Emergencies in Patients With Inherited Hemoglobin Disorders—An Emergency Department Perspective

Emergencies in Patients With Inherited Hemoglobin Disorders—An Emergency Department Perspective Rebecca Hampton, MD*z, Vinod Balasa, MDyz, Sheryl E. Allen Bracey, MD, MSTz

Hemoglobin (Hb) disorders presenting to the emergency department (ED) can be a diagnostic and management problem if not properly recognized. It is important to understand the nomenclature and pathophysiology of these entities. Common Hb disorders presenting to the ED include sickle cell disease, thalassemias, and methemoglobinemia. Complications of sickle cell disease comprise the majority of illness from Hb disorders seen in the ED or outpatient setting. These complications include pain crisis, sepsis, acute chest syndrome, and cerebrovascular accidents. Rapid diagnosis and treatment are necessary to minimize morbidity and mortality. In a case-based format, the clinical presentation, assessment, and management of the above will be discussed to help clinicians practice in an evidence-based fashion. Clin Ped Emerg Med 6:138-148 ª 2005 Elsevier Inc. All rights reserved. KEYWORDS hemoglobin disorders, sickle cell disease, thalassemias, methemoglobinemia

I

nherited hemoglobin (Hb) disorders are widely prevalent, and it is estimated that approximately 7% of the world’s population are carriers of such disorders [1]. Although these conditions occur most commonly in tropical regions, population migrations have ensured that they are now encountered in many regions of most countries. The clinical manifestations of these disorders are quite varied, and as a result, these inherited Hb disorders can create diagnostic and management dilemmas in the emergency department (ED). The first step is to understand the nomenclature and pathophysiology of these entities. All normal Hb’s are tetramers of 2 pairs of dissimilar globin chains. Inherited Hb disorders can be classified into 2 main categories—the structural Hb variants and the thalassemias [2]. The structural Hb variants mostly occur from a genetic defect that results in abnormal structure of 1 of the globin chains in the Hb molecule [3]. The majority of these hemoglobinopathies are the result of point mutations in the globin chains and other changes, such as amino acid substitutions, deletions, insertions, extended chains, and fusions. Although more than 700 structural Hb variants have been identified, only 3 (Hb S, Hb C, and Hb E) reach high-enough frequencies to impact on clinical popula-

138

tions [1]. Table 1 lists the clinical relevance of these entities. The effect of these defects varies from clinically insignificant to very significant, depending on the disease, and is further discussed in the following sections. The most prevalent among these structural variants is Hb S, which results from a substitution in codon 6 of the b-globin gene, specifying the insertion of valine in place of glutamic acid in the b-globin chain [4]. The following 3 cases will illustrate clinical presentations of sickle cell disease (SCD) and their ED management and treatment.

Case 1 Patient A, a 16-year-old African-American boy with a history of SCD presented to the ED with a 3-day history TDepartment of Emergency Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229. yDivision of Hematology/Oncology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229. zDivision of Emergency Medicine, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. Reprint requests and correspondence: Rebecca R. Hampton, MD, Department of Emergency Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229.

1522-8401/$ - see front matter ª 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2005.06.002

Emergencies in patients with inherited hemoglobin disorders Table 1

139

Clinically significant hemoglobinopathies.

Hemoglobinopathy Hb S Hb C Hb E Hb M Methemoglobinemia

Mutation Location

Clinical Manifestations

A2 b 2S A2 b 2C

b -Chain b -Chain b -Chain

a -Chain or b -chain heme iron in oxidized form Fe3+ Absence of reductive pathways, NADH-cytochrome b5 reductase deficiency

of fever, cough, and breathlessness. Five days prior, he had been evaluated and treated for severe pain in his legs and arms at the same ED. He complained of persistent and worsening pain in both his lower extremities and pain in his chest, in spite of oral narcotic therapy. His medical history included multiple vasoocclusive, painful crises, including an episode of priapism, and he had received multiple blood transfusions over his lifetime. On examination, the patient was febrile to 39.18C, diaphoretic, and uncomfortable. He had a heart rate of 80 beats per minute and a blood pressure of 116/84 mm Hg. His conjunctivae were icteric; his mucous membranes were moist, and there was no cyanosis. Cardiovascular examination revealed positive S1 and S2 with a II/VI systolic ejection murmur. He was tachypneic with a respiratory rate of 26 breaths per minute and had labored respiration with suprasternal and intercostal retractions. Auscultation of his lungs demonstrated a shallow respiratory effort, decreased breath sounds in the right midzone and lower zone, and scattered crepitations on the right side. There was no lower extremity edema or pain upon dorsiflexion of his ankles. Abdominal examination revealed no tenderness to palpation and no organomegaly. He was alert and oriented, and his mood was anxious. His oxygen saturation by pulse oximetry was 89% and improved to 94% with supplemental oxygen of 6 L/min via face mask. Laboratory investigations included a complete blood count which revealed a white blood cell count of 17 500/AL with 62% neutrophils, 25% lymphocytes, 9% monocytes, 2% eosinophils, 1% basophils, and 1% atypical lymphocytes. The Hb was 8 g/dL, with a reticulocyte count of 25% and a platelet count of 206 000/AL. A chest x-ray revealed a right lower-lobe consolidation with a moderately sized right pleural effusion. An arterial blood gas analysis performed in the ED on room air showed hypoxemia and metabolic acidosis with an oxygen saturation of 90%, Po2 59 mm Hg, Pco2 29 mm Hg, pH 7.32, and Hco3 13. In the ED, he received antipyretics and supplemental oxygen and was started on antibiotic therapy with cefotaxime 2 g IV, and a packed red blood cell transfusion was initiated after 20 mL/kg of normal saline was infused. Over the next hour, while waiting for a bed to become

