more frequently as symptoms dictate. Others, including asymptomatic patients with SC disease or S beta + thal, should be seen every 6 months. A blood count as well as a reticulocyte count should be performed, and a urinalysis and routine chemistry tests should be repeated annually. With advancing age, complications such as chronic organ failure often require more frequent visits and more extensive laboratory evaluations.

Attention should be focused particularly on abnormalities of renal function such as renal tubular acidosis and hyperuricemia (see Chapter 18, Renal). During initial and followup visits, it is important to discuss the general nature and variability of the disease with the patient and to explain the significance of symptoms. Specifically, complications such as gallstones, aseptic necrosis, and priapism should be mentioned. Also, the issues of childbearing and birth control should be addressed, and the patient's spouse or partner probably should be included in these discussions (see Chapter 13, Contraception and Pregnancy).

It is particularly important to instruct patients about how to respond to acute illness. They should be instructed to seek immediate care for events such as high fever, productive cough, and symptoms of acute anemia such as sudden dyspnea, weakness, or dizziness. Discussion with the patient should include the identification of available means of transportation to the emergency room. Painful episodes should initially be managed at home with rest, a warm environment, increased oral fluids, and mild analgesia or other modalities of pain management (see Chapter 7, Painful Events). If pain persists or fever develops, the patient should contact his or her physician or go to an emergency department. The procedure to be followed for a particular emergency department should be discussed in detail; if a prior call from the physician can facilitate the visit, the patient should know whom to call at night or on weekends and holidays.

Patients should keep a small supply of an intermediate strength oral narcotic analgesic (codeine, hydrocodone, or oxycodone) and should be instructed to use it for attacks of pain that do not respond to aspirin, acetaminophen, or ibuprofen. They should be informed that most pharmacists will not accept a telephone prescription for a narcotic and should be instructed on how to obtain another supply.

Certain matters of general health care are particularly important to patients with sickle cell disease; for example, it is important for the physician to discuss the hazards of cigarette smoking and excessive alcohol intake. Although strenuous exercise may have to be avoided in most patients, a well-planned exercise program should be encouraged (see "Counseling" in Chapter 1, Child and Adolescent Health Care Maintenance).

Most patients eat poorly during painful crises, and because patients with hemolytic anemia have an increased need for folic acid, daily supplements of 1 mg should be prescribed at those times. The danger of masking a vitamin B12 deficiency is small, but even young African-American patients are at risk. There is no evidence that any other form of vitamin supplementation is of value in sickle cell disease.

The patient's employment should also be discussed. Arrangements for obtaining "doctor's notes" after an absence from work, filling out forms, and refilling prescriptions should be outlined for all patients with a chronic disease. Medical providers should be familiar with procedures for seeking legal assistance if workplace discrimination because of disability is perceived.

VOCATIONAL GOALS

Individuals with sickle cell disease can pursue a variety of vocations and professions, and they should be encouraged to do so. There are very few vocational choices that should be discouraged, except jobs requiring strenuous physical exertion, exposure to high altitudes, or extreme temperature variations (see Chapters 1 and 4).

Students should not be discouraged by rigorous academic programs or long courses of study; instead, they should be encouraged and supported. However, individuals with sickle cell disease should be informed of any special considerations that are needed to facilitate their studies. For instance, they should be encouraged to inform their education program director or their employer that they have sickle cell disease and that students with sickle cell disease may take longer to complete their academic program or may require special considerations in completing their course of study.

PSYCHOSOCIAL COUNSELING

Intervention by a social worker or mental health professional is often indicated for a variety of psychosocial concerns and problems that affect sickle cell patients and their families. Physicians in private practice may not have direct access to the services of psychologists or social workers. Such services may be available, however, through local social service agencies.

The nurse's role in the management of psychosocial issues is equally important. The responsibility of nurses--often the primary providers of care and the health professionals most often seen by patients--includes the integration of other professionals into health care efforts and the identification of special patient needs. Also, nurses can provide psychosocial counseling, preventive health care information, and patient and community education (see Chapter 3, Patient Care Coordination).

DENTAL CARE

Dental procedures requiring local anesthesia can be performed in the dentist's office as with any other patient, but procedures requiring general anesthesia necessitate hospitalization. The use of nitrous oxide as an anesthetic agent for office dental procedures is controversial and requires consultation between the physician and dentist. The customary administration of at least 50 percent oxygen with nitrous oxide alleviates the risk of sickling. Concentrations of less than 20 percent oxygen should be avoided. Patients should be fully alert before leaving the office. Prophylactic antibiotics should be used with operations such as extractions or root canal therapy, if there is a question of rheumatic heart disease or mitral valve prolapse or if an orthopedic prosthesis has been implanted.

SURGERY AND ANESTHESIA

The question of prophylactic preoperative blood transfusion is addressed in Chapter 10. Intraoperative overexpansion of blood volume should be prevented, particularly in patients whose cardiac status is precarious. No special precautions are needed for local or regional anesthesia such as a pudendal block. Careful epidural anesthesia can be a good compromise for gynecologic or proctologic procedures. Operation in a "bloodless field" with the use of tourniquets may be hazardous. If possible, an alternative technique or prior exchange transfusion, or both, should be used. With all types of anesthesia, intraoperative hypothermia should be prevented.

After surgery, it is extremely important to ensure hydration and, at the same time, prevent circulatory congestion. Adequate records of the amount of intravenous and oral intake should be maintained; urine output and fluid drainage should be measured and recorded, and patients should be weighed daily. Minor hyponatremia (130-140 meq/L) can be tolerated but care should be taken to avoid hypernatremia (see Chapter 21, Surgery and Anesthesia). Efforts should be made to ensure deep breathing and coughing, to avoid atelectasis.

EXPERIMENTAL THERAPY

There has been no established method of treatment for the prevention of vaso-occlusive pain crisis and other complications of sickle cell disease. A number of experimental therapeutic approaches, including use of hydroxyurea, erythropoietin combined with hydroxyurea, short-chain fatty acids (such as butyrate derivatives), and clotrimazole, are currently under investigation (see Chapter 23, Experimental Therapy).

BIBLIOGRAPHY

Aluoch JR. The treatment of sickle cell disease: a historical and chronological literature review of the therapies applied since 1910. Trop Geogr Med 1984:36(suppl):S1-S26.

Charache S. Treatment of sickle cell anemia. Ann Rev Med 1981;32:195-205.

Embury SH, Hebbel RB, Mohandas N, Steinberg MH. Sickle cell disease: basic principles and clinical practice. New York: Raven Press, 1994.

Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639-44.

Serjeant GR. Sickle cell disease. Oxford: Oxford University Press, 1992.

Vichinsky EP, Johnson R, Lubin BH. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol 1982;4:328-33.

Chapter 3--Patient Care Coordination

The complexities of sickle cell disease demand intricate coordination of health care services. Because of their unique educational preparation, mid-level practitioners (MLPs) (i.e., nurses, physician assistants (PAs), clinical nurse specialists, and nurse practitioners) are best suited for assuming this responsibility. Discussion of patient care coordination; preventive health care; home management, including pain management and comfort measures; patient education; and education of other health care providers will be included in this chapter. Inpatient, outpatient, and emergency department care also will be highlighted.

PATIENT CARE COORDINATION

Because of the chronic nature of sickle cell disease, multidisciplinary and subspecialty referrals are often necessary. The MLP may serve as the liaison among the patient, the primary care provider, and the specialist. All individual treatment plans must be developed with patient and parent participation to identify problem areas that may adversely affect compliance with required care. Ongoing assessments are necessary to identify the need for referrals to other professionals for further interventions.

PREVENTIVE CARE

At each visit, MLPs should emphasize the importance of regular health care examinations to patients during steady states. The expected schedule of visits, routine tests, and immunizations should be carefully outlined. Special procedures that are part of the standard of care such as EKGs, pulmonary function tests, neuropsychiatric testing, and necessary immunizations should be discussed. The patient or parent must be able to demonstrate an understanding of these procedures before being asked to sign a consent form.

