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Evidence-Based Management Of Sickle Cell Disease In The Emergency Department Abstract Professor, UT College of Medicine, Chattanooga, TN Andy Jagoda, MD, FACEP Professor and Chair, Department of Nicholas Genes, MD, PhD Emergency Medicine, Mount Sinai Assistant Professor, Department of School of Medicine; Medical Director, Emergency Medicine, Mount Sinai Mount Sinai Hospital, New York, NY School of Medicine, New York, NY Author Jeffrey Glassberg, MD Instructor of Emergency Medicine, Mount Sinai School of Medicine, New York, NY Peer Reviewers Sohan Parekh, MD, RDMS Sickle cell disease (SCD) is the most common genetic disease in the US, affecting approximately 100,000 individuals. In SCD, genetically mutated hemoglobin (HbS) forms rigid polymers when deoxygenated, giving red blood cells a characteristic sickled shape. Increased blood viscosity and cell adhesion produce intermittent vaso-occlusion. The vaso-occlusive phenotype of SCD, which is marked by higher hemoglobin, manifests with frequent painful crises and is associated with a higher risk for developing acute chest syndrome. The hemolytic phenotype is characterized by lower baseline levels of hemoglobin and elevated markers of hemolysis. There are no reliable markers of vaso-occlusive crisis (VOC), ie, vital signs and laboratory tests are normal. After intravenous (IV) opiate titration, patient-controlled anesthesia (PCA) pumps are encouraged. Excess IV fluids have been associated with development of atelectasis, a risk factor for acute chest syndrome. Acute chest syndrome has clinical symptoms similar to pneumonia; these patients will develop progressive hypoxemia, acute respiratory distress syndrome, and death if exchange transfusion is not initiated. Editor-in-Chief August 2011 Volume 13, Number 8 Clinical Assistant Professor of Emergency Medicine, University of Texas Medical Branch, Galveston TX; University Medical Center Brackenridge and Dell Children’s Medical Center, Austin TX William Zempsky, MD Head, Division of Pain and Palliative Medicine, Connecticut Children’s Medical Center; Professor of Pediatrics, University of Connecticut School of Medicine, Hartford, CT CME Objectives Upon completing this article, you should be able to: 1. 2. 3. 4. Discuss the most common complications of SCD and their presentations. Discuss current and developing treatments for the management of complications related to SCD. Discuss age-related strategies for the management of stroke in patients with SCD. Distinguish between the different forms of SCD based on hemoglobin electrophoresis. Date of original release: August 1, 2011 Date of most recent review: July 10, 2011 Termination date: August 1, 2014 Medium: Print and Online Method of participation: Print or online answer form and evaluation Prior to beginning this activity, see “Physician CME Information” on page 21. Shkelzen Hoxhaj, MD, MPH, MBA Scott Silvers, MD, FACEP Chief of Emergency Medicine, Baylor Chair, Department of Emergency College of Medicine, Houston, TX Medicine, Mayo Clinic, Jacksonville, FL Keith A. Marill, MD Assistant Professor, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA International Editors Peter Cameron, MD Academic Director, The Alfred Emergency and Trauma Centre, Monash University, Melbourne, Australia Corey M. Slovis, MD, FACP, FACEP Professor and Chair, Department of Emergency Medicine, Vanderbilt University Medical Center; Medical Giorgio Carbone, MD Michael A. Gibbs, MD, FACEP Editorial Board Director, Nashville Fire Department and Chief, Department of Emergency Professor and Chief, Department of William J. Brady, MD International Airport, Nashville, TN Charles V. Pollack, Jr., MA, MD, Medicine Ospedale Gradenigo, Emergency Medicine, Maine Medical Professor of Emergency Medicine FACEP Jenny Walker, MD, MPH, MSW Torino, Italy Center, Portland, ME; Tufts University and Medicine Chair, Resuscitation Chairman, Department of Emergency Assistant Professor, Departments of School of Medicine, Boston, MA Amin Antoine Kazzi, MD, FAAEM Committee & Medical Director, Medicine, Pennsylvania Hospital, Preventive Medicine, Pediatrics, and Associate Professor and Vice Chair, Emergency Preparedness and Steven A. Godwin, MD, FACEP University of Pennsylvania Health Medicine Course Director, Mount Department of Emergency Medicine, Response, University of Virginia