Hemolytic anemia, vasoocclusive crisis Mild hemolytic anemia, splenomegaly Benign mild hemolytic anemia and mild splenomegaly, common in Southeast Asians Cyanotic at birth, hemolytic anemia Cyanosis, blood is brown in color

available in the intensive care unit, the nurse noticed that the patient’s oxygen saturation continued to worsen, and he was hypoxic even on supplemental oxygen of 12 L/min via nonrebreather mask. A repeat arterial blood gas analysis revealed severe respiratory acidosis with an oxygen saturation of 88%, Po2 54 mm Hg, Pco2 59 mm Hg, pH 7.17, and Hco3 5. He underwent emergency intubation using rapid sequence intubation, and a repeat chest x-ray performed to check the placement of the endotracheal tube revealed bilateral infiltrates in the midzone and lower zone, along with an increase in the previously noted right-sided pleural effusion. The patient was transferred to the intensive care unit, and a second unit of packed red blood cells was transfused. A diagnostic pleural tap was performed which demonstrated an exudative fluid. The resulting Gram stain and culture were negative. His clinical condition stabilized, and his antibiotic coverage was widened with the addition of azithromycin. Over the next 5 days, the patient was slowly weaned off the ventilator and was extubated on day 6 of hospitalization and had normal oxygen saturation of greater than 93% on room air by day 9, associated with a significant improvement in his pleural effusion. He was discharged from the hospital on day 12 in good condition.

Case 2 Patient B is a 9-month-old African-American girl brought to the ED with a history of being extremely fussy and irritable for 2 days and a fever of 1-day duration. The mother also stated that the child had decreased oral intake for the past 4 days and, upon further questioning, revealed that the child’s 6-year-old brother was having a sore throat and fever for the past week. Medical history was unremarkable except for an ED visit to a community hospital in another state at 5 months of age for swelling of the child’s fingers. The child had been prescribed analgesics, and the symptoms had resolved. As the family was of a poor economic status, they had been moving periodically to different towns and cities in search of stable employment. The mother stated that the child had received some bshotsQ but was unable to provide any specific information regarding immunization status.

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140 There was no family history of any major medical illnesses or anemia, according to the mother. The child was not receiving any medications at home. On examination, the child was pale and listless and was responding poorly to verbal but appropriately to painful stimulation. Vital signs included a temperature of 39.58C, heart rate of 142 beats per minute, respiratory rate of 42 breaths per minute, and blood pressure of 94/68 mm Hg. The child was mildly dehydrated, and both the length and weight were between the 10th and 25th percentiles for age. The tympanic membranes were normal in appearance, and the tonsils were not enlarged or inflamed. There was no significant cervical or other peripheral lymphadenopathy. Examination of the cardiovascular system revealed tachycardia and a grade II/VI systolic ejection murmur. The lungs were clear to auscultation. Abdominal examination was remarkable for splenomegaly, with the spleen palpable 3 cm below the left costal margin. The extremities were well perfused with a capillary refill time of less than 2 seconds. There were no signs of meningeal irritation. A fluid bolus of 20 mL/kg of normal saline was administered over 30 minutes; blood was obtained for counts, electrolytes, liver profile, and culture, and a dose of ceftriaxone (50 mg/kg) was administered intravenously. Laboratory studies revealed a white blood cell count of 12 600 with a differential count of 67% neutrophils, 28% lymphocytes, 4% monocytes, and 1% eosinophils. The Hb was 7.3 g/dL, and the platelet count was 324 000. The peripheral smear was reported to show anisocytosis, fragmented red cells, and 2+ sickling. The liver profile was remarkable for a mild elevation of unconjugated bilirubin, and the electrolytes were within the reference range. A second fluid bolus of 20 mL/kg of normal saline was administered for mild hypotension. Blood pressure improved, and the child was transferred to the ward for further management. Within 4 hours, the child developed severe hypotension with persistent fevers. The child was administered packed red blood cells, fluids, and pressor support with dopamine and dobutamine in the intensive care unit. The child’s cardiovascular status continued to deteriorate, and the child expired approximately 8 hours after admission. The family refused an autopsy, and on the next day, the laboratory reported gram-positive cocci from the blood culture; the organism was subsequently identified as Streptococcus pneumoniae.

