Clinical and Health Affairs
Emergency Management of Sickle Cell Disease Complications
Review and Practice Guidelines
By John L. Hick, M.D., Stephen C. Nelson, M.D., Karen Hick, M.D., and M. Obinna Nwaneri, M.D.
Abstract
The prevalence of sickle cell disease (SCD) in Minnesota is increasing because of the influx of immigrants from Africa, India, and countries in Latin America. Clinicians, families, and individuals with the disease have expressed the need to educate health care professionals in emergency settings about the standards of care for treating pain and other complications of SCD. Late last year, the Minnesota Department of Health and the Minnesota Hemoglobinopathy Collaborative created guidelines for treating patients with complications of SCD in the emergency department. This article provides additional background information to support the guidelines.
Hemoglobin S (Hgb S) is an abnormal hemoglobin caused by a substitution of valine for glutamine at the 6th position on the beta-hemoglobin chain. Hgb S is prone to polymerize or gel when exposed to stressors such as low oxygen tensions and acidic environments. This polymerization causes the red blood cell (RBC) to assume the characteristic “sickle” deformity and increases endothelial adhesion resulting in vascular occlusion.
Sickle cell disease (SCD) is a general term for hemoglobinopathies involving Hgb S. This group of inherited RBC disorders primarily affects people of African, Mediterranean, Indian, and Middle Eastern descent, although they can also occur in certain Caribbean, Central American, and South American Latino populations.1 The most common form of SCD is hereditary recessive homozygous hemoglobin S or HbSS. Less common (and less clinically severe) are the hemoglobin SC (HbSC) and Sb thalassemia forms of the disease in which some functional-but-abnormal globin chains are produced. Hemoglobin S0 thalassemia is also uncommon, but it is more severe because no functional globin chains are produced. Hb S0 thalassemia is clinically indistinguishable from HbSS disease.
Advances in management of SCD have improved median survival for those with HbSS to 50 years. Survival for patients with HbSC is only a few years less than that of the African American population in general.2
Sickle cell disease occurs in approximately 1 in 600 African Americans. The prevalence in Minnesota is increasing, as changing demographics make the state more ethnically diverse. Approximately 500 Minnesotans have SCD, according to 2000 census data. The Minnesota Department of Health’s Newborn Screening Program detects more infants with hemoglobinopathies than with congenital hypothyroidism, galactosemia, phenylketonuria, and congenital adrenal hyperplasia combined. Of the approximately 68,000 babies screened annually in Minnesota, 15 are diagnosed with SCD. Another 1,000 infants are found to have other hemoglobin abnormalities.
The complications of SCD are many, and treatment of SCD patients with a given complaint (eg, seizure) often differs from standard therapies for non-SCD patients; thus, it is critical that medical staff providing acute care to patients with SCD understand the disease, its typical complications, and the therapies for those problems. Because of the complexity and chronicity of SCD, most patients and their families know their disease well and have hematologists who are very involved in their care. All may provide useful information during an emergency department (ED) encounter.
Clinicians, families, and, most importantly, individuals with SCD in Minnesota have expressed a need to educate health care professionals and to increase awareness of the existing standards of care for treating pain and other complications of SCD in an emergency setting.
To better educate providers, the Minnesota Hemoglobinopathy Collaborative, a group of parents, physicians, and support personnel, and the Minnesota Department of Health convened a workgroup in 2004 to evaluate appropriate analgesia and symptom-based care recommendations for patients with SCD who present to EDs. Experts in hematology, emergency medicine, pediatrics, pediatric emergency medicine, and family medicine worked with a broad group of patients, parents, social workers, and other interested parties to review available literature and craft a useful, brief document that can serve as a reference in hospital EDs. This project culminated in the production and formal release of the Minnesota Sickle Cell Disease Emergency Guidelines on Sept. 13, 2005. Copies of and background information on the guidelines were sent to emergency physicians, emergency nurses, and hematologists throughout Minnesota. The guidelines are also available online at www.health.state.mn.us/divs/fh/mcshn/nbsprov.htm.