Associate Professor, Associate Chair System, Philadelphia, PA Sinai Medical Center, New York, NY University of California, Irvine; Health System Operational and Chief of Service, Department Michael S. Radeos, MD, MPH Ron M. Walls, MD American University, Beirut, Lebanon Medical Director, Charlottesvilleof Emergency Medicine, Assistant Assistant Professor of Emergency Professor and Chair, Department of Albemarle Rescue Squad & Dean, Simulation Education, Hugo Peralta, MD Medicine, Weill Medical College Emergency Medicine, Brigham and Albemarle County Fire Rescue, University of Florida COMChair of Emergency Services, Hospital of Cornell University, New York; Women’s Hospital, Harvard Medical Charlottesville, VA Jacksonville, Jacksonville, FL Italiano, Buenos Aires, Argentina Research Director, Department of School, Boston, MA Peter DeBlieux, MD Gregory L. Henry, MD, FACEP Emergency Medicine, New York Dhanadol Rojanasarntikul, MD Scott Weingart, MD, FACEP Louisiana State University Health CEO, Medical Practice Risk Hospital Queens, Flushing, New York Attending Physician, Emergency Associate Professor of Emergency Science Center Professor of Clinical Assessment, Inc.; Clinical Professor Medicine, King Chulalongkorn Medicine, Mount Sinai School of Medicine, LSUHSC Interim Public of Emergency Medicine, University of Robert L. Rogers, MD, FACEP, Memorial Hospital, Thai Red Cross, FAAEM, FACP Medicine; Director of Emergency Hospital Director of Emergency Michigan, Ann Arbor, MI Thailand; Faculty of Medicine, Assistant Professor of Emergency Critical Care, Elmhurst Hospital Medicine Services, LSUHSC Chulalongkorn University, Thailand John M. Howell, MD, FACEP Medicine, The University of Center, New York, NY Emergency Medicine Director of Clinical Professor of Emergency Maryland School of Medicine, Maarten Simons, MD, PhD Faculty and Resident Development Senior Research Editor Medicine, The George Washington Baltimore, MD Emergency Medicine Residency Wyatt W. Decker, MD University, Washington, DC; Director Joseph D. Toscano, MD Director, OLVG Hospital, Amsterdam, Professor of Emergency Medicine, of Academic Affairs, Best Practices, Alfred Sacchetti, MD, FACEP Emergency Physician, Department The Netherlands Assistant Clinical Professor, Mayo Clinic College of Medicine, Inc, Inova Fairfax Hospital, Falls of Emergency Medicine, San Ramon Department of Emergency Medicine, Research Editor Church, VA Rochester, MN Regional Medical Center, San Thomas Jefferson University, Matt Friedman, MD Ramon, CA Francis M. Fesmire, MD, FACEP Philadelphia, PA Emergency Medicine Residency, Director, Heart-Stroke Center, Mount Sinai School of Medicine, Erlanger Medical Center; Assistant New York, NY Accreditation: EB Medicine is accredited by the ACCME to provide continuing medical education for physicians. Faculty Disclosure: Dr. Glassberg, Dr. Parekh, Dr. Zempsky, Dr. Jagoda, and their related parties report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation. Commercial Support: This issue of Emergency Medicine Practice did not receive any commercial support. Case Presentation • In the middle of a busy evening shift, you encounter a 25-year-old man with a chief complaint of sickle cell crisis. He states that he has had an upper respiratory infection for about a week, followed by progressive pain to his lower back and legs. At home, he has been taking 4-mg tablets of hydromorphone every 3 hours, which reduces his pain score from a 10 to a 9. His vital signs are as follows: heart rate of 77, blood pressure of 115/70 mm Hg, respiratory rate of 14 breaths per minute, and temperature of 36.9°C (98.4°F). He does not appear to be uncomfortable and is sitting in bed using a cellular phone. The nurse has placed a peripheral IV, delivering a 1-L bolus of NS. You get the CBC results, and his hemoglobin is 10.2 mg/dL. You ask yourself several questions: • Can this patient be having a crisis without a drop in hemoglobin? • Is there a blood test I can do to confirm that he is truly having a crisis? • Is the patient addicted to opiates or drug-seeking? • What fluids should I administer? • What kind of opiates should I administer? • Should I administer supplemental oxygen? You are surprised that despite many years of practice you are not sure of the answers and wonder why that is. Introduction Sickle cell disease is the most common genetic disease in America,1 affecting