Preventive care also includes education about recognizing acute and life-threatening events associated with sickle cell disease. Early recognition and prompt reporting of symptoms may prevent or minimize complications. The parents of children with sickle cell disease must be taught how to use a thermometer and palpate the spleen, and they should be asked to demonstrate their ability to perform these procedures. Reinforcing the need for prophylactic penicillin may improve compliance. In addition, the MLPs should talk with patients about when to call for advice and when to seek immediate medical attention. Transportation planning should be discussed before an emergency situation arises.

Age-appropriate education should continue into adulthood along with an emphasis on preventive health care. The importance of regular health care maintenance and visits other than for episodic acute care cannot be overemphasized. Reviewing the symptoms of acute events and the significance of early treatment of complications are crucial and can be provided by the MLP.

PATIENT EDUCATION

The complexity of sickle cell disease mandates ongoing patient education. Specific medical treatment modalities such as those outlined in this management guide will require the development of appropriate interventions individualized to maximize compliance. During the initial assessment, the patient's and/or family's understanding of the disease should be explored as well as their understanding of general and specific treatment plans. It is important that the family thoroughly understands both the general and specific treatment plans before they are implemented. The MLP must assess the patient's and family's knowledge base of sickle cell disease regularly.

TRANSITION FROM PEDIATRIC TO ADULT CARE

Many factors must be considered before the transition from pediatric to adult health care can occur. The process can be traumatic for medical staff members and the family as well as the patient. The patient must be ready developmentally and must have the full support of the family as well as the pediatric and adult staff members. As patients leave the pediatric setting, they will have to learn how to assume increasing responsibility for their own health care. This move toward independence will be reflected in other aspects of their life such as in their job, school, and relationships. Ideally, patients should attend joint pediatric/adult sessions and then move gradually to full adult care. Participation in a support group may help the patient through the transition. Efforts must be made to transfer medical records and other pertinent information to the adult care practitioner.

EDUCATION OF OTHER HEALTH CARE PROVIDERS

Understanding the pathophysiology, treatment, and complications of sickle cell disease is important so that health caregivers can provide optimal care. MLPs should be a resource for house staff members, inpatient and outpatient nursing staff members, and public health, school health, and other health staff members. Management conferences and workshops are effective methods of education. A comprehensive health care team, including physicians, social workers, genetic counselors, and MLPs, offers the best approach to effective health care delivery and education.

HOME HEALTH CARE MANAGEMENT OF PAINFUL EPISODES

Painful episodes are the most common complication of sickle cell disease. Home health care management and close telephone followup can reduce the need for frequent hospital visits. Because fever can be a sign of infection or extensive tissue damage, patients should be urged to purchase thermometers and learn how to use them prior to telephone contacts. The health care practitioner can provide information about home comfort measures such as warm baths or showers, massages, and relaxation therapy. Pain that requires medical evaluation rather than home care should be carefully reviewed with the patient (see Chapter 7, Painful Events).

LEG ULCER CARE

Evaluation of the patient's understanding of the prescribed treatment plan (see Chapter 16, Leg Ulcers) should be done at each contact. Demonstration of how the treatment plan will be administered at home should help to increase compliance. Home care referral should be made if indicated. Successful outpatient and home management for chronic, recurring leg ulcers reduces the need for hospitalization.

CHELATION THERAPY

A chronic transfusion program may be instituted to treat severe complications of sickle cell disease (see Chapter 10, Transfusion). Patients on chronic transfusion programs should be evaluated for iron overload (hemosiderosis). When iron overload is documented, chelation therapy with deferoxamine mesylate (Desferal (registered trademark)) may be initiated. The MLP should develop a teaching plan for home chelation, and written instruction must be provided to assist the patient or parent through each step of the procedure. Compliance with home chelation therapy must be monitored carefully. The MLP should coordinate yearly visits to ophthalmology and audiology specialists for early detection of possible adverse effects of deferoxamine mesylate.

INPATIENT CARE

After a careful history and physical assessment are done, a health care plan using techniques proven effective in the past can be instituted and appropriate goals for hospitalization established. Continuity of care is important for the hospitalized patient. Thus, the assignment of a primary caregiver can help to reduce the stress of the hospitalization and associated fears. This individual should explain hospital procedures and specific treatment modalities to the patient carefully. Finally, the primary caregiver should also participate in discharge planning and referral to appropriate resources when indicated.

OUTPATIENT CARE

In the outpatient setting, the MLP should focus on health maintenance, prevention, early recognition, treatment of complications, and patient education. Evaluations should identify patient and practitioner concerns about illness, analgesic therapy, management, compliance, social adjustment, and school and/or work performance. Health care plans are developed to help patients maintain wellness and to be active participants in receiving the best possible care. A close relationship with school health faculty is beneficial for school-age patients.

EMERGENCY DEPARTMENT CARE

MLPs must identify and promptly treat acute events associated with sickle cell disease. Proper education of emergency room staff members will ensure a timely response to life-threatening complications (i.e., sepsis, acute anemic events). To help provide continuity of care, an updated database that includes baseline hematologic values and other pertinent information necessary for providing emergency care should be maintained. Communication is essential between emergency department staff members and the sickle cell clinic or physician's office.

SUMMARY

Patient care interventions for individuals with sickle cell disease are both supportive and treatment oriented. A delicate balance must exist between providing supportive care and fostering independence to ensure that patients become well-informed, active participants in their care.

BIBLIOGRAPHY

Butler DJ, Beltran LR. Functions of an adult sickle cell group: education, task orientation, and support. J Health Soc Work 1993;18:1.

Cohen A, Martin M, Mizanin J, Konkle DF, Schwartz E. Vision and hearing during deferoxamine therapy. J Pediatr 1990;117(2, Part 2):326-30.

Pack B (guest ed). Symposium on sickle cell disease. Nurs Clin North Am March 1983;18:129-229.

Rivers R, Williamson N. Sickle cell anemia--complex disease, nursing challenge. RN J 1990;53:24-9.

Rosen DS. Transition to adult health care for adolescents and young adults with cancer. Cancer 1993;71(suppl):3411-4.

Schidlow DV, Fiel B. Live beyond pediatrics. Transition of chronically ill adolescents from pediatric to adult health care systems. Med Clin North Am 1990;74:1113-9.

Vichinsky E, Johnson R, Lubin B, et al. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol 1982;4:3.

Chapter 4--Psychosocial Management

As in other chronic illnesses, psychosocial issues affect social, emotional, academic, and vocational adaptation to sickle cell disease throughout the patient's life cycle. The patient's care providers must be aware of these factors and respond appropriately. Many of the psychosocial factors are associated with developmental life stages. The following is a developmental framework for examining the psychosocial aspects of sickle cell disease. Suggestions for appropriate interventions are offered.

THE INFANCY THROUGH PRESCHOOL STAGE

Early and appropriate psychosocial counseling for the family of a newly diagnosed infant with sickle cell disease is extremely important. Parents may have a number of concerns pertaining to social, emotional, and environmental issues related to their baby's diagnosis. Such issues may include nutrition, health insurance, the need for adequate housing, and assistance in dealing with feelings ("genetic guilt") about having a child with a chronic hereditary illness.

To assist families with the multiple nonmedical issues that might confront them, health care providers need to know about available community resources. For example, the local social services department or a State government's Crippled Children's Program may be able to identify potential housing, medical, and financial assistance. The social services department may also provide case management services that link and coordinate counseling and support services for the family.

In addition to addressing the concrete medical needs of the patient and family, attention must be given to their emotional and psychological needs. The physician should provide an opportunity for the parents to talk, ask questions, and express their feelings (anger, guilt, fear, denial, helplessness, etc.). These sessions should be repeated as necessary. Parents should be given factual information about their child's condition, its inheritance, and problems that may occur in the future. Parents also need information and instruction on how best to provide home management and care of their infant. With sound teaching, encouragement, and support, the parents can become effective participants with health care professionals in the care of their child. This approach can have a positive influence on parental coping and compliance.