Case 3 A 4-year-old boy with a history of SCD was brought to the ED with a sudden onset of decreased ability to move his left upper extremity upon waking from a nap. There was no history of trauma, seizures, loss of consciousness, fever, or any other symptoms in the past few days. The medical history was remarkable for having been confirmed to have SCD in infancy, based on a strong

family history of SCD. He had regular follow-up in the sickle cell clinic and was receiving penicillin prophylaxis. His previous SCD-related complications included 2 episodes of febrile illness, 1 episode of splenic sequestration, 3 episodes of pain, and an episode of acute chest syndrome 2 weeks before this presentation. He had received a packed red blood cell transfusion during the recent hospitalization for acute chest syndrome. On examination, the child was alert and responded appropriately to questions. He was well hydrated, anicteric, and afebrile. His vital signs included a heart rate of 76 beats per minute, respiratory rate of 18 breaths per minute, and blood pressure of 100/70 mm Hg. Examination of his cardiovascular and respiratory systems and abdominal examination revealed no clinical abnormalities. Neurological examination revealed intact cranial nerves and a normal gait. His left upper extremity showed increased tone with some weakness (grade 3 of 4—full range of motion against gravity). The other extremities revealed normal tone and strength. No sensory deficits were noted. Laboratory investigations revealed normal electrolytes, glucose, liver, and renal profiles. His white blood cell count was 7300 with a normal differential, the Hb was 8.4 g/dL, and the platelet count was 400 000. A computed tomography scan of the brain was obtained emergently and revealed no abnormalities. He was admitted to the intensive care unit, and red blood cell apheresis was performed with Hb S– negative red blood cells with a target hematocrit of 30%. The child remained clinically stable, and his left upper extremity weakness resolved over 48 hours. He was discharged home and was scheduled to receive long-term transfusion therapy to prevent recurrent intracerebral vascular complications.

Case 1: Discussion One of the most clinically relevant and prevalent hemoglobinopathies is SCD. SCD is an autosomal recessive genetic disease of Hb synthesis as a result of a single–amino acid substitution in the b-globin chain of the Hb molecule, specifically, valine for glutamate [4,5]. The Hb S gene is found predominantly in people of African origin (40%), which includes 8% of African Americans [4]. Because the disease requires 2 alleles for sickle cell, this unfortunately leads to a rate of 0.15% of African-American newborns who are homozygous (SS) for the disease. The gene is also found (less frequently) in individuals from the Mediterranean, Middle East, and India. The gene is established in tropical African populations because its expression in heterozygotes, known as sickle cell trait, protects against malaria. This differs from the homozygous expression (SCD), which is a hemolytic anemia and vasoocclusive condition [3]. The pathophysiology of the disease dictates its severity and clinical manifestations. The majority of SCD in the

Emergencies in patients with inherited hemoglobin disorders United States is comprised of 4 genotypes: sickle cell anemia (Hb SS), sickle Hb C disease (Hb SC), and 2 types of sickle b thalassemia, Sb + thalassemia and Sb 0 thalassemia. Children with Hb SS and Sb 0 thalassemia usually have more severe disease, as seen in Table 2. SCD is a complex disease affecting a number of organ systems, resulting in acute and chronic manifestations of the disease. It is important for ED clinicians to recognize these manifestations. Table 3 shows an extensive list of clinical manifestations of SCD during childhood and adolescence. Acute illness in SCD patients often presents like other common childhood illnesses, with signs and symptoms including fever, cough, and abdominal pain. However, in this group of patients, these symptoms are frequently not benign and cannot be overlooked. Delaying treatment for SCD patients can significantly increase their morbidity and mortality [7]. One of the most common symptoms of SCD is vasoocclusive events or pain crises. These crises are characterized by severe excruciating pain caused by sickle-shaped red blood cells trapped in small blood vessels causing localized ischemia. Triggers for pain crises include dehydration, fever, cold exposure, and emotional stress [8]. Therapy includes intravenous/oral hydration in dehydrated patients and pain management in the form of nonsteriodal anti-inflammatory drugs, such as ketorolac, and opiates such as morphine. It is key to use sufficient doses of medication to significantly reduce the pain and to use the clinical information from the family on what worked best for their child in past episodes to insure clinical improvement acutely. Opiates should be given intravenously for rapid onset of action and given in frequent fixed intervals to avoid underdosage and inadequate pain control. It is useful to assess pain in a standard manner using pain measurement scales [9]. Older children and adults requiring inpatient therapy are candidates for patient-controlled analgesia for optimal management of pain. It is important to remember that these patients deal with pain on a daily basis. As a physician, it is important not to judge how comfortable the patient looks, but to ask for the patient’s input when assessing the patient’s pain so that proper pain management will occur. Table 4 shows an algorithm for the Table 2

Complications of Hb SS, Hb SC, and thalassemia.

Complications Acute chest syndrome Infection Priapism Severe anemia Splenic sequestration Stroke

Hb db + Hb db 0 Hb SS Hb SC Thalassemia Thalassemia ++++

++++

++++

++

++++ ++++ ++++ ++++

++++ ++++ ++++ ++++

+++ ++++ +++ ++

+ ++ + 0

++++

++++

++

0

Data from Quirolo and Vinchinsky [6].