approximately 100,000 individuals.2 Since the discovery of SCD 100 years ago, our understanding of the disease has changed dramatically. Research has revealed that the genetic mutations underlying SCD not only result in sickleshaped red blood cells (RBCs) but also completely alter the rheologic properties of the blood, causing clinical manifestations in every organ system. Despite major advances in our understanding of the disease, literature to guide clinical decisions in the treatment of SCD is sorely lacking. This issue of Emergency Medicine Practice presents a synopsis of the latest evidence regarding the pathophysiology, diagnosis, and treatment of emergent complications of SCD. Critical Appraisal Of The Literature Table Of Contents A literature search was performed using PubMed, using the search terms pain, vaso-occlusion, acute chest syndrome, stroke, avascular necrosis, priapism, sepsis, osteomyelitis, transient red cell aplasia, pulmonary hypertension, hyphema, fat embolism, splenic sequestration, hepatic sequestration, hemolysis, and iron overload. A total of 596 articles from 1964 to the present were reviewed. The Cochrane Database was searched for systematic reviews using the key term sickle cell, which identified 35 reviews. Guidelines released by the National Institutes of Health (National Heart, Lung, and Blood Institute) in 2002 and the American Pain Society (APS) in 1999 were also reviewed. Both of these guidelines represent consensus statements and are not systematic, evidence-based guidelines. Using standard evidence-level scales, the majority of clinical evidence in SCD falls into the weaker and moderately-strong categories. There are several reasons for this. First, SCD is a rare disorder, and properly designed clinical trials are often too resource-intensive to perform. Second, SCD research is severely underfunded (cystic fibrosis, a disease that is one-third as common as SCD, receives millions of dollars more in funding each year). A third and final issue is the effect of medical advances on our knowledge of the disease. For example, many observational studies of SCD were performed before the development of the pneumococcal vaccine. This and other advances in preventive medicine may call into question results of earlier observational and interventional trials. When available, recommendations Abstract........................................................................ 1 Case Presentation.......................................................2 Introduction................................................................2 Critical Appraisal Of The Literature.......................2 Etiology........................................................................ 3 Pathophysiology........................................................3 Differential Diagnosis................................................4 Prehospital Care.........................................................4 Emergency Department Evaluation........................ 5 Diagnostic Studies...................................................... 6 Treatment Of Vaso-Occlusion...................................6 Controversies And Cutting Edge For Vaso-Occlusive Crisis.............................................8 Disposition For Vaso-Occlusive Crisis.................... 9 Special Circumstances: Other Complications Of SCD..................................................................... 9 Clinical Pathway For Management Of Pain In SCD.................................................................... 10 Risk Management Pitfalls For SCD....................... 14 Time- And Cost-Effective Strategies For Patients With SCD................................................ 16 Summary................................................................... 16 Case Conclusion....................................................... 16 References..................................................................17 CME Questions......................................................... 