In some cases, counseling and reassurance of parents by the physician is not sufficient to allay anxiety and reduce guilt or resolve deep-seated emotional and psychological conflicts. Referral to a family and child services agency or other community mental health facility can be helpful in this situation. With specialized individual, family, and group counseling, parents together or individually are usually able to work through social, emotional, and environmental conflicts. Often, parental understanding and comprehension of the genetic implications of their child's medical condition remain inadequate. If so, ongoing association with genetic counseling services should be considered.

Established programs in the community that provide services to patients and families affected by sickle cell disease or other genetic disorders should be used. Parents can also benefit from interacting with other parents in mutual support and self-help groups.

THE SCHOOL-AGE STAGE

Children with sickle cell disease should be enrolled in a regular classroom unless there are specific reasons to do otherwise. Parents should notify appropriate school officials of their child's condition. It is helpful to have written information that can be shared with the teacher, school nurse, and other school officials. This information can be in the form of a brochure or pamphlet containing general information about sickle cell disease or a letter from the patient's physician specifically describing the child's condition and any special needs. Medical or nursing staff should be available to provide consultation and education to teachers about sickle cell disease.

Parents may ask the physician to complete a variety of forms or write letters describing their child's illness and its management or requesting special bus transportation, the use of special school facilities (such as an elevator), exemption from certain physical education activities, or home or hospital school instruction. The physician should consider these requests carefully, discuss them fully with the parents and others involved, and understand completely the nature of the request. Although these requests relative to their child's school may be appropriate and valid, they may also be indicative of the parents' need for a better understanding of their child's health status and his/her actual limitations. Children should be encouraged to study and remain in school. Although school attendance may be interrupted periodically due to illness (usually infections and painful episodes), once the illness is resolved the child should return to school and other usual activities. Hospital-based school programs can assist the child who has frequent hospitalizations to maintain age-appropriate school performance.

To accommodate the child's school program, physician visits should be scheduled after school hours when possible. Telephone followups are often helpful. Socialization and peer interaction are important functions of the educational system, and inappropriate use of a home tutoring program during and following illnesses can interfere with the child's social and psychological development. Usually this service is not needed unless the child is convalescing at home for more than 2 weeks. During brief illnesses at home, parents can request that the child's teacher assign a study partner to bring assignments home to the patient and keep him or her abreast of school activities. Because school policies vary, parents should check with the school or school board to find out what services or resources are available. The physician and nurse practitioner can be extremely important advocates.

Recognition of the importance of school does not negate the importance of other activities of a growing child. Like all children, children with sickle cell disease should be encouraged to have hobbies and other age-appropriate interests. Parents should understand that children with sickle cell disease need not be treated any differently from unaffected children. This is especially true during the quiescent periods when there are no sickle cell-related problems. Keeping the child's lifestyle as normal as possible helps in development of a positive self-image. Many children with sickle cell disease have successfully attended summer camp, some camps specifically for children with sickle cell disease and others unrelated to sickle cell disease. Such activities foster independence and provide the child with an opportunity to be more similar to his or her peers.

THE ADOLESCENT STAGE

Adolescence (ages 13 to 19) represents a period of transition marked by physical, emotional, and social changes. There may be concerns for adolescents with sickle cell disease in this age group. This is the stage when concerns about body image, peer group acceptance, and physical attractiveness are very important. Specific physical characteristics and complications of sickle cell disease can hinder the social and emotional adjustment of the affected teenager. Such characteristics as jaundiced eyes, enuresis, delayed physical maturation and growth retardation, unpredictable pain episodes, and complications such as avascular necrosis of the hip joint, chronic leg ulcers, and the residual effects from stroke can make coping very difficult. Episodes of priapism require both medical and psychological care, especially in adolescents. Fortunately, only a few teenage sickle cell patients are faced with these complications, and they may benefit from individual or group counseling. Therapy groups that include teenagers with the same or similar disabilities can be very successful. A support group for adolescent patients is especially important because they may hide their disease from peers and teachers. Such groups help teenagers learn how peers cope with common problems and concerns.

Overprotection by parents, family, and friends can pose very serious problems for some adolescents. They want to be independent but are forced to be dependent when they become ill. Sensitive counseling of both parents and the adolescent can be helpful. The physician dealing with the adolescent must keep the parents informed and give them an opportunity to participate in medical decisions.

Delayed development of secondary sexual characteristics and/or slow physical growth in adolescent patients requires counseling and reassurance. Just like other teenagers, teenage patients with sickle cell disease want to resemble their unaffected peers in every way, including capabilities and interests.

Often the physician is asked by the adolescent with sickle cell disease if he or she can participate in sports or other activities that require considerable physical strength and endurance. In the absence of contraindications, participation in such activities should be encouraged. The teenager with sickle cell disease needs to be able to set his or her own pace when participating in activities such as swimming, tennis, or basketball and should be able to stop and rest when tired. Some teenagers may be able to compete in competitive sports.

Sexuality in the teenager with sickle cell disease is often no different from that in their more healthy peers. Some will be sexually active, and it is important to provide advice on contraception and sexually transmitted diseases. Failure to acknowledge problems of sexuality and associated risks may result in serious complications later. When appropriate, adolescents should be referred to family life clinics. Pregnancy in adolescents with sickle cell disease presents medical, psychological, and social problems. Pregnant adolescents can usually benefit from counseling and services offered by a social worker.

At this stage of life, teenagers should give serious consideration to college, careers, and their future as adults. Discussion with gainfully employed adults with sickle cell disease, particularly with professionals who have sickle cell disease, can be very helpful. Adolescent sickle cell patients should be encouraged to consider careers that are consistent with their medical condition. Such career aspirations often require college or vocational training. Referral to vocational rehabilitation, precollege orientation programs, or other training and career programs can be extremely helpful. Referral to key community resource agencies such as departments of employment (job services) and social or youth services can establish important linkages.

THE ADULT STAGE

Adult patients with sickle cell disease may encounter psychosocial and socioeconomic problems, including unpredictable interruptions of social and economic life due to recurring painful episodes. Adults are often faced with unemployment, lack of health insurance coverage, and inability to qualify for public assistance or disability insurance. If the young adult is employed, frequently this employment is unstable and does not offer fringe benefits like health insurance coverage. Assistance with payment for medical services may be available for adult sickle cell patients through the local public medical assistance program, Social Security Administration, and State vocational rehabilitation services.

Most sickle cell patients do not show obvious disability, and it may be difficult for them to qualify for assistance. Eligibility for public assistance in disability and Supplemental Security Income programs is based on the extent of the disability as well as income eligibility. The patient must qualify in both categories to be determined eligible. The physician's report of the patient's physical status is crucial in helping to determine his or her eligibility. The physician should carefully document the clinical course of the patient's illness, including the number and dates of hospital admissions, emergency room visits, acute visits, organic and physical dysfunctions, and the blood count and the need for blood transfusions. To provide a comprehensive picture of the patient's condition, it may be necessary to provide more information than that specifically requested.

In addition to social and environmental difficulties, the adult patient may experience emotional and psychological problems, including relationship difficulties, loneliness, low self-esteem, and preoccupation with death. Consultation with or referral to a mental health practitioner is beneficial to the patient and physician when he or she observes patient behavior that is indicative of failure to cope, depression, or other signs of psychological or emotional dysfunction. Support and self-help groups may be beneficial for these patients.

BIBLIOGRAPHY

Conyard S, Krishamurthy M, Dosik H. Psychosocial aspects of sickle cell anemia in adolescents. Health Soc Work 1980;5:20-6.

Duncan D, Scott RB. Coping with sickle cell disease: a profile and perspective of a pioneer self help group. J Natl Med Assoc 1988;80:221-4.

Eisenberg MG, Sutkin LC, Mary AJ (eds). Chronic illness and disability through the life span. Effects on self and family. New York: Springer Publishing Company, 1984.

Gilbert SK. The health insurance plight of patients with sickle cell disease. J Natl Med Assoc 1986;78:663-5.