141 Table 3 Clinical manifestations of SCD during childhood and adolescence. Acute Manifestations Acute chest syndrome* Aplastic crisisT Bacterial sepsis or meningitis* Recurrent vasoocclusive pain Splenic sequestration* Stroke* Priapism Chronic Manifestations Anemia Jaundice Splenomegaly Functional asplenia Cardiomegaly and functional murmurs Hyposthenuria and enuresis Proteinuria Cholelithiasis Restrictive lung disease* Pulmonary hypertension Avascular necrosis Transfusional hemosiderosis* *Potential cause of morbidity/mortality (American Academy of Pediatrics [AAP] Section on Hematology/Oncology Committee on Genetics [7]).

management of pain in sickle cell crisis. The following pictogram in Figure 1 depicts the pathophysiology of sickle formation [9]. As demonstrated in Case 1, acute chest syndrome is 1 of the most serious and life-threatening complications of SCD, making it the leading cause of mortality and morbidity in affected patients, since the impact of more effective antimicrobials and the pneumococcal vaccine [12]. Patient A demonstrated symptoms that cannot be ignored in SCD: fever, cough, breathlessness, and recent pain crisis. Acute chest syndrome is caused by a vasoocclusive crisis involving the pulmonary vasculature. As a result, patients usually have chest pain, fever, cough, tachypnea, dyspnea, and hypoxemia. The clinical manifestations are often not distinguishable from pneumonia on chest x-ray (Figure 2) [8]. Laboratory findings in acute chest syndrome include an increased white blood cell count and infiltrate on chest radiographs. Chest x-rays may be normal early in the illness course. As demonstrated in Case 1, in severe cases, the clinical deterioration may be rapid and severe. In the ED, these patients should be closely monitored and should receive supplemental oxygen and/or ventilatory support, and blood must be sent for type and crossmatch. Reducing the percentage of sickled Hb is important. Early transfusion and, in some instances, total blood volume exchange transfusions are necessary for patients who do not improve or have worsening hypoxia [8,14]. Intravenous fluids for hydration and analgesics should be used with caution as not to cause pulmonary edema and respiratory depression.

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142 Table 4

Management of vasoocclusive crisis in SCD.

Mild or Moderate Pain Crisis Hydration: 1.5 maintenance with either oral (if tolerated) or IV fluids. IV fluid options include D5 (5% dextrose) 1/4 NS and D5 1/2 NS Analgesia: nonsteroidal analgesia with or without codeine Admission criteria: Admit if pain worsens, oral fluid intake is inadequate, or repeat visits to the ED have occurred Severe pain crisis Hydration: 1.5 maintenance with IV D5 1/4 NS or D5 1/2 NS Analgesia: morphine sulfate, 0.10-0.15 mg/kg IV Admission criteria: admit unless pain is markedly reduced and patient can take oral fluids

otitis media, is diagnosed. The child with SCD that presents with a fever greater than 38.58C should receive a blood culture, a complete blood count with reticulocyte

NS indicates normal saline. Data from Cohen [10] (Table 77.3).

The etiology of acute chest syndrome is still controversial. It is thought to be caused by either infection or pulmonary fat emboli (infarction), or both [12,14]. Infection can develop from a variety of gram-positive and gram-negative pathogens such as S pneumoniae or Haemophilus influenzae B [8]. Recent data have shown Mycoplasma pneumoniae to be more commonly associated with acute chest syndrome. SCD patients with pulmonary complications need to be identified early because they may progress rapidly to respiratory failure [7,12]. Aggressive broad antibiotic coverage is necessary. Treatment with an antibiotic from the macrolide class, as well as a third-generation cephalosporin, is generally recommended [15]. Incentive spirometry should be encouraged to avoid pulmonary atelectasis and hypoxia secondary to splinting caused by chest pain and thoracic bone infarction. [16] Current medical literature suggests that sickle cell patients with acute chest syndrome have thoracic bone infarction secondary to vasoocclusion of thoracic bone marrow leading to life-threatening pulmonary infiltrates [16]. The incidence of infiltrates and atelectasis is reduced in patients who receive incentive spirometry [16].

Case 2: Discussion Children with SCD, especially younger children, are at risk for septicemia, which is an important cause of mortality and morbidity [17,18]. These children are at risk because of impaired immunologic function that is caused by splenic dysfunction. Impairment of splenic function can occur in infants as young as 3 months. Children with SCD are at risk for severe infections with encapsulated organisms such as S pneumoniae and H influenzae. Therefore, children with SCD presenting with fever should be managed aggressively assuming the presence of serious bacterial infection [17]. Fever in this vulnerable group cannot be considered benign, even if a focus of infection, such as upper respiratory infection or

Figure 1 Sickle cell formation. Reprinted with permission from electronic file of New England Journal of Medicine online images [11].