20 Available Online At No Charge To Subscribers EM Practice Guidelines Update: “Current Guidelines For ED Management Of STDs, Sexual Assault, And Emergency Contraception,” www.ebmedicine.net/STDS Emergency Medicine Practice © 2011 Should I give him IV ketorolac? Are there any other medications that might help? 2 ebmedicine.net • August 2011 in this article are evidence-based. Recommendations based on accepted practice or expert consensus are explicitly noted as such. vascular occlusion. Some speculate that venous and arterial thrombosis also play a role. Of the 5 SCD genotypes listed in Table 1, HbSS is the most severe. The genotype HbSC is associated with a higher level of total hemoglobin and a lesssevere course; however, these patients are at greater risk for avascular joint necrosis. In patients with HbS beta thalassemia, the severity of disease is determined by the severity of the thalassemia mutation. Patients with mild HbS beta+ thalassemia will have near-normal lives, whereas the natural history of HbS beta0 thalassemia is similar to HbSS. An important caveat when diagnosing SCD is the fact that the results of the electrophoresis cannot be interpreted for diagnostic purposes if the patient has been transfused within 90 days before blood is drawn. Transfusion is used in patients with SCD to prevent complications of surgery, strokes, and painful crises as well as to manage acute complications such as acute chest syndrome and priapism. Often, the goal of transfusion therapy is to reduce the HbS level to less than 30%; therefore, a patient with SCD who has recently received a transfusion will appear to have sickle cell trait on electrophoresis. For this reason, it is important to obtain a transfusion history from all patients with SCD. If the diagnosis of SCD is in doubt for a patient who has recently been transfused, other secondary clinical and laboratory indicators must be used to confirm for the presence of SCD. Etiology Sickle cell disease arises from genetic mutations on the beta-globin subunit of the protein hemoglobin. Offspring receive 1 gene from each parent, and both genes must carry the sickle cell mutation in order to have sickle cell disease. The most common mutation is the substitution of valine for glutamine at codon 6, which results in an abnormal hemoglobin called HbS. Other beta-globin mutations that result in SCD include HbC (substitution of lysine for glutamine at codon 6) and beta thalassemia. The laboratory test used to diagnose SCD, hemoglobin electrophoresis, provides the fractional percents of each type of hemoglobin produced by an individual. Typical hemoglobin electrophoresis patterns are provided in Table 1. Differentiating between sickle cell trait (HbAS) and HbS beta thalassemia can be challenging because there will be varying amounts of normal hemoglobin (HbA) in both conditions. In general, if there is more HbA than abnormal HbS, then the diagnosis is sickle cell trait. If the reverse is true, the diagnosis is more likely to be HbS beta thalassemia. Sickle cell trait has been associated with increases in sudden death upon strenuous physical exertion or maternal labor3-11 as well as ocular complications after minor eye trauma12,13; however, there is no evidence that patients with sickle cell trait manifest vaso-occlusion or pain. Many experts believe that the propensity towards sudden death during intense anaerobic exercise is due to systemic acidosis and hypoxia that promotes sickling and diffuse micro- Pathophysiology The abnormal hemoglobins produced in individuals with SCD form rigid polymers in response to deoxygenation. These polymers give red blood cells their characteristic sickled shape.3 Although it was origi- Table 1. Genotypes And Phenotypes Of Different Sickling Disorders % of hemoglobin type/total hemoglobin in a typical patient Genotype HbS HbA HbF HbC HbA2 Clinical Course - 96% 2% - 2% No manifestations 50% 2% - 2% No manifestations* Not Sickle Cell Disease HbAA (normal) HbAS (trait) 45% Sickle Cell Disease HbSS 95% - 3% - 2% Severe HbSC 48% - 3% 47% 2% Moderate HbS beta0 93% - 2% - 5% Severe HbS beta (moderate) 85% 6% 5% - 4% Moderate HbS-beta (mild) 70% 23% 3% - 4% Mild + + *Patients with sickle cell trait are at risk for delayed hemorrhage after eye trauma, sudden death upon exhausting physical exertion, and possibly venous thrombosis. Sickle cell trait is associated with none of the manifestations of sickle cell disease and does not cause painful crises. August 2011 • ebmedicine.net 3 Emergency Medicine Practice © 2011 nally postulated that the manifestations of SCD were due to the peculiar shape of the RBCs, this theory has been rejected as our understanding of the pathophysiology of SCD progressed.4 Today, we know that the blood in individuals