This article provides additional background and reference material that supports the guidelines in order to help acute care physicians better understand them and implement their recommendations. It is not intended to be a comprehensive review of SCD.1-3
Patient Evaluation and Management
When a patient with SCD arrives at the ED, evaluation should include eliciting the patient’s symptoms and obtaining the patient’s vital signs (including oxygen saturation). Patients presenting with neurologic or chest symptoms, in particular, should be emergently triaged into the ED. Infants and young children with fever or other acute complaints, such as pain or abdominal symptoms, should be expedited for ED placement.
Patients Presenting with Pain Periodic episodes of pain are a major symptom of SCD and the most common reason people with SCD go to hospital EDs. Acute pain episodes are more frequent in some patients than others, with 5% of patients accounting for 30% of inpatient-hospital-stay days.4 Infection, cold exposure, and physical or emotional stress may provoke acute pain episodes,5 which are thought to originate from micro-infarctions caused by local capillary sickling and ischemia. Acute pain episodes often recur in the same areas of the patient’s body and are usually caused by small vessel vaso-occlusion. Complaints of pain in other areas should prompt further evaluation for other underlying causes.
Dactylitis, or vaso-occlusive disease of the digits, can occur in the very young and is indicated by swollen, tender digits. Otherwise, most pain episodes are not accompanied by physical exam manifestations, although fever, skin tenderness, warmth, and leukocytosis can be present and sometimes mimic cellulitis.
Adequate analgesia is critical for treating acute pain episodes. The amount of analgesia needed should be based on the patient’s subjective assessment of his or her distress, as no physiologic or laboratory markers can determine pain severity in a patient presenting to the ED. Patients with SCD do not demonstrate tachycardia, hypertension, or the usual sympathetic markers of adrenergic activity. Analgesia provided in the ED is often inadequate both in dose and frequency.6 For those reasons, aggressive analgesia should be initiated intravenously (lower extremity access in adults should be avoided because of the high incidence of ulcers). If IV access is not easily obtainable, subcutaneous or oral medications may be used. In addition, normal saline can be given to ensure euvolemia, as patients often come to the ED dehydrated because of poor oral intake of fluids due to pain.
Morphine and dilaudid are the preferred analgesics for patients with SCD-related pain. Meperidine (Demerol) should be avoided because of the potential for seizures caused by its breakdown product normeperidine. Aggressive dosing (0.1mg/kg/dose morphine or equivalent) should be repeated as needed every 5 to 10 minutes until the pain is under control. Some patients may have developed tolerances to narcotics, which can increase their dosing requirements. Adjunctive treatments such as nonsteroidal anti-inflammatories (assuming normal renal function) and nonmedical therapies (distraction techniques, warm packs) should also be used to help control pain. Oxygen therapy for patients with normal oxygen saturation provides no apparent benefit in resolving pain. Over time, higher oxygen tensions will inhibit erythropoietin production and possibly exacerbate anemia or cause rebound sickling when withdrawn).7-9
Patients presenting with acute pain episodes do not require laboratory testing if their pain is easily controlled and no other complications are present.10 Patients who are admitted to the hospital from the ED, particularly pediatric patients, should have their hemoglobin and reticulocyte count checked to ensure that they are not having an aplastic crisis. Blood cultures should be obtained when infection is suspected, and a tube should be obtained on all acutely ill patients with SCD for cross match in case transfusion or exchange transfusion (replacement of a portion of the patient’s blood with nonsickling donor RBCs) is needed.
Hydroxyurea therapy has improved the lives of many patients with SCD by reducing pain crises and other complications. It is now being used in children as young as 18 months.11-13 An increased risk of complications, including a higher risk of vaso-occlusive events such as strokes, with intermittent use limits therapy to compliant patients.