Emergencies in patients with inherited hemoglobin disorders

Figure 2 Chest x-ray findings of acute chest syndrome. Reprinted with permission from New England Journal of Medicine [13].

count, chest x-ray (when clinically indicated), and antibiotic therapy [18]. All infants younger than 6 months and girls younger than 1 year should have a sterile urine obtained. Recommended antibiotic therapy by expert committees includes a third-generation cephalosporin; ceftriaxone, or cefotaxime [17]. If there is a high index of suspicion, vancomycin should be added to protect against penicillin-resistant strains of S pneumoniae until culture results become available. Once antibiotic therapy is initiated, previous studies have shown that patients can be managed either in an inpatient or an outpatient setting, based on their risk of complications. A study by Wilimas et al [17] found that sickle cell patients who are considered to be at low risk for sepsis can be safely managed in an outpatient setting lowrisk patients were nontoxic-appearing, with a reassuring white blood cell count (between 5000 and 30 000), temperature less than 408C, and absence of pulmonary infiltrates, and a reassuring Hb. In this scenario, low-risk patients are given ceftriaxone (75 mg/kg per dose up to 2 g) after obtaining a complete blood count, reticulocyte count, and a blood culture and are sent home to follow-up with a physician in 24 hours for reevaluation. Conversely, highrisk patients are managed in an inpatient setting, with transfer to intensive care as needed. Patients who do progress to septic shock should be managed accordingly with adequate oxygenation, aggressive intravenous fluids and blood products, and inotropic agents as required. In summary, all SCD patients with fever must be managed with extreme caution because of the risk of overwhelming bacteremia which can rapidly lead to septic shock. Alternatively, those patients deemed to be low risk can still be managed conservatively (after obtaining blood counts and blood culture and administration of antibiotics) in an outpatient setting with close follow-up.

Case 3: Discussion Stroke or cerebrovascular accident is a major complication of SCD, affecting approximately 10% of affected children,

143 and is a leading cause of death and disability in both children and adults [19]. Patients at greatest risk for stroke are those with sickle cell genotype SS [19] Peak age of presentation of stroke in the pediatric population is between 4 and 6 years [19]. Anatomically, the most common cause of brain infarction is blockage of the intracranial internal carotid and middle cerebral arteries. Fortunately, patients with stroke usually present with obvious signs such as acute hemiparesis, aphasia or dysphasia, seizures, severe headaches, cranial nerve palsy, altered mental status, or coma [20]. Of all these symptoms, the most common tends to be hemiparesis. Although cerebrovascular accidents typical have a dramatic presentation, on many occasions, presentation can be very subtle, such as a slight limp. Occasionally, the neurological symptoms may be transient and may not be present on physical examination, that is, transient ischemic attacks. Although most strokes strike without warning, some children may experience severe headaches before the onset of neurological symptoms. Many times, in SCD patients, it is difficult to distinguish weakness from pain in a sickle cell crisis, from weakness secondary to stroke. As a result, the clinician should have a high index of suspicion for stroke in a patient with any new neurological finding on physical examination. Initial laboratory analysis includes a complete blood count with reticulocyte count, and type and crossmatch, for possible blood or exchange transfusion. Imaging includes noncontrast computed tomography and/or magnetic resonance imaging of the head to rule out acute intracranial hemorrhage, assess for obstructive hydrocephalus, and assess for lateralizing signs as a prodrome to possible herniation [7,20]. Magnetic resonance angiography has been found to be diagnostic in assessing cerebrovascular pathology [16,20]. In regard to prevention, transcranial Doppler ultrasonography is a useful screening tool for identifying sickle cell patients at risk for first or recurrent stroke. In addition, the institution of long-term transfusion therapy in high-risk individuals has been demonstrated to be effective in significantly decreasing the risk of stroke [20,21]. Initial therapy for sickle cell–mediated cerebrovascular accident is immediate 1.5- to 2-fold volume exchange transfusion in an intensive care unit setting to reduce Hb S to less than 30% of total Hb. After acute clearance of symptoms or as the stroke evolves, there is a significant risk of reoccurrence. For this reason, these patients should be started on a longterm transfusion therapy. Studies have shown that patients not on a long-term transfusion program have an 80% chance of recurrent stroke within 3 years of the initial event [20]. Long-term transfusion involves regularly scheduled blood transfusions aimed at reducing the percentage of Hb S and not at normalizing the Hb level. Special attention should be made not to aggressively transfuse to obtain a bnormalQ Hb level because this may

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144 increase blood viscosity and increase the risk for stroke. Long-term use of blood transfusions is not a benign intervention, and significant numbers of these patients sustain complications including infections, transfusion reactions, red cell alloimmunization, and iron overload.