Hobbs N, Perrin JM. Chronically ill children in America. Rehabil Lit 1984;45:7-8.

Hobbs N, Perrin JM, Henry TD. Chronically ill children and their families. San Francisco: Josey-Bass Publishers, 1985.

Hurtig AL, Viera CT. Sickle cell disease: psychological and psychosocial issues. Urbana and Chicago: University of Chicago Press, 1986.

Kumar S, Powars D, Allen J, Haywood LJ. Anxiety, self concept, and personal and social adjustments in children with sickle cell anemia. J Pediatr 1976:88(5):859-63.

Leavell SR, Forg CV. Psychopathology in patients with sickle cell disease. Psychosomatics 1983;24:23-5, 28-9.

Nash KB (ed). Psychosocial aspects of sickle cell disease: past, present, and future directions of research. New York: Haworth Press, Inc., 1994.

Newman B, Newman D. Development through life. Illinois: Dorsey Press, 1978:187-211.

Weiss JO. Psychosocial stress in genetic disorders: a guide for social workers. Soc Work Health Care 1981;6:17-31.

Chapter 5--Newborn Screening

Newborn screening for sickle cell disease is an effective first step to reduce morbidity and mortality in individuals with the disease. Parents of newborns with a positive screening test result for sickle cell disease must be contacted before the child becomes 2 months of age to confirm the diagnosis. The diagnosis should be confirmed by a laboratory with expertise in analysis of variant hemoglobins. If a child who is presumed to have sickle cell disease through newborn screening is not retested by 4 months of age, he or she should be started on penicillin VK (125 mg given orally twice a day) pending confirmation; the medication can be discontinued in the rare instance that the hemoglobin screening test result was erroneous or is found to represent a benign disorder. Once the disease diagnosis is confirmed, the infant must receive care in an ongoing and comprehensive medical program that includes oral penicillin given twice a day for the prevention of overwhelming Streptococcus pneumoniae infection and parent education about sickle cell disease. The medical program should be staffed by health care professionals who are sensitive to the special needs of infants with sickle cell syndromes and are aware of their propensity to life-threatening infection and death from complications such as acute splenic sequestration and acute chest syndrome.

All infants, of every ethnic group, should be tested to ensure the identification of all affected newborns. Where possible, sickle cell disease screening should be coupled with other newborn screening tests performed to detect hypothyroidism and inborn errors of metabolism. Several screening methodologies are acceptable, including hemoglobin electrophoresis on cellulose acetate and citrate agar, isoelectric focusing, and high-pressure liquid chromatography. Because of the high concentration of Hb F in newborns, solubility tests or sickle cell preparations (sodium metabisulfite) should not be used to confirm the presence of Hb S until the infant has reached 12 months of age and should never be used as a sole diagnostic laboratory procedure. States that test for sickle cell disorders as part of their newborn screening procedures usually confirm the original test result by retesting the child and will also request a repeat specimen if the history indicates that the child was transfused before the blood sample was obtained. It must be emphasized that the responsibility for a final and definitive diagnosis rests with the child's physician.

Red cells of normal newborns contain hemoglobins F and A, "FA," the hemoglobin in highest concentration being listed first. The hemoglobin pattern or phenotype is due to predominance of Hb F at birth. Newborns with sickle cell trait have an "FAS" phenotype, with more Hb A than Hb S. Infants with SC disease have an "FSC" pattern, those with SS disease, S beta o thal, and S HPFH each have an "FS" phenotype on newborn screening. Although infants with S beta + thal will generally have an "FSA" pattern on screening, the percentage of Hb A may be so small that these infants will also have an "FS" phenotype. Definitive diagnosis may require testing both parents or deoxyribonucleic acid (DNA) typing of the infant or retesting the infant after 9 months. It is important to remember that newborns with "FA" patterns are not necessarily hematologically normal--they do not have sickle cell disease but may have thalassemia or another disorder of red blood cells. When definitive diagnostic tests cannot be performed in early infancy, it is best to assume that the infant has SS disease, the most common of the FS disorders. When infants are doubly heterozygous for sickle cell and another abnormal hemoglobin other than C, definitive identification by a knowledgeable hematologist is necessary.

In addition to identifying the affected newborn, newborn screening also provides an opportunity to identify couples at risk for having children with sickle cell disorders. Parents of newborns identified with sickle cell trait or hemoglobin C trait should be offered testing for all hemoglobinopathies, including thalassemia, and be appropriately counseled.

Newborn screening may identify variant hemoglobins other than S or C. When these are co-inherited with Hb S, a definitive diagnosis must be made. Hemoglobin So Arab disease, for instance, is as serious a condition as SS disease, while the combination of Hb S and Baltimore is as benign as sickle cell trait. If the child has only Hb A and the variant, further diagnostic tests are usually unnecessary, if the child is hematologically normal in other aspects.

BIBLIOGRAPHY

Grover R, Shahidi S, Fisher B, et al. Current sickle cell screening programs for newborns in New York City, 1979-80. Am J Public Health 1983;73:249-52.

Newborn screening for sickle cell disease and other hemoglobinopathies. Pediatrics (suppl) 1989;83(5).

Pearson HA, O'Brien RT, McIntosh S, et al. Routine screening of umbilical cord blood for sickle cell disease. JAMA 1974;227(4):420-1.

Powars DR. Natural history of sickle cell disease: the first ten years. Semin Hematol 1975;12(3):267-85.

Rogers DW, Clarke JM, Cupidore L, et al. Early deaths in Jamaican children with sickle cell disease. Br Med J 1978;1(6126):1515-6.

Stern KS, Davis JG (eds). Newborn screening for sickle cell disease: issues and implications. New York: Council of Regional Networks for Genetic Services, Cornell University Medical College, 1984. (Copies available from the National Maternal and Child Health Clearinghouse).

US Department of Health and Human Services, Public Health Service, Sickle Cell Disease Guideline Panel. Sickle cell disease: screening, diagnosis, management, and counseling in newborns and infants. Clinical Practice Guideline Number 6. Rockville, Maryland: Agency for Health Care Policy and Research, 1993; AHCPR publication no. 93-0562.

Chapter 6--Infection

Serious bacterial infections are a major cause of morbidity and mortality in patients with sickle cell disease. Severe, overwhelming septicemia/meningitis due to S. pneumoniae is the most common cause of death during early childhood, but enteric organisms emerge as important pathogens in older patients. Because of the patient's asplenic condition, and because of disordered humoral immunity, infections in patients with SS disease are more likely to cause morbidity, disseminate, and resist eradication than in individuals unaffected by the disease. Infections also may enhance susceptibility toward vaso-occlusive complications. Prevention and early, aggressive treatment of infection are critical in the management of patients with sickle cell disease.

PREVENTION

Immunization

Children with SS disease have a normal antibody response to vaccines and should receive all immunizations recommended by the American Academy of Pediatrics (these change periodically, and the most current recommendations should be followed (see Table 2)). In addition, children should receive pneumococcal vaccine. Some clinicians recommend that the influenza vaccine be administered according to epidemiologic considerations.

Antibiotic Prophylaxis

Prophylactic penicillin is so effective in reducing the number of life-threatening episodes of pneumococcal sepsis in children with SS disease under age 5 years that most States screen newborns for the disease so they can be placed on the drug by 2 to 3 months of age. Oral penicillin VK (125 mg given twice a day up to age 3 years, then 250 mg given twice a day) is the preferred form of treatment. Prophylaxis should be given to children with SS disease and S beta o thal starting at 2 to 3 months of age and continuing until at least age 5 years. Prophylaxis in older children has not been shown to be beneficial and may be unnecessary after pneumococcal immunizations are complete and antibody titers are protective. Some clinicians give prophylaxis to children with SC disease or S beta + thal: there is an increased risk of severe infection in such patients, although it is less than in SS disease or S beta o thal. Compliance with penicillin prophylaxis can be achieved, provided that a dedicated team of physicians, nurses, and health care educators engage families in intensive educational programs.

