Focus On... Critical Decisions: Pediatric Sickle Cell Disease, Part I

By Bernard L. Lopez, MD, MS, and Cynthia Obi, MD

From the EM Model
8.0 Hematologic Disorders
8.5 Red Blood Cell Disorders

Bernard L. Lopez, MD, MS, and Cynthia Obi, MD, wrote “Pediatric Sickle Cell Disease.” Dr. Lopez is professor and vice chair of Academic Affairs, in the Department of Emergency Medicine, and associate dean for student affairs and career counseling at Jefferson Medical College in Philadelphia, Pennsylvania. Dr. Obi is an emergency physician at Methodist West Houston Hospital, Katy, Texas. Robert C. Solomon, MD, is Medical Editor of ACEP News and editor of the “Focus On… Critical Decisions” series, core faculty in the emergency medicine residency at Allegheny General Hospital, Pittsburgh, Pennsylvania, and assistant professor in the Department of Emergency Medicine at Temple University School of Medicine, Philadelphia. Mary Anne Mitchell is an ACEP staff member who reviews and manages the ACEP “Focus On… Critical Decisions” series.

Disclosures
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, all individuals in control of content must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.

Dr. Lopez, Dr. Obi, Dr. Solomon, and Ms. Mitchell have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this article. There is no commercial support for this activity.

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). The American College of Emergency Physicians is accredited by the ACCME to provide continuing medical education for physicians.

The American College of Emergency Physicians designates this enduring material for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

"Focus On… Critical Decisions: Pediatric Sickle Cell Disease" is approved by the American College of Emergency Physicians for 1 ACEP Category I credit.

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Objectives
On completion of this lesson, you should be able to:
1. Identify the common and life-threatening emergency department presentations of sickle cell disease (SCD) in children.
2. Describe the diagnosis and management of acute chest syndrome.

Sickle cell disease (SCD) is a hereditary hemoglobinopathy that is characterized by anemia and a wide array of pathology secondary to intermittent small blood vessel occlusion. It is estimated that 1 in 600 African Americans in the United States has the disease; in addition, SCD can be seen in people of Indian, Mediterranean, and Middle Eastern descent. Children with SCD presenting to the emergency department represent a unique challenge. Even though vasoocclusive crisis (VOC) is the most common presentation, there is a much higher incidence of potentially life-threatening pulmonary, central nervous system, gastrointestinal, and infectious complications in children because of the unique anatomic and physiologic characteristics of children. This, along with the challenges in obtaining an accurate history and physical examination, makes it important that emergency physicians understand the complexities of SCD in children.

Pediatric Sickle Cell Anemia
Acute Vasoocclusive Crisis
VOC is the hallmark of SCD and is the most common emergency department presentation of the pediatric patient, representing over 90% of all visits.1 VOC is due to ischemia or infarction of tissue that results from the sludging of sickled and nonsickled RBCs within the microvasculature and results in the mild to severe pain seen in this crisis.
Although a number of biologic (infection, dehydration, menstruation, physical exertion, hypoxia), environmental (change in ambient temperature), and emotional (anxiety, depression) precipitants for VOC exist, most VOC occurs spontaneously, and the cause is often not identified.

CRITICAL DECISION
What are the findings associated with clinically significant complications of sickle cell disease in children?

Preverbal children may present with fussiness, inconsolable crying, altered sleep patterns, or diminished feeding. Verbal children typically describe pain in almost any part of the body. It is most commonly seen in the chest, abdomen, low back, and extremities. In typical acute VOC, the pain in the spine, long bones, and chest is thought to occur from bone marrow ischemia as well as bone marrow hyperplasia (secondary to enhanced RBC production). The patient and/or caregiver may note similar patterns of pain in location and severity from crisis to crisis and may thus be able to describe whether the current episode is “typical.” The pattern can mimic other emergent conditions (acute abdomen, pulmonary embolus, renal colic), making diagnosis more challenging. The duration of a painful crisis varies but is typically 4 to 6 days. Some patients, however, can experience pain for weeks and could return to the emergency department for multiple visits during this time. Although most patients with SCD are able to manage their pain as outpatients, 10% to 20% have pain severe enough to require emergency department treatment and possible inpatient care.2