Other Complications of SCD SCD can be associated with several other complications such as splenic sequestration, aplastic crisis, priapism, and other serious bacterial infections such as osteomyelitis [22]. Splenic sequestration is an acute illness and is characterized by a sudden enlargement of the spleen, caused by large volumes of blood (mainly sickled cells) entrapped in the spleen. As a result, Hb levels may fall acutely more than 2 g/dL less than the patient’s normal value, causing circulatory compromise [7]. Prompt diagnosis and therapy with red blood cell transfusions are therefore crucial to prevent hypovolemic shock. Surgical splenectomy may be indicated in certain patients to prevent recurrences [15]. Aplastic crisis is a phenomena caused by temporary cessation of red cell production in children with SCD, with a corresponding decrease in the reticulocyte count. Most cases, approximately 80%, are thought to be caused by human parvovirus B19 [15,23]. Diagnosis is made by comparing baseline blood and reticulocyte counts to those obtained during the acute illness. Therapy is initiated if the patient is symptomatic, that is, tachypnea, tachycardia, or hypoxia. Therapy includes simple blood transfusion to raise serum Hb back to the patient’s baseline and to prevent heart failure secondary to severe anemia. Because parvovirus B19 is contagious, affected children should be isolated from pregnant women, who are at risk for miscarriage with infection, and from immunocompromised patients and those with chronic illness [23]. Priapism, a painful prolonged erection of the penis, can be another unfortunate complication of SCD. It is thought to be caused by sickling of the red blood cells producing venous stasis in the erectile tissue of the penis. The resulting stasis causes ischemia, hypoxia, and pain. Initial treatment involves intravenous hydration and analgesia. Episodes refractory to this initial management include direct irrigation of the corporeal bodies (erectile tissue) of the penis, usually performed by a urologist [7]. Children with SCD are also at risk for other serious infections, particularly osteomyelitis, most commonly caused by Salmonella species or Staphylococcus aureus [15]. Bone pain or joint pain with localized swelling and decreased range of motion, along with fever, should alert the physician to the possibility of osteomyelitis. Increased white blood cell count and elevated erythrocyte sedimentation rate are common laboratory findings. Patients with suspected infections with these organisms should be started on the appropriate broad-spectrum

antibiotic and have diagnostic imaging performed to confirm the diagnosis. Long-term treatment options for SCD are limited and include hydroxyurea and bone marrow transplantation. Hydroxyurea increases the amount of red blood cells which produce Hb F. Previous research has established that Hb F has a protective effect, reducing the risk of sickling in patients with high amounts of Hb S [9]. Bone marrow transplantation as a treatment option for sickle cell anemia is available for approximately 1% of the pediatric patients with the disease [9]. Ideal candidates are individuals younger than 16 years, with severe disease and with complications such as recurrent stroke or recurrent acute chest syndrome, are transfusion-dependent with complications such as iron overload, and most importantly, have HLA-matched donors [9]. The potential advantages of these therapies over standard treatment with long-term transfusions need further study.

Case 4 A 6-month-old infant girl was brought to the ED with a history of irritability and diarrhea for the past 10 days. Further questioning revealed that the infant had feeding problems for the past 2 months and had been treated for repeated ear infections and colds on 4 previous occasions by a local physician. The child was born at term to a 28-year-old gravida 2 mother. The parents were immigrant farm workers from Thailand and were cousins. Their other child was a 5-year-old girl reportedly in good health. On examination, the infant was noted to be listless, with no response to verbal commands and poor response to painful stimuli. Extreme pallor was present; vital signs revealed a temperature of 388C, heart rate of 180 beats per minute, and respiratory rate of 30 breaths per minute, and the blood pressure was not recordable. Height and weight were less than the 10th percentile for age. The infant had a gallop rhythm with a grade II/VI systolic ejection murmur; lungs were clear to auscultation. The abdomen was distended with the liver edge palpable 3 cm below the left costal margin, and marked splenomegaly was also noted with the spleen tip palpable below the level of the umbilicus. Capillary refill time was greater than 4 seconds. No icterus was noted. Because of difficult venous access, an intraosseous line was placed, and O-negative packed red blood cells were slowly transfused. A complete blood count obtained before initiating the transfusion revealed a white blood cell count of 13 000 with a differential of 52% neutrophils, 48% lymphocytes, 7% monocytes, 2% eosinophils, and 1% basophils. The Hb was 3 g/dL, and the platelet count was 400 000. All the red cell indices were markedly low, and the peripheral smear showed severe microcytosis, anisocytosis, and poikilocytosis with many fragmented red cells, schistocytes, occasional target cells,

Emergencies in patients with inherited hemoglobin disorders teardrop cells, and many normoblasts. Liver and renal function tests were within normal limits. After a 10 mL/kg transfusion of packed red blood cells, the infant’s condition improved, and she was more responsive to verbal stimuli; the blood pressure improved to 68/36 mm Hg. A second packed red blood cell transfusion was administered with further improvement in the clinical condition of the infant. Subsequent evaluation including a Hb electrophoresis revealed findings suggestive of b thalassemia major, which was confirmed on testing of the parents, both of whom had findings suggestive of the carrier state for b thalassemia.

Case 4: Discussion Thalassemia is best defined as a genetic defect that results in production of an abnormally low quantity of Hb chain(s). This results in an imbalance of globin chains and decreased production of red blood cells, which are also hypochromic and microcytic. Furthermore, there is an increased accumulation and precipitation of the complementary globin chains that leads to an increase in red cell destruction and inadequate production [6]. The thalassemias are the most common genetic disorder in the world, with the milder forms occurring more frequently [6,24]. The thalassemia syndromes are classified according to the particular globin chains that are ineffectively synthesized, namely, the a, b, db, and edb thalassemias [25,26]. Table 5 contains a complete listing of the thalassemias. a and b thalassemias are the only disorders seen commonly [1,2]. a Thalassemia tends to occur in people of African, Indochinese, Chinese, and Malaysian descent. b Thalassemia tends to occur mostly in people of African and Mediterranean descent [24]. Normal a-globin chain production is controlled by 4 a-globin genes located on chromosome 16, and a thalassemia most commonly results from the deletion of 1 or more of these genes [27]. Table 5