with SCD behaves abnormally at all times, whether or not sickled cells are present. Several systems are abnormally activated at baseline and during a sickle cell crisis including platelet activation,5,6 endothelial activation,7-9 leukocyte activation,8,10 acute phase reactants,11 and cell adhesion molecule activation.7,12-15 The result of these processes is an increase in both blood viscosity and cell adhesion that causes intermittent vaso-occlusion which manifests most frequently as an acute painful episode or VOC. mia, with baseline hemoglobin levels ranging from as low as 4 mg/dL to as high as 14 mg/dL along with a compensatory reticulocytosis. Markers of hemolysis, including increased serum lactate dehydrogenase (LDH), indirect hyperbilirubinemia, and low haptoglobin will be present to varying degrees. Many patients with SCD are placed on chronic transfusion regimens to mitigate or prevent severe complications, resulting in iron overload. Laboratory findings include markedly elevated ferritin levels and low total iron binding capacity. Clinical findings of iron overload include liver, pancreas, and heart failure. Phenotypic Variation In Sickle Cell Disease The VOC is the hallmark manifestation of SCD and is the most common reason for presenting to the emergency department (ED)21 and hospital admissions.22 It can manifest as excruciating pain to any part of the body, although the lower back and legs are the most common.23,24 Triggers include infection, stress, dehydration, and changes in weather, but frequently there is no discernable precipitant.25,26,27 For the emergency clinician, the keys are to form an appropriate differential diagnosis, aggressively manage pain, and avoid contraindicated therapies. Table 2 lists the common and rare complications of SCD. Differential Diagnosis The severity of SCD presentations varies tremendously. Some patients exhibit incredibly mild courses and survive into the eighth decade of life, while others have a relentless and progressive course and do not live past early childhood. The clinical manifestations of SCD affect every organ system. The hallmark of SCD is the VOC. Other manifestations include acute chest syndrome, stroke, splenic and hepatic sequestration, progressive renal injury and failure, avascular necrosis, osteomyelitis, sepsis, pulmonary hypertension, skin ulcers, priapism, retinopathy, and several others. The factors that determine why some patients have severe presentations while others do not are poorly understood; however, certain markers of SCD severity are well-accepted. The persistence of elevated fetal hemoglobin (HbF) levels (an alternative hemoglobin that can function in place of the defective HbS) is associated with decreased morbidity. Elevated baseline leukocyte counts, elevated inflammatory markers, and the presence of a comorbid diagnosis of asthma16-18 are associated with increased SCD morbidity. Based on these manifestations, patients with SCD generally fall into 2 phenotypic groups: hemolytic and vaso-occlusive.19 Vaso-occlusion is the process that results in the manifestations of SCD that are best known to the emergency clinician (VOC pain crises, acute chest syndrome, stroke); however, hemolysis also makes an important contribution. The vaso-occlusive phenotype, marked by relatively higher hemoglobin levels, typically manifests with frequent painful crises and higher risk for the development of acute chest syndrome or stroke. In contrast, the hemolytic phenotype is associated with lower baseline levels of hemoglobin and elevated markers of hemolysis. These patients tend not to have painful crises or acute chest syndrome. Instead, they present with leg ulcers and pulmonary hypertension.19 Patients with SCD exhibit a range of laboratory findings. All patients will have some degree of aneEmergency Medicine Practice © 2011 Prehospital Care An extensive review of the literature uncovered no evidence with which to make specific recommendations about the prehospital care of individuals with SCD. Based on accepted standards of practice, the following recommendations can be made: • Avoid oxygen unless the patient is in respiratory distress. • Administer IV fluid boluses only to hypotensive patients. • Administer IV opioids by emergency medical services personnel if the patient is in pain and venous access is obtained. • Transport patients who are already being