Anemia
Anemia can result from increased hemolysis due to the fragility of sickled RBCs. Hyperhemolytic crisis is characterized by increased destruction of RBCs and can be seen in VOC or with associated infection. Decreased hemoglobin, increased reticulocyte count, increased bilirubin, and increased lactic dehydrogenase are typical laboratory findings. Aplastic crisis occurs when RBC production is suppressed. There is variability in the decrease in hemoglobin, and the reticulocyte count is typically less than 2%. Infection is the most common etiology, with parvovirus B-19 as the most common agent. Aplastic crisis can also serve as the trigger for a VOC episode.3

Dactylitis
Dactylitis (or hand-foot syndrome) is the earliest clinical manifestation of SCD. It occurs most commonly in children between the ages of 6 months and 2 years. Dactylitis often presents with acute, symmetric, painful swelling of the dorsal part of the hands and feet and is caused by ischemia and infarction of the bone marrow. The edema is nonpitting and involves the soft tissue over the metacarpals and metatarsals and the proximal phalanges of the hand and feet. It occurs in these areas in this age group because hematopoiesis occurs in these peripheral areas. As children age, hematopoiesis shifts to more central locations such as the arms or legs. Patients can be febrile, and the physical examination will show erythema, warmth, and tenderness. Radiographs typically do not demonstrate bony abnormalities. Interestingly, patients who develop dactylitis before 12 months of age are 2.6 times as likely to develop severe SCD during their lives.4

Infection
SCD patients are particularly at risk for infection by organisms such as Pneumococcus, Staphylococcus species, Haemophilus influenzae, and Salmonella. Children can present with signs of pneumonia, urinary tract infection, or meningitis. Children with SCD have a several hundred-fold higher risk for sepsis than healthy children. The risk for overwhelming sepsis is highest before age 3.5

Stroke
Children with SCD are at increased risk for stroke, with a 400-fold increase in cerebral infarction when compared to patients without the disease.6 Stroke incidence peaks between 4 and 6 years of age, and it is estimated that 10% of all SCD patients will suffer a stroke by age 20.7 Although a variety of neurologic deficits can be found (based on the area of insult), hemiplegia is the most common physical examination finding, followed by focal seizures. Additional findings include any focal neurologic deficit, headache, seizure, and change in mental status.

Splenic Sequestration
The abdomen is the second most common site of pain in SCD after the musculoskeletal system. The spleen serves as a filter for abnormal RBCs and is one of the first organs to suffer from the effects of intravascular sickling. Children between 5 months and 2 years are the most vulnerable to acute splenic sequestration crisis, a condition in which the spleen acutely sequesters large numbers of RBCs. This results in obstruction of venous outflow from the spleen, leading to pooling of red cells and platelets within the spleen. Diminished flow leads to an acidotic environment, further sickling, increased blood viscosity, and further obstruction.
Acute splenic sequestration is characterized by a rapid fall in hemoglobin, a rise in reticulocyte count, a fall in platelet count, acute pain and tenderness in the left upper quadrant with sudden increase in the size of the spleen, and signs and symptoms of hypovolemia.7 Splenic sequestration varies in severity from mild to life threatening.