Table 2 Recommended Immunizations

Birth (or at first visit) Hepatitis B vaccine #1, hepatitis B immunoglobulin if mother HBsAg**

1 month old (or 4 weeks after first visit) Hepatitis B vaccine #2

2 months old DTaP #1, HbcV #1* or Tetrammune, OPV #1

4 months old DTaP #2, HbcV #2 or Tetrammune, OPV #2

6 months old DTaP #3, HbcV #3, OPV #3 or Tetrammune, hepatitis B vaccine #3 (or 6 months after second vaccine)

12 to 15 months old Measles, mumps, rubella (MMR)

5 months old HbcV booster

15 to 18 months old DTaP booster #1, OPV #3

24 months old Pneumococcal vaccine

4 to 6 years old DTaP booster #2, pneumococcal vaccine booster, OPV #4, MMR (at or before school entry)

14 to 16 years old TD booster

Annually Influenza vaccine

*See MMWR 1993;42:RR-13, (combination of DPT and HbcV) can be used to replace these vaccines. **See Pediatrics 1994;94:774-5; AAP Committee on infectious disease regarding polio vaccine at 6 months. DTaP = diphtheria tetanus acellular pertussis vaccine. DTP = diphtheria tetanus pertussis vaccine. HbcV = Haemophilus influenzae type b conjugate vaccine. OPV = oral polio virus vaccine. TD = tetanus diphtheria toxoids vaccine.

Neither the pneumococcal vaccine nor available antibiotics has been shown to eliminate nasopharyngeal colonization with S. pneumoniae, Neisseria meningitis, and H. influenzae in normal young children or those with sickle cell disease. Prophylactic antibiotics prevent bacteremia and tissue invasion, despite continued nasopharyngeal carriage or reexposure. When failure occurs, it may be due to a variety of microbiologic causes as well as a lack of patient compliance. As discussed below, the emergence of penicillin- and cephalosporin-resistant S. pneumoniae is a serious evolving problem in many communities and may ultimately undermine the effectiveness of the established prophylactic regimen. Clinicians should be aware that recommendations concerning the use of prophylactic penicillin and the choice of empiric antibiotics in patients with sickle cell disease may well undergo tremendous change during the next few years. At present, the most effective approach is a combination of traditional pneumococcal vaccination and regular penicillin prophylaxis; it is hoped that newer conjugated pneumococcal vaccines will prove protective in infancy.

MANAGEMENT

Pediatric Infection

Fever in a child younger than age 5 years with SS disease often indicates life-threatening bacterial infection. It is estimated that there is a 400-fold increased risk of pneumococcal septicemia/meningitis in this population. Fortunately, H. influenzae infections have become exceedingly rare with the advent of the H. influenzae - vaccine.

Children with sickle cell disease and septicemia generally have fever greater than 102 oF (38.9 oC), but temperatures below 102 oF may also be seen, especially early in the clinical course. In febrile children with sickle cell disease, administration of antibiotics should occur promptly, even for minimal clinical indications such as significant fever, chills, etc. The patient should be evaluated for causes of fever such as otitis media, pneumonia, or urinary tract infection. Chest x-ray, blood, urine, and throat cultures should be obtained without waiting for test results. Lumbar puncture should be performed even if there are only minimal indications of meningitis. An antibiotic effective against S. pneumoniae and H. influenzae should be promptly administered, preferably intravenously. Because penicillin- and cephalosporin-resistant S. pneumoniae are now identified in many regions of the country, antibiotics such as vancomycin have been added to the typical empiric therapy regimen in those areas. It is critical to be aware of the susceptibility patterns of the local flora when selecting empiric therapy. The choice of subsequent antibiotics can be guided by results of cultures and clinical course.

Practice varies widely on indications for admitting febrile SS children to the hospital. There is, however, consensus that all SS children with any of the following be admitted for inpatient treatment:

* Temperature greater than 40 oC (> 104 oF).

* Seriously ill appearance.

* Hypotension.

* Poor perfusion, dehydration.

* Pulmonary infiltrate.

* Corrected white blood count greater than 30,000 or less than 5,000/mm3.

* Platelet count less than 100,000/mm3.

* Hemoglobin less than 5 g/dL.

* History of S. pneumoniae sepsis.

Several centers with expertise in treating large numbers of patients with sickle cell disease in an ambulatory setting have successfully used long-acting parenteral cephalosporins (e.g., ceftriaxone sodium) to treat febrile children as outpatients. This approach is appropriate only when the following conditions apply:

* The patient is clinically at low risk for sepsis (i.e., none of the above factors is present).

* The patient, family, and clinic are capable of impeccable followup, and the patient has immediate emergency access to the hospital.

* The endemic flora have been demonstrated to be sensitive to cephalosporins.

* A successful followup program has been established.

If septicemia is confirmed by a positive blood culture, the child should be hospitalized, and therapy should be continued for a minimum of 5 to 7 days. Bacterial meningitis should be treated for 10 days or at least 7 days after cerebrospinal fluid sterilization has occurred. On the other hand, if blood, urine, and throat cultures are negative after 3 days and the patient is well, antibiotic therapy can be discontinued and the diagnosis presumed to be a viral illness. If fever persists and cultures are negative, the patient should be reevaluated.

Infections in Older Children and Adults

Because pneumococcal infections become less frequent after the first decade of life and infections due to other pathogens found in the general population become more common, a systematic bacteriologic evaluation should be used before administering antibiotics. A persistent fever higher than 101 oF should not be assumed to be due to vaso- occlusive crisis. Infections tend to occur in already damaged areas such as lungs, kidneys, and bones.

Urinary Tract Infections

Pyelonephritis in patients with SS disease is difficult to treat, recurs regularly, and is often associated with septicemia. This is particularly serious during pregnancy. Urine cultures are essential before therapy and should be repeated 1 to 2 weeks after cessation of therapy. Treatment consists of antibiotics and hydration. Urologic evaluation and chronic suppressive antibiotic therapy may be appropriate for patients with repetitive infection.

Osteomyelitis

Osteomyelitis must be differentiated from the more common (~50:1) diaphyseal bone infarction because the two conditions present with similar clinical and imaging findings but are treated differently. Similarly, septic arthritis must be distinguished from the more common joint effusion associated with acute painful episodes. It is essential to establish a bacterial diagnosis (from blood or aspirated joint or subperiosteal fluid) before long-term antibiotics are started to treat osteomyelitis or septic arthritis. Blood cultures may be particularly helpful in the setting where infarcted bone is seeded during an episode of bacteremia.

Increasing antibiotic resistance among Salmonella isolates is a major problem. Even if in vitro susceptibility tests suggest efficacy for tetracyclines, cephalosporins, and aminoglycosides, these antibiotics often fail. Ampicillin, quinolines, and trimethoprim-sulfamethoxazole have been demonstrated to be effective (when indicated by in vitro sensitivity tests). Chloramphenicol can also be effective, but its potential for bone marrow suppression requires frequent monitoring of the reticulocyte count. The tendency of Salmonella to establish chronic, intracellular infection requires prolonged treatment typically--1 month of intravenous antibiotic therapy, followed by months of oral treatment. Public health procedures should be implemented to prevent spread of infection to family members.

Bacteriologically proven staphylococcal osteomyelitis requires high-dose penicillinase-resistant penicillin (e.g., nafcillin) for several weeks. If adequate blood levels of the antibiotic can be achieved, a regimen such as 2 weeks of intravenous therapy followed by 4 to 6 weeks of oral therapy can be given. The necessity for surgical incision and drainage or debridement in osteomyelitis of any cause should be based on clinical judgment.

BIBLIOGRAPHY

Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR. Emergence of drug-resistant pneumococcal infection in the United States. JAMA 1994;271:1831-5.

Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314:1593.

Leggiadro RJ. Penicillin- and cephalosporin-resistant Streptococcus pneumoniae and emerging microbial threat. Pediatrics 1994;93:500-3.