Other Complications of SCD Patients may present in the ED with a number of other critical conditions related to their SCD. Emergency physicians should consult with the patient’s hematologist or the appropriate on-call physician when confronted with the following cases:
1. Infection. Patients with SCD, especially infants and young children, are at high risk for encapsulated organism infection caused by functional asplenia. All febrile patients with SCD should be presumed to have bacteremia until proven otherwise. Blood cultures should be obtained and empiric therapy with ceftriaxone started. If the patient is sick enough to require supplemental oxygen or be admitted to intensive care, the addition of vancomycin is suggested. All febrile children and any febrile adult with respiratory symptoms or without a clear source of infection should have a chest X-ray. Prophylactic penicillin can be discontinued during antibiotic therapy. Generally, children younger than 1 year with signs of infection should be admitted to the hospital. Older children and adults who are otherwise well and without evidence of chest crisis or significant laboratory abnormalities may be managed as outpatients in consultation with the hematology staff.14
2. Acute chest syndrome. Acute chest syndrome (ACS) is defined as a new pulmonary infiltrate plus some combination of fever, chest pain, and signs and symptoms of pulmonary disease such as tachypnea, cough, and dyspnea. This definition is vague because there are many causes of ACS and its pathogenesis is not thoroughly understood. ACS is second only to pain crisis as a cause for hospitalization and accounts for approximately 25% of deaths in patients with SCD.15 Hypoxemia, which results in further sickling and progression of the disease, is present in 70% of affected patients (<95% or 3% below normal for patient).15 Asthma may contribute to a higher incidence of ACS and a more severe clinical course.16
Intravenous antibiotics (eg, ceftriaxone plus azithromycin plus or minus vancomycin) and high-flow oxygen therapy should be provided to patients with suspected ACS.3,17 Dexamethasone 0.3mg/kg every 12 hours has also been shown to be beneficial in ACS patients.18 Incentive spirometry may help prevent additional atelectasis and thus reduce progression of ACS. Bronchodilators should be used as needed.
Emergency staff should obtain a complete blood count, blood cultures, and a cross match so that transfusion or exchange transfusion can be expedited if needed. In addition, they should consult with hematology, as severe cases may require nitric oxide administration, mechanical ventilation, and extra-corporeal membrane oxygenation.
3. Neurologic symptoms. Seizure, acute headache, and symptoms of stroke in a patient with SCD often require an emergent exchange transfusion to reverse or ameliorate central nervous system vessel sickling. Intravenous fluids, supplemental oxygen, and neurologic imaging (emergent MRI/MRA if available, otherwise noncontrast CT) are recommended in such cases, and the patient’s blood should be sent for cross matching.
Febrile patients should have a lumbar puncture, and appropriate antibiotics should be started for possible meningitis. Patients with seizures should be treated with standard therapies, although they may not respond well to anti-epileptic medications. Acute stroke occurs in 11% of patients with SCD, most often in those between 4 and 10 years of age.19,20 Hemorrhagic strokes are more common in adults than in children. Patients with stroke syndromes, which are usually related to large vessel (eg, middle cerebral artery) involvement, should be treated with immediate exchange transfusion. Systemic thrombolytic therapy is not generally advisable, especially for pediatric patients, because it is associated with a higher incidence of serious bleeding complications. Emergent neurologic consultation or transfer to an appropriate center should be arranged.
4. Abdominal emergencies. Splenic sequestration crisis is usually seen in children younger than 3 years of age. Children suffering such a crisis present with abdominal pain, tender splenomegaly, falling hemoglobin (>2g/dL below baseline), and rising reticulocyte counts because the spleen is trapping massive quantities of RBCs. Pancytopenia is often present in such patients, and infection is a frequent precipitating event. Death can occur within hours in severe cases of splenic sequestration.
If the patient is unstable or severely anemic (>4g/dL below baseline or <5g/dL), transfusion should be started immediately. Transfusion to just below normal hemoglobin levels or partial exchange transfusion are standard therapies in such cases. Although older patients with HbSC and S-beta thalassemia may have sequestration events, these events tend to be much milder than in young children.
Splenic infarctions may also cause pain without splenomegaly or anemia. Recurrent small splenic infarctions result in a small, poorly functioning spleen by 3 to 5 years of age.