Gallbladder Disease
Cholelithiasis is a relatively common occurrence in HbSS SCD patients because of repeated episodes of hemolysis with resultant bilirubin gallstone formation. The onset of cholelithiasis begins by age 4, and prevalence increases with age. Gallstones develop in approximately 30% of patients with SCD by age 18.7 Cholecystitis should be considered in SCD patients with abdominal pain; choledocholithiasis should be considered in patients with signs and symptoms of cholangitis or pancreatitis.
Intrahepatic cholestasis describes the reduction or complete prevention of bile excretion from the liver. In the SCD patient, this can result from erythrocyte sickling within the liver sinusoids, which leads to hepatic ischemia.8 Two types of intrahepatic cholestasis can be seen in patients with SCD. Most common is benign cholestasis (benign hyperbilirubinemia), in which the patient’s only symptoms are jaundice and possibly pruritus. It is a self-limited process that resolves without any particular therapy. Progressive cholestasis, on the other hand, although quite rare, has an extremely high mortality rate. These patients will present with right upper quadrant abdominal pain, fever, nausea, vomiting, and jaundice. They can develop a bleeding diathesis, encephalopathy, and renal failure. Abdominal examination reveals hepatomegaly with a tender right upper quadrant. Patients can become coagulopathic because of reduced synthesis of coagulation factors with resulting elevation of prothrombin and partial thromboplastin times. In progressive cholestasis, hepatic ischemia affects all aspects of liver function, which helps to explain its extremely high mortality rate and many symptoms.

Priapism
Priapism is a prolonged (4 hours or longer), painful erection caused by failure of timely penile detumescence. The mean age at which it occurs is 12 years, and it has been estimated that up to 90% of male patients with SCD will experience at least one episode by age 20.7 Untreated priapism can lead to cellular damage, fibrosis, and impotence.9

CRITICAL DECISION
Is it pneumonia, pulmonary infarction, or acute chest syndrome?

Acute chest syndrome is the most common cause of death, the leading cause of admission to an ICU, and the second most common cause (after VOC) of hospitalization in children with SCD.10,11 The classic findings in acute chest syndrome are chest pain, hypoxia, fever, and a chest radiograph with new pulmonary infiltrates. Other findings include cough, dyspnea, and wheezing. Acute chest syndrome can be easily confused with pneumonia, pulmonary infarction, and pulmonary embolism. With severe presentations, it can even be confused with acute respiratory distress syndrome (ARDS). Acute chest syndrome tends to present 2 to 3 days after an episode of VOC; however, it can also present simultaneously with an acute infection. It can be difficult, if not impossible, for emergency physicians to distinguish among pneumonia, pulmonary infarction, and acute chest syndrome. The etiology of acute chest syndrome is multifactorial and includes both infectious and noninfectious causes, and it has been postulated that pneumonia and lung infarction are precipitants of acute chest syndrome.12 Infectious agents include Streptococcus pneumoniae, H. influenzae, and Klebsiella pneumoniae. Noninfectious causes include pulmonary microvascular sludging, in situ pulmonary vascular thrombus formation, pulmonary parenchymal infarction, and bone marrow fat embolization.

Summary
Understanding SCD is crucial for any emergency physician who treats patients of African or Mediterranean descent. Children with SCD represent a unique challenge, given the potential for life-threatening pulmonary, central nervous system, gastrointestinal, and infectious complications associated with the unique anatomic and physiologic characteristics of children. The additional challenge posed by the difficulties in obtaining an accurate history and physical examination makes it important that emergency physicians understand the complexities of SCD in children.

Editors Note: In next month’s ACEP News we will continue our discussion of SCD in children, focusing on the evaluation and management of this disorder.

References
1. Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am. 2005;19:785-802.
2. Ballas SK. Complications of sickle cell anemia in adults: guidelines for effective management. Cleve Clin J Med. 1999;66:48-58.
3. Okpala I. The management of crisis in sickle cell disease. Eur J Haematol. 1998;60:1-6.
4. Fixler J, Styles L. Sickle cell disease. Pediatr Clin North Am. 2002;49(3):1193-1210.
5. Riddington C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev. 2002;3:CD003427.
6. Switzer JA, Hess DC, Nichols FT, Adams RJ. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006;5:501-512.
7. Wilson RE, Krishnamurti L, Kamat D. Management of sickle cell disease in primary care. Clin Pediatr. 2003;6:753-761.
8. Banerjee S, Owen C, Chopra S. Sickle cell hepatopathy. Hepatology. 2001;33:1021-1028.
9. Smith JP. Sickle cell priapism. Hematol Oncol Clin North Am. 1996;1363-1371.
10. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. 1994;84:643-649.
11. Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med. 2008;359:2254-2265.
12. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342(25):1855-1865.

 

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