followed by a specific hematology service to that hospital whenever possible. Table 2. Acute Complications Of Sickle Cell Disease 4 Common Rare Extremely Rare Vaso-occlusive crisis Infection Stroke Cholelithiasis Priapism Acute coronary syndrome Splenic sequestration Osteomyelitis Transient red cell aplasia Hepatic sequestration Renal infarction Splenic infarction Retinal detachment Mesenteric ischemia ebmedicine.net • August 2011 Emergency Department Evaluation visual analog scale,29 and the Wong-Baker FACES™ Pain Rating Scale for children.30 Important elements of the history for complaints other than pain are discussed in the Special Circumstances: Other Complications of SCD section on page 9. History Obtaining a history on an individual with SCD can be divided into 2 parts: addressing the acute complaint and characterization of the severity of the patient’s disease. Table 3 lists the key components for evaluation of ED patients with SCD. The hematologist should be alerted to all ED visits, as follow-up has been associated with reduced bounce-back visits. The first step is to form an appropriate differential diagnosis. For example, pain is the most common complaint associated with ED visits for SCD, but VOC must be a diagnosis of exclusion; once other causes have been sufficiently ruled out, proceed with a pain evaluation. What follows is a discussion of the evaluation for a patient with the chief complaint of pain. Specific elements of the evaluation for other complaints (infection, neurologic complaints) are discussed in their component sections. Opiate Addiction And Drug-Seeking Behavior In Sickle Cell Disease Many emergency clinicians are concerned that their SCD patients are addicted to opiates or are seeking drugs. Furthermore, there is widespread belief that prescribing opiates in the ED will foster addiction and enable drug-seeking behavior.31 Qualitative32 and quantitative33 studies of opiate use in SCD patients indicate that rates of true addiction are low (below 5%). For the emergency clinician, the following recommendations can be made: unless there is clear evidence that the patient does not actually have SCD, take the patient’s complaint seriously and use opiates aggressively. It is true that a small fraction of people with SCD exhibit drug-seeking behavior to feed addiction or divert drugs to supplement income. It is also true that an attempt by the emergency clinician to identify drug-seeking patients and deny them analgesia will inevitably result in denial of analgesia for patients who deserve pain relief and compassionate care. Patients in need of treatment for addiction or diversion should be identified at follow-up with hematology or primary care, not in the ED. Historical Evaluation Of Pain Key questions include the locations, severity, and duration of pain; the exact amount of oral opiates taken at home; and the effect these opiates had on the pain score. Any validated pain assessment tool is acceptable, and there is insufficient evidence to recommend any particular one. Well-validated pain assessment tools include the verbally administered 0-10 numerical rating scale,29 the 100-millimeter Physical Examination The physical examination on an individual with SCD should focus on several areas. Examine the eyes and mucous membranes for jaundice, and if present, ask the patient if this is significantly changed from baseline. Auscultate for cardiac murmurs and focal pulmonary abnormalities. When examining the abdomen, pay close attention to the liver and spleen, as both can be a site of significant red cell sequestration. For each pain location, examine carefully for signs of infection (tenderness, erythema, fluctuance) as cellulitis, osteomyelitis, and abscess often masquerade as vaso-occlusive pain. Table 3. Elements Of The Sickle Cell Disease History Determine Severity of Patient’s SCD What complications of SCD have you had? Pain Acute chest syndrome Stroke Infections Avascular necrosis Priapism Cholecystitis Splenic sequestration Renal failure Pulmonary hypertension Pulmonary disease Leg ulcers Vision loss Use Of Vital Sign Abnormalities To Assess Pain Severity Many emergency clinicians use the presence or absence of abnormal vital signs to help objectively quantify the severity of a patient’s pain. Few studies specifically address this question; however, vital sign data from interventional clinical trials