Chronic hemolysis of sickled cells results in a high incidence of gallstones and related complications including pancreatitis, cholecystitis, and cholangitis. Hepatic congestion from blood flow obstruction also can occur and presents as right upper-quadrant pain, hepatomegaly, and elevated liver function.
5. Hematologic complications. Aplastic crisis may present with other complications of SCD. Up to 80% of cases of aplastic crisis are caused by human parvovirus B19 infection (the cause of Fifth disease or erythema infectiosum). Aplastic crisis results in severe anemia with suppressed reticulocyte counts.21,22 Empiric antibiotic therapy with ceftriaxone should be initiated in case of a bacterial cause. Oxygen should be provided through a nasal cannula or a simple mask to symptomatic or severely anemic patients (Hgb <5g/dL), although some children who don’t have underlying cardiopulmonary disease may be managed without supplemental oxygen. Transfusion may be required for some patients with severe anemia.
6. Genitourinary symptoms. Priapism is not uncommon in patients with SCD. Analgesia, hydration, and subcutaneous terbutaline (0.01mg/kg/dose; max of 0.25 mg/dose) should be administered. If the priapism does not resolve in 2 hours, consult with a urologist before performing corporal aspiration, injecting dilute epinephrine solution, or doing corporal irrigation. Exchange transfusion has been used in the past but is generally now discouraged in favor of urologic interventions. Microscopic hematuria is common and does not require immediate workup. Painless gross hematuria may be caused by papillary necrosis, infection, infarction, and renal medullary carcinoma. In the absence of evidence of infection, active urinary sediment, or altered renal function testing, these patients may be referred for outpatient follow-up to their primary hematologist. Patients with painful hematuria should be imaged in order to rule out obstruction and stone disease.23
Pregnancy Pregnant patients with SCD are at risk for many complications. An initial diagnosis of pregnancy in the ED should prompt admission to the hospital for further evaluation unless both the patient’s hematologist and the gynecology staff believe outpatient evaluation is acceptable.
Discharge Criteria
Disposition decisions should generally be made in consultation with the patient’s hematologist. Most patients presenting with a pain crisis should be comfortable enough to be discharged after 2 to 4 hours of therapy; if not, they should be admitted. Short-stay admission to the ED or another area of the hospital when available is a reasonable choice for many patients with simple acute pain episodes. Hospital admission is necessary when additional workup or treatment for other diagnoses is required. Discharged patients should be followed closely and should be able to continue their care as outpatients. Patients with a fever should generally be admitted to the hospital, although select adults and children can be managed as outpatients. Patients with new or worsening hypoxemia, acidosis, anemia, or with any of the critical conditions discussed earlier (except resolved priapism) should be admitted.
Conclusion
Exciting new therapies may soon be available for patients with SCD, including the use of inhaled nitric oxide and oral L-arginine to reduce endothelial dysfunction.24-26 Bone marrow transplant can cure HLA-matched individuals, and research into stem cell and genetic interventions is ongoing.1 For now, these advances will have little effect on emergency care of SCD patients who suffer disabling pain and serious complications of their disease. We hope this discussion and the new Minnesota Sickle Cell Disease Emergency Guidelines will provide a framework that facilitates timely interventions and referral to ensure the best possible clinical outcomes for this challenging group of patients. MM
John Hick is an assistant professor of emergency medicine at the University of Minnesota and a faculty physician at Hennepin County Medical Center in Minneapolis. Stephen Nelson is director of the hemoglobinopathy program in the department of pediatric hematology/oncology at Children’s Hospitals and Clinics of Minnesota. Karen Hick is a clinical instructor of emergency medicine at the University of Minnesota and a faculty physician at Children’s Hospitals and Clinics of Minnesota. M. Obinna Nwaneri is a clinical assistant professor of medicine at the University of Minnesota.
The authors thank the Minnesota Hemoglobinopathy Collaborative, Dana Brown, and Abbie Abboud for their efforts on behalf of the Minnesota Department of Health, and the workgroup members for their ideas and dedication to the care of SCD patients.
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