Overturf GD, Powars D, Baraff LJ. Bacterial meningitis and septicemia in sickle cell disease. Am J Dis Child 1977;131:784-7.

Pearson HA, Gallagher D, Chilcote R, et al. Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics 1985;76:392-7.

Sarnaik S, Kaplan J, Schiffman G, et al. Studies on pneumococcal vaccine alone or mixed with DTP and on pneumococcus type 6B and Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugates in two- to five-year-old children with sickle cell anemia. Pediatr Infect Dis 1990;9:181-6 (erratum, Pediatr Infect Dis 1990;9:308).

Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991;325:1453-60.

Wilimas JA, Flynn PM, Harris S, et al. A randomized study of outpatient treatment with ceftriaxone for selected febrile children with sickle cell disease. N Engl J Med 1993;329:472-6.

Zarkowsky HS, Gallagher D, Gill FM, et al. Bacteremia in sickle hemoglobinopathies. J Pediatr 1986;109:579-85.

Chapter 7--Painful Events

Painful crises in sickle cell disease are believed to be caused by ischemic tissue injury resulting from the obstruction of blood flow produced by sickled erythrocytes. The reduced blood flow causes regional hypoxia and acidosis, which further increases the sickling process and may increase the ischemic injury. Painful crises vary in intensity and duration, usually lasting 4 to 6 days but sometimes persisting for weeks. They may vary in intensity from time to time during the course of a single episode. Hypoxia, infection, fever, acidosis, dehydration, menstruation, sleep apnea, obstructive snoring, and exposure to cold may precipitate such events. In addition, patients often cite anxiety, depression, and physical exhaustion as precipitators. In many instances, no precipitating event can be identified.

The frequency and severity of repeated painful crises vary widely among patients. A few patients state that they are always "in pain" and repeatedly request hospitalization. Conversely, approximately one-third of patients rarely seek hospital-based treatment. Many patients can manage painful events at home.

In general, painful crises are a measure of disease severity and have been reported to correlate with early death in adult patients, but we are unable to predict which individuals will be so adversely affected. High hemoglobin levels, low fetal hemoglobin, and a baseline white blood cell (WBC) count of 15,000 are factors that place individuals at greatest risk. A painful crises is one of the most common settings in which death occurs in adult patients. Acute chest syndrome, central nervous system events, bone marrow embolism, and acute multiorgan failure syndrome may suddenly occur during a severe painful crises. In a patient in pain, overtreatment with narcotic drugs or intravenous fluids and other iatrogenic events increase the morbidity of therapy. Pain management requires ongoing assessment of the patient for sites of pain, degree of pain, and effects of pain and pain relief on at least a daily basis.

Pain should be treated as early as possible because undertreatment or persistent pain can debilitate the patient both physically and psychologically. Some of the recognized physical sequelae of unrelieved pain such as stress and dehydration are also precipitating events for acute painful episodes and may account for the not uncommon finding of a patient who initially presents with focal pain but develops diffuse pain within hours of the onset of the crises.

ASSESSMENT OF PATIENTS

There is no clinical or laboratory finding that is pathognomonic of painful episodes in sickle cell disease. The diagnosis of a painful episode is often made solely on the basis of the medical history and physical examination. The possibility that pain is precipitated by a concurrent medical condition such as infection should be considered, and the physician should search for a precipitating illness in every instance.

Bones are the most common site of pain. Dactylitis, or the hand-foot syndrome (acute, painful swelling of the hands and feet), is the first manifestation of sickle cell disease in many infants. Irritability and refusal to walk are other common symptoms. After infancy, musculoskeletal pain can be symmetrical, asymmetrical, or migratory, and it may or may not be associated with swelling, low-grade fever, redness, or warmth. In both children and adults, sickle vaso- occlusive episodes are difficult to distinguish from osteomyelitis, septic arthritis, synovitis, rheumatic fever, or even gout.

When abdominal or visceral pain is present, care should be taken to exclude sequestration syndromes (spleen, liver) or the possibility of an acute condition such as appendicitis, pancreatitis, cholecystitis, urinary tract infection, pelvic inflammatory disease, or malignancy. Pneumonia ("chest syndrome," see Chapter 8) develops during the course of 20 percent of painful events and can present as abdominal pain. In adults, chest pain may be due to vaso-occlusion in ribs and often precedes a pulmonary event. The lower back is also a site for painful crises in adults.

Patients should be seen by a physician immediately if any of the following high-risk factors exist:

* Fever greater than 101 oF, lethargy, dehydration, or pallor.

* Severe abdominal pain.

* Acute pulmonary symptoms.

* Neurologic symptoms or pain associated with extremity weakness or loss of function.

* Acute joint swelling.

* Recurrent vomiting.

* Pain not relieved by conservative measures.

* Priapism.

LABORATORY TESTS

* Painful events are not commonly associated with changes in the patient's usual hemoglobin level. Concurrent reticulocytopenia is occasionally present. The WBC may be similar to the patient's baseline value; a higher value with an elevated band count suggests that infection is present.

* If a fever greater than 101 oF is present, an aggressive evaluation should be done to find the source (see Chapter 6, Infection).

* If pulmonary symptoms are present, a chest x-ray should be obtained, and measurement of arterial blood gases should be considered (see Chapter 8, Lung).

* If osteomyelitis or septic arthritis is suspected, direct aspiration of the bone or joint and cultures of the aspirates should be obtained. Radiographs and radioisotope or MRI scans may help separate infarction from infection, but they are not always reliable.

* Serum electrolytes and blood pH levels should be obtained for severely ill patients. There is a relatively high incidence of electrolyte disorders in patients with sickle cell disease, and a decreased weight may be an important sign of dehydration.

GENERAL PRINCIPLES OF THERAPY

In general, the management of acute painful episodes has five essential elements, including health care provider- patient relationships, identification and treatment of any precipitating or associated events, pain assessment, hydration, and analgesics.

Health Care Provider-Patient Relationships

Patients with sickle cell disease have repeated episodes of sudden unexpected pain that often result in fear of a life- threatening event or fear of how they will be treated by health care providers. The health care provider should work to alleviate that fear by providing consistent empathetic treatment. Ideally, continuity of care should be provided. If the patient must be seen by someone unfamiliar with his or her clinical course and previous painful episodes, the new physician should discuss the patient's care with a health care provider who is familiar with the patient. Because this may not always be possible, a consistent approach to pain discussed in advance with the family and outlined in the patient's record is essential. Making a card available to the family and health care providers that describes the patient's steady-state laboratory test results (Hb, reticulocyte count, alloantibodies, bilirubin), clinical problems, and pain medication treatment can decrease certain problems and foster patient trust. In addition, health care facilities should develop a general protocol for the management of pain in sickle cell disease so that patients can be treated in the absence of individualized data.

Identification and Treatment of Any Precipitating or Associated Events

The patient must be thoroughly evaluated with an accurate history, physical examination, and assessment at each presentation for a painful crisis to be certain that no other illness requiring specific treatment is present. It is essential that a painful episode be considered a manifestation of an underlying illness other than sickle cell disease until proved otherwise. These underlying illnesses are often infections or inflammatory conditions that require additional testing.

Pain Assessment

A comprehensive approach to pain assessment requires an evaluation of the patient's perception of pain, physiological responses, and behavioral responses. However, the mainstay of pain assessment must be patient self- reporting. Neither behavior nor physiological responses replace the patient's self-report. Patients in severe pain may use smiling, laughter, and singing as coping mechanisms, and such actions should not be misunderstood. The goal of therapy is pain relief, and when it is achieved, the patient may temporarily exhibit normal behavior (walking about, visiting). Such behavior does not necessarily indicate that the episode is completely resolved.

Each patient should be evaluated by a measurement tool that includes pain intensity and distress scales and an anatomic pain distribution assessment chart. The course of the painful episode should be accurately assessed using these tools at regular intervals (every 3 to 4 hours), particularly before changes in medication are made. Because patients often manage pain at home and do not report pain to their physician, home pain diaries are helpful in understanding and managing such pain.