are sufficient to recommend against this practice. In a recent randomized controlled trial of inhaled nitric oxide for VOC that included 150 subjects, mean blood pressure measurements were below 120/70 mm Hg.34 In another randomized controlled trial of ketoprofen for the management of VOC pain, only one of the patients in What surgeries have you had? Cholecystectomy Splenectomy Joint replacement Tonsillectomy How often do you have pain? How often do you come to the ED for pain? Have you ever been on chronic transfusions? Do you take hydroxyurea or other medications? What medicines do you take for pain at home? What is your baseline hemoglobin level? Abbreviations: ED, emergency department; SCD, sickle cell disease. August 2011 • ebmedicine.net 5 Emergency Medicine Practice © 2011 the trial presented with tachycardia.35 A single-center, retrospective review of 459 VOC episodes specifically looked at blood pressure during crisis and found zero episodes of hypertension associated with VOC.36 Thus, individuals with SCD will usually not exhibit vital sign abnormalities, and many will not manifest distress even when in excruciating pain. tive observational cohort, elevations in hs-CRP were significantly associated with the presence of VOC.43 Standard institutional CRP assays are unreliable because elevations occur days after the onset of crisis. The LTE4 has also shown correlation with presence of VOC in a small prospective cohort,37 but this test is not readily available. Diagnostic Studies Treatment Of Vaso-Occlusion In all but the simplest cases, laboratory evaluation for ED patients with SCD should include CBC, liver function studies, and reticulocyte count. In patients with worsened scleral icterus, back pain, fever, or signs that suggest hemolysis, additional tests would include alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and bilirubin fractionation. Blood typing and screening is necessary if hemoglobin has dropped more than 1 mg/dL below baseline or if there is concern that the patient may need a transfusion. Triage All SCD patients with a complaint of pain should be triaged as an Emergency Severity Level (ESI) level 2 and moved into the ED immediately. Assignment to the waiting room after triage is inappropriate. Patients should be assessed by an emergency clinician and given initial analgesia within 30 minutes of arrival.44,45 Opiate Therapy The cornerstone of VOC management is administration of IV opiates. Available evidence with respect to the type of opiate, method of administration, and use of adjuvant therapies is presented in this review. In the absence of IV access, subcutaneous or oral administration is preferred over intramuscular, as altered tissue perfusion in SCD results in unreliable absorption of opiates from muscular beds. The NIH and APS guidelines for the management of acute pain recommend IV opiate administration and reassessment every 15-30 minutes until the pain is significantly improved (typically a drop in pain score of 2 or more).45,46 Limited ED resources may make this guideline difficult to follow; however, pain usually improves after 2 to 3 doses of IV opiates if administered in rapid succession. Can Laboratory Studies Be Used To Objectively Identify Vaso-Occlusive Crisis? Laboratory tests are ordered to determine severity of disease and to compare clinical markers of disease with baseline values. Laboratory tests do not assist the clinician in determining whether or not the patient is having VOC (ie, they cannot help determine whether or not a patient is being untruthful about his pain). Several studies have explored the patterns of various laboratory markers during VOC, and although there are promising experimental assays, there are no commercially available laboratory tests that can objectively identify VOC. Two small observational cohort studies found no relationship between the presence of VOC and hemoglobin level, white blood cell (WBC) count, reticulocyte count, or change in hemoglobin from baseline.37,38 Larger prospective interventional clinical trials have noted hemoglobin concentrations of 8-10 mg/ dL during crisis, which are not significantly different from baseline.34,35,39 Furthermore, there is evidence that reductions in hemoglobin are actually associated with decreased VOC. A before-and-after study of 7 patients found that regular phlebotomy significantly reduced frequency