145 The clinical severity of disease varies, depending on the number of gene deletions in each individual, as discussed later. In contrast, b thalassemias are generally due to point mutations in the b-globin gene, located on chromosome 11. In addition to point mutations, deletion forms of b thalassemia have also been identified. In general, heterozygous state for the b thalassemia gene results in mild hemolytic anemia, usually a symptomless carrier state (b thalassemia minor). The homozygous state results in the severe transfusiondependent form designated b thalassemia major or Cooley anemia [23]. The term thalassemia intermedia is used to describe the broad spectrum of different forms of thalassemia in which the clinical manifestations lie between these extremes. Progressive iron overload results from regular red cell transfusion therapy; which is the most common therapeutic modality used in patients with chronic hemolytic anemias, such as thalassemia and SCD. Each milliliter of red blood cells contains approximately 1.1 mg of iron [28]. Iron overload results in cardiac complications, including arrhythmias and congestive heart failure, which are the most common causes of death in thalassemia patients. Other complications of transfusional overload include hepatic fibrosis and endocrine abnormalities, such as diabetes mellitus, hypothyroidism, hypoparathyroidism, and delayed growth and development. Management of iron overload involves the use of chelation therapy to attain a negative iron balance (ie, iron excretion greater than iron input) [28]. Deferoxamine has been successfully administered subcutanteously over prolonged periods, and compliance with therapy has been the main obstacle to effective chelation. Other oral chelators are currently undergoing clinical trials and may soon be available. SCD and thalassemia, along with their multiple complications, are the most commonly encountered hemoglobinopathies in the ED. However, a rare condition called methemoglobinemia deserves mention as it

The thalassemias.

Thalassemia Type a Thalassemia 1-Gene deletion 2-Gene deletion trait 3-Gene deletion, Hb H 4-Gene deletion b Thalassemia b 0 or b + heterozygote trait b 0 Thalassemia b + Thalassemia severe Silent d Thalassemia (d d b )0 Thalassemia (d d b )+ Thalassemia

Laboratory Findings

Clinical Expression

Normal Microcytosis, mild hypochromia Microcytosis, hypochromia Anisocytosis, poikilocytosis

Normal Normal, mild anemia Mild anemia, usually no transfusions Hydrops fetalis

Variable microcytosis Microcytosis, nucleated red blood cell Microcytosis, nucleated red blood cell Microcytosis

Normal Transfusion-dependent Transfusion-dependent/thalassemia intermedia Normal with only microcytosis

Hypochromia Microcytosis

Mild anemia Mild anemia

Adapted from Quirolo and Vinchinsky [6] (Table 454.9-4).

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146 constitutes an important consideration in the differential diagnosis of infants and young children with cyanosis. Methemoglobinemia is caused by Hb with increased amounts of iron oxidized to the ferric rather than the ferrous form. As a result, this Hb is not effective for binding oxygen and causes cyanosis depending on the amount of methemoglobinemia. Causes of methemoglobinemia can be divided into 3 basic categories: genetic enzyme deficiencies, abnormal Hb’s, and exposure to certain drugs and toxins. One of the most common genetic causes is hereditary methemoglobinemia, a recessive disease trait caused by enzyme deficiency of nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase. The purpose of this enzyme, found normally in red blood cells, is to convert methemoglobin to normal functioning Hb. There are 2 forms of hereditary methemoglobinemia, type I and type II. Type I is caused by deficiency of NADH cytochrome b5 reductase enzyme, exclusively in the red blood cell. Clinically, these patients have cyanosis as their only symptom [25]. This is the most common form of methemoglobinemia seen in the ED and often manifests with an oxidant stress or during a diarrheal illness as reversible methemoglobinemia. Type II hereditary methemoglobinemia is secondary to a deficiency of the enzyme not only in red blood cells, but in all cells and tissues. Clinically, this disease is much more severe, with patients exhibiting developmental delay, mental retardation, neurological impairment, and often premature death [25]. Carriers or heterozygotes of type II disease may only have symptoms of methemoglobinemia during exogenous oxidant stress, that is, drugs, medicines, and present with cyanosis. Abnormal Hb variants that cause methemoglobinemia are typically called Hb M. Hb M is typically an inherited autosomal dominant disease trait caused by amino acid substitution of tyrosine for proximal or distal histidine on the a- or b-chain of Hb. The resulting effect is poor reduction of the iron molecule (the ferric state rather than the ferrous state) and impaired oxygen binding of the heme molecule. Clinically, these infants present with cyanosis, as demonstrated by the infant in Case 4. The location of the defect, a- or b-chain, dictates the timing of cyanosis. a-Chain defects present with cyanosis from birth, and b-chain defects present after the first few months of life. The most common cause of methemoglobinemia is exposure to particular drugs or toxins. The mechanism of action of these agents is via direct oxidation of Hb, forming methemoglobin, or indirectly via formation of free radicals which then in turn oxidize Hb to methemoglobin. See Table 6 for a list of drugs and toxins that commonly cause methemoglobin. An unlikely source of methemoglobinemia has also been identified in young infants (b6 months of age)