Hydration

Dehydration, which causes red cell dehydration and promotes sickling, frequently occurs in patients with sickle cell disease because of reduced fluid intake, increased insensible water loss, and a high incidence of hyposthenuria. Because of hyposthenuria, measurement of urine-specific gravity cannot be relied on to reflect the patient's hydration status. For mild pain, liberal oral hydration is sufficient. For patients with more severe pain, oral hydration should always be attempted if there are sufficient personnel to evaluate and encourage fluid intake. Intravenous hydration is recommended in all other situations. The basic objectives of fluid therapy include correction of fluid and electrolyte deficits, maintenance of normal serum electrolyte concentrations, and administration of fluid volumes (IV + P.O.) to equal 1-1/2 times the daily requirement. The choice of initial parenteral fluid is dictated by the patient's hydration status and electrolyte values. For uncomplicated painful crises, 5 percent glucose in 0.25-0.5 percent normal saline is recommended as the initial fluid replacement. The amount for adult patients is approximately 3 L/day if cardiac status is normal, while that for children is based on the patient's weight.

Parenteral hydration should be monitored closely to avoid iatrogenic congestive heart failure or electrolyte imbalance. Because excessive renal sodium losses occur in some patients, serum electrolytes should be monitored at least every other day. In general, serum sodium concentrations between 130 and 135 mg/dL do not need correction. Elevated sodium concentrations should be avoided. Physical examinations, including daily weight and records of intake and output, are essential. The presence of cardiomegaly on physical examination or chest x-ray usually does not indicate cardiac failure, and brisk parenteral rehydration usually can be safely accomplished. Patients should be monitored closely, however, for tachycardia, tachypnea, rales, gallop rhythm, hepatomegaly, or excessive weight gain.

Analgesics

The goal of analgesic therapy is to provide prompt pain relief. Often, this is not achieved because of inadequate understanding of the clinical pharmacology of analgesics, excessive concern about narcotic addiction, or well-meaning but misguided use of placebos. There is no role for the use of placebos in the evaluation or treatment of the pain of sickle cell disease. The choice of therapy is based on potency, mode of action, and side effects of analgesics (see Table 3). Medication should be administered on a fixed-time schedule, with a dosing interval that does not extend beyond the duration of the desired pharmacological effect. Meperidine is contraindicated in patients with renal dysfunction or central nervous system disease, because its metabolite normeperidine (which is excreted by the kidney) can cause seizures.

Patient-controlled programs for severe pain, either dose titration methods or patient-controlled analgesia (PCA) devices, are the preferred treatment methods. This approach maintains pain control, decreases anxiety, and addresses individual pain relief needs within an acceptable level of adverse effects.

Dose titration without PCAs may be done using a number of techniques. It is essential in any titration program that frequent, accurate, and timely assessment of the patient's condition by a physician and nurse be done. If this is not possible in the institution, consideration should be given to transferring the patient to an institution that can provide them. In all cases, a written plan must be developed and implemented at the beginning of therapy; the results of the assessment must be recorded, preferably on a flowsheet. Use the simplest dosing schedule and least invasive pain relief method first. The following are three regimens that can be used. In each titration method, the first (loading) dose is based on prior analgesic history and the patient's condition, including intensity and sites of pain:

(1) After the loading dose, reassess the patient at 30- minute intervals and, based on the assessment, treat with one-quarter to one-half of the loading dose until the patient experiences relief. This method requires very close observation of the patient and should not be used if this cannot be provided.

(2) Dose and dosing intervals are prescribed based on the patient's prior history. "Rescue" dosing (for breakthrough pain) is given at one-quarter to one-half the loading dose for recurrent pain between regular doses (e.g., 8 mg of morphine every 3 hours, with 2-4 mg for pain occurring in the interval). Readjust fixed dosing if the patient requires more than three rescue doses in 12 hours.

(3) After the loading dose, increase or decrease the next fixed dose by one-quarter to one-half, depending on the patient's response.

A PCA program usually includes an initial loading dose when a narcotic has not been given recently. The PCA pump delivers intravenous boluses of narcotic on patient demand at a preprogrammed dose and interval. In addition, a lockout may be programmed to prevent further dosing once a maximum dose in a 4-hour period has been reached. Because the patient adjusts his/her own dose, treatment is "titrated to effect." A continuous infusion setting is available and is often used for low-dose infusions, particularly at night. A typical starting PCA program with morphine sulfate could be as outlined below:

1. Loading dose (if needed) 0.05 mg morphine/kg.

2. 1-hour dose limit 0.06-0.1 mg/kg/hr (divided into 4-8 doses).

3. 4-hour lockout limit: 0.2-0.3 mg/kg.

4. A continuous night (10:00 pm-7:00 am) IV infusion rate of 0.02 mg/kg/hr is added without changing the 4-hour lockout limit. Other schemas such as using a formula based on the previous 24 hours of care or treatment can be found in the literature.

5. Standard orders should include:

a. No other narcotics given.

b. Close proximity to nursing station.

c. Patient training in PCA.

d. Observations (which must be charted):

- respiratory rate q 1 hr

- blood pressure, heart rate q 2 hr

- pain and sedation scores q 2 hr

- incentive spirometry q 1-2 hr when awake.

Records of the amount of analgesic actually administered and its clinical effect must be carefully preserved, to help in managing future painful crises.

The effect of the route of administration on drug absorption must always be considered. The oral route is generally at least one-half (range one-half to one-sixth) as effective as the parenteral route, depending upon the drug (see equi- analgesic table). Oral administration, however, avoids many of the complications of parenteral therapy. When potent narcotics are used, the physician should remember that side effects include respiratory depression, nausea, vomiting, pruritus, hypotension, constipation, increased secretion of antidiuretic hormone, and changes in the seizure threshold. Synthetic narcotics such as pentazocine, butorphanol, and nalbuphine should be used with caution and should not be used in conjunction with other narcotics because they are agonist-antagonists and may induce withdrawal symptoms or psychotomimetic effects.

Nonnarcotic analgesics are used to treat mild-to-moderate pain. In patients with severe pain, adding these analgesics to narcotic therapy increases analgesia and has a significant narcotic-sparing effect. Therefore, concurrent use of both is recommended. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) are a helpful adjunct in severe pain in patients who can tolerate their gastrointestinal side effects because while they decrease inflammation at the tissue site, they do not cause sedation, respiratory depression, or bowel or bladder dysfunction. They should not be used in children or for more than 5 days because of the risk of gastrointestinal bleeding and renal disease. Ketorolac tromethamine, an NSAID, is available for parenteral use; preliminary results suggest that it is helpful as an adjunct or primary agent in moderate-to-severe pain. Oral NSAIDs may be useful in patients with chronic pain or arthritis. Care must be taken in patients with compromised renal function because these drugs may cause additional kidney damage. Aspirin, which can cause hyperuricemia, should be avoided in patients with gout. Acetaminophen is the analgesic of choice if the patient is unable to tolerate NSAIDs or aspirin. However, acetaminophen should be used with caution in patients with liver disease because it can cause severe hepatic damage in high doses. Like its parent compound, phenacetin, chronic use can cause renal damage--always a problem in adults with SS disease.

PAIN MANAGEMENT

Prevention

Because all painful episodes cannot be prevented, patients should know how to manage mild pain and should be taught to recognize symptoms suggestive of serious problems. Optimal management of patients with painful events requires adequate education of the patient, family, and health care providers. Conditions that expose the patient to hypoxia, dehydration, and extreme cold should be avoided. Mountain climbing, flying in unpressurized aircraft, and swimming in frigid water are potentially hazardous. If air travel is necessary, patients should be advised to travel in pressurized aircraft, refrain from alcohol consumption, maintain an increased fluid intake, move about the plane periodically, and stay warm. Fluid intake (juices, soft drinks, and bouillon) should be increased during fevers, high ambient temperatures, and increased physical activity.

Home-Based Management

The majority of painful events can be managed successfully at home, thus fostering patient self-esteem and independence. The success of a home-based program depends on patient education, including not only an explanation of the pathophysiology ("What happened?") but also the expectations and limitations of such treatment ("When should I go to the hospital?"). In addition, the patient should be taught to recognize the more serious complications of sickle cell disease to avoid delay in treatment.

Complete home management programs include specific guidelines for oral fluid intake and effective analgesics. Oral intake, often described in terms of ounces of fluid per day, should be at least 150 cc/kg/day for children and 3 to 4 L/day for adults. Soft drinks, juices, and bouillon are recommended. Fluids devoid of electrolytes should not be the sole source of oral hydration because they can produce an electrolyte imbalance.

NSAIDs, acetaminophen, or aspirin are recommended for mild pain, with the precautions noted above. Codeine is the preferred oral narcotic for more severe pain and should be given with nonnarcotics. More potent oral narcotics such as morphine, hydromorphone, or oxycodone are rarely indicated. Individual patients respond differently to specific analgesics, and open communication between physician and patient is needed. Nausea does not represent allergy to oral narcotics. Patients truly allergic to codeine may be able to use oxycodone. Whenever narcotic agents are given by repeated prescription, it must be established with the patient that such drugs will be obtained from one physician so that the use of the drug may be accurately monitored.

A few patients request excessive amounts of narcotics. Careful records of the number of tablets dispensed should be kept, and records should be reviewed before prescriptions are refilled. The number of tablets to be dispensed should be written in words (e.g., "ten," not "10"), and it is preferable to prescribe doses for a limited period of time (i.e., a week, not a month).

Emergency Department Management

The goals of emergency department management are to assess the clinical problem, treat the pain aggressively in a supportive environment, and make an appropriate diagnosis. High-risk patients should be admitted directly to the hospital. The guidelines for emergency department management are as follows:

* Give appropriate analgesics in a titration regimen to relieve pain and establish a useful regimen. Suggested doses and intervals of administration are based on the severity of the pain (see Table 3).

* Administer IV fluids if necessary (see "Hydration" above); closely monitor fluid intake. The choice of fluids should be designed to maintain adequate electrolyte balance.

Table 3 Recommended Dose and Interval of Analgesics Necessary To Obtain Adequate Control in Sickle Cell Disease

Severe/Moderate Pain

1. Morphine

Dose Rate

Parenteral: 0.1-0.15 mg/kg/dose every 3-4 hours. Recommended maximum single dose 10 mg.

P.O.: 0.3-0.6 mg/kg/dose every 4 hours.

Comments

Drug of choice for pain, lower doses in the elderly and infants, and in patients with liver failure or impaired ventilation.

2. Meperidine (Demerol (registered trademark))

Dose Rate

Parenteral: 0.75-1.5 mg/kg/dose every 2-4 hours. Recommended maximum dose 100 mg.

P.O.: 1.5 mg/kg/dose every 4 hours.

Comments

Increased incidence of seizures. Avoid in patients with renal or neurologic disease or who receive monoamine oxidase inhibitors.

3. Hydromorphone

Dose Rate

Parenteral: 0.01-0.02 mg/kg/dose every 3-4 hours.

P.O.: 0.04-0.06 mg/kg/dose every 4 hours.

4. Oxycodone

Dose Rate

P.O.: 0.15 mg/kg/dose every 4 hours.

5. Ketorolac

Dose Rate

Intramuscular: Adults: 30 or 60 mg initial dose, followed by 15 to 30 mg every 6-8 hours.

Children: 1 mg/kg load, followed by 0.5 mg/kg every 6 hours.

Comments

Equal efficacy to 6 mg MS, helps narcotic-sparing effect, not to exceed 5 days. Maximum 150 mg first day 120 mg maximum subsequent days. May cause GI irritation.

6. Butorphanal

Dose Rate

Parenteral: Adults: 2 mg every 3-4 hours.

Comments

Agonist-antagonist. Can precipitate withdrawal if given to patients who are being treated with agonists.

MILD PAIN

1. Codeine

Dose Rate

P.O.: 0.5-1 mg/kg/dose every 4 hours. Maximum dose 60 mg.

Comments

Mild-to-moderate pain not relieved by aspirin or acetaminophen; can cause nausea and vomiting.

2. Aspirin

Dose Rate

P.O.: Adults: 0.3-0.6 mg/dose every 4-6 hours. Children: 10 mg/kg/dose every 4 hours.

Comments

Often given with a narcotic to enhance analgesia. Can cause gastric irritation. Avoid in febril children.

3. Acetaminophen

Dose Rate

P.O.: Adults: 0.3-0.6 gm every 4 hours. Children: 10 mg/kg/dose.

Comments

Often given with a narcotic to enhance analgesia.

4. Ibuprofen

Dose Rate

P.O.: Adults: 300-400 mg/dose every 4 hours. Children: 5- 10 mg/kg/dose every 6-8 hours.

Comments

Can cause gastric irritation.

5. Naproxen

Dose Rate

P.O.: Adults: 500 mg/dose initially, then 250 every 8-12 hours. Children: 10 mg/kg/day (5 mg/kg every 12 hours).

Comments

Long duration of action. Can cause gastric irritation.

6. Indomethacin

Dose Rate

P.O.: Adults: 25 mg/dose every 8 hours. Children: 1-3 mg/kg/day given 3-4 times.

Comments

Contraindicated in psychiatric, neurologic, renal diseases. High incidence of gastric irritation. Useful in gout.

* If the pain is relieved for 3 to 4 hours, administer an oral narcotic and observe for 1 hour. If moderate or severe pain returns, repeat the parenteral narcotic dose and observe. When pain is under control, give an adequate dose of an effective oral narcotic analgesic, if feasible, using equi- analgesic dosing guidelines. If relief is maintained, discharge the patient with a small prescription and follow up within 1 week. If significant pain persists, admit the patient to the hospital. A final dose of parenteral narcotics "for the road" is not recommended.

* Most hospitals have guidelines for the duration of a patient's stay in the emergency department. These may be difficult rules to follow in the case of patients with painful crises. Holding areas for sickle cell disease are recommended to avoid unnecessary hospitalizations. Each patient's management plan should be individually designed.

Patients who require continuing treatment with parenteral narcotics or who cannot take adequate amounts of fluid orally require hospital admission.

INPATIENT MANAGEMENT

A management plan should be developed by the responsible physician, written in the hospital record, and discussed with the patient and other personnel involved in the patient's management. It is important to record this information on a regular basis in the hospital record and to help the patient develop coping skills. A pain measurement and description tool that evaluates pain intensity, mood, distress, and anatomic distribution should be used along with a sedation (level of consciousness) scale.

Fluid intake and urinary output should be monitored carefully, and patients should be weighed daily. Due to the high risk of acute chest syndrome, incentive spirometry and pulse oximetry may be useful. The proper composition of the fluids should maintain adequate electrolyte balance.

Standard pain management with parenteral narcotics should be given by a patient-controlled technique. If a titration technique has not been instituted in the emergency department, it should be initiated when the patient is admitted to the floor and pain is not controlled. If PCAs are not used, narcotics should be given on a fixed schedule (not as needed for pain), with rescue dosing for breakthrough pain as needed. Except when contraindications exist, concomitant use of NSAIDs should be standard treatment. Nurses should be instructed not to give narcotics if the patient is heavily sedated or respirations are depressed. When the patient shows signs of improvement, narcotic drugs should be tapered gradually to prevent a withdrawal syndrome. It is usually advisable to observe the patient on oral pain-relief medications for 12 to 24 hours before discharge from the hospital.

There are several new methods for administering narcotics such as transdermal and epidural administration of morphine. New methods of narcotic administration may be attempted in institutions where there is expertise in their use, where adequate monitoring is available, and appropriate use of standard techniques has not resulted in acceptable pain control.

ALTERNATIVE PAIN MANAGEMENT TECHNIQUES

Behavior modification programs, relaxation therapy, self- hypnosis, and transcutaneous electrical nerve stimulation may