of VOC.40 The presence or absence of sickled RBCs is also unreliable as an objective measure of crisis. Although there have been no formally designed observational studies to test this, it is well known that sickled RBCs will be present in patients with SCD regardless of whether they are in crisis.41,42 Experimental assays for objective identification of VOC have included markers of inflammation such as high-sensitivity c-reactive protein (hs-CRP) and urinary leukotriene E4 (LTE4). In one prospecEmergency Medicine Practice © 2011 Type Of Opiate – Available Evidence In a 66-patient factorial design pediatric study of continuous infusion morphine versus intermittent bolus codeine or meperidine, continuous infusion morphine was associated with superior analgesia.47 In a phase I pediatric trial of intranasal diamorphine in conjunction with oral or IV opiates, rapid reductions in pain scores with few adverse effects were observed.48 A small randomized trial comparing PCA to continuous infusion of morphine showed similar pain scores but reduced opiate consumption and opiate side effects in the PCA group.49 A 45-patient trial of bolus dose IV morphine versus morphine PCA in the ED found similar analgesic efficacy but shorter time to pain relief and shorter ED length of stay with PCA.50 In a placebo-controlled randomized trial of children admitted for VOC, after an initial dose of IV morphine, oral morphine was equivalent (with trends towards superiority) to IV morphine.51 6 ebmedicine.net • August 2011 pain is accomplished by developing individualized pain control plans for patients who are known to the hematology service. In the past, this was done by keeping a 3-ring binder in the ED. Today, many electronic medical records software packages can accomplish the same thing in a paperless fashion. Type Of Opiate – Recommendations And Commentary Because of the renal abnormalities prevalent in patients with SCD, meperidine should be avoided. Almost all patients with SCD will have some degree of renal insufficiency owing to chronic medullary infarctions. Patients with SCD have supranormal proximal tubule function, which causes increased creatinine secretion. Consequently, the serum creatinine level underestimates the degree of renal dysfunction so that a patient with a creatinine level of 1.0 mg/dL may have significant renal dysfunction with decreased glomerular filtration rate (GFR). Compared with other opioids, meperidine is a relatively poor analgesic; however, it is often requested because of its euphoric effects. The metabolite of meperidine, normeperidine, is a renally cleared cerebral irritant, and upon accumulation in the blood, adverse effects ranging from dysphoria to seizures can result. Because renal dysfunction in SCD is so common, meperidine should be reserved for only brief treatment courses (no more than 48 hours at doses no higher than 600 mg/24 hours) for patients who have allergies or uncorrectable intolerances to other opioids. Morphine, fentanyl, and hydromorphone are acceptable opiate options. Initially, administer opiates via IV push every 15 minutes until the patient’s pain is moderately improved (at least a 2-point reduction on a 0-10 scale, preferably below 5). Intranasal diamorphine is an acceptable alternative in children. After initial IV opiate titration, place the patient on PCA pump, if available, even if the patient might be discharged. The PCA pumps should be programmed with a basal rate in addition to demand boluses. (See Table 4). In the author’s opinion, optimal treatment for Non-Opiate Therapies For a summary of non-opiate therapies for VOC, see Table 5 on page 8. Acetaminophen There is no clinical evidence regarding the use of acetaminophen for VOC. Anecdotal reports suggest an opiate-sparing effect. Acetaminophen is generally a safe medicine, even in the setting of liver dysfunction; thus, it is recommended as an adjuvant medication in the management of VOC. In patients with iron overload from transfusion regimens, avoid prolonged use of acetaminophen. Antihistamines There is no clinical evidence regarding the use of antihistamines in the treatment of VOC. Since antihistamines may mitigate the histaminergic effects of morphine administration and are anecdotally associated with opiate-sparing effects, they can be used as adjuvant therapy. Non-Steroidal Anti-Inflammatory Drugs – Available Evidence Case