with gastroenteritis who develop a metabolic acidosis. The culprit in these cases is thought to be nitritereducing bacteria, which indirectly oxidize fetal Hb to methemoglobin. Regardless of the etiology, clinical manifestations and symptoms depend on the concentration of methemoglobin in comparison to normal Hb. When 10% to 30% of Table 6 Drugs or environmental toxins that can cause methemoglobinemia. Drugs Acetanilid Alloxan Aniline Arsine Benzene derivatives Benzocaine* Bivalent copper Bismuth subnitrate Bupivacaine hydrochloride* Chlorates Chloroquine* Chromates Clofazimine Dapsone* Dimethyl sulfoxide Dinitrophenol Ferricyanide Flutamide Hydroxylamine Lidocaine hydrochloride* Methylene blue Naphthalene Nitrates Nitric oxide Nitrites Nitrofuran Nitroglycerin Sodium nitroprusside Paraquat Phenacetin* Phenazopyridine hydrochloride Phenol Phenytoin Prilocaine hydrochloride* Primaquine phosphate Rifampin Silver nitrate Sodium valproate Sulfasalazine Sulfonamides Trinitrotoluene Environmental Toxins Exhaust fumes Foods containing nitrates or nitrites Well-water containing nitrates Soap enemas Data from Rehman [29] and Cohen [10]. *More likely to cause methemoglobinemia.

Emergencies in patients with inherited hemoglobin disorders Hb is methemoglobin, the only clinical manifestation is cyanosis [8,25]. However, as these levels rise to 30% to 50%, affected individuals have symptoms such as dyspnea, nausea, tachycardia, dizziness, fatigue, and headache. As levels approach 50% to 55%, symptoms such as lethargy, stupor, and loss of consciousness occur. Levels higher than 70% result in death usually secondary to cardiac arrhythmias and circulatory failure [25]. Diagnosis of methemoglobinemia can be confirmed both clinically and by laboratory analysis. Clinically, patients with methemoglobinemia are cyanotic and do not improve with oxygen administration. In young children, it is important to distinguish methemoglobinemia from congenital and other anatomic cardiac lesions causing cyanosis via echocardiography. Measurement of oxygen saturation with pulse oximetry is usually inaccurate and falsely elevated. Partial pressure of oxygen is normal on arterial blood gas; however, oxygen saturation will be low on direct blood oximetry. Blood drawn for analysis may appear chocolate brown instead of red if the concentration of methemoglobin is more than 30%. A quick and inexpensive test can be done by placing several drops of blood on filter paper, noting that after 1 minute, normal blood appears bright red and blood affected by methemoglobinemia appears reddish brown [8]. The laboratory gold standard for measuring methemoglobin levels is spectrophotometry or gas chromatography–mass spectrometry. Patients with suspected genetic causes of methemoglobinemia should have NADH cytochrome b5 reductase enzyme assays and hemoglobin electrophoresis to aid in diagnosis. In addition, a complete blood count with reticulocyte count and type and crossmatch should be obtained because some of the drugs that cause methemoglobinemia can also cause hemolytic anemia, which may need further management. It is important to note that there is no cure for Hb M, only avoidance of oxidative substances or drugs that may trigger methemoglobinemia. Patients with hereditary methemoglobinemia respond well to ascorbic acid, 300 to 600 mg orally per day [25]. Therapy for methemoglobinemia is dependent on 2 factors: the severity or the methemoglobin level and the etiology. Methemoglobin levels less than 30%, especially if the patient is not symptomatic, do not warrant treatment because normal red blood cell metabolism will reduce methemoglobin over a reasonable time. For symptomatic patients with levels more than 30%, first-line treatment is methylene blue, 2 mg/kg of a 1% solution given over 5 minutes. For those patients who do not respond, or for those patients who are severely ill, a second dose should be given. Dextrose should be given with methylene blue because it acts as a substrate in the oxidative process. Hyperbaric oxygen and exchange transfusion should be considered in those nonresponders who are extremely ill [8].

147

Summary In the ED, the inherited Hb disorders may be encountered in a variety of clinical presentations. Patients with the clinically milder forms of hemoglobinopathies are typically identified as having these disorders only as an incidental finding as they usually do not present to the ED for hemoglobinopathy-related issues. In contrast, patients with the more severe forms of these disorders tend to present with symptoms that are more or less directly related to their hemoglobinopathy. Examples include signs of severe hemolysis and signs of anemia in the case of the thalassemia disorders, or hemolysis, anemia, sepsis, vasoocclusion, and specific organ-related complications in the case of SCD. These presentations usually require immediate interventions to prevent morbidity and mortality. Alternatively, these patients may also present with symptoms related to chronic organ damage from either the disease itself or from its treatment such as long-term blood transfusions, which can result in iron overload, heart failure, liver cirrhosis, and diabetes secondary to pancreatic insufficiency. A basic knowledge of the pathophysiology of these disorders and a good index of suspicion are necessary for the diagnosis and appropriate management of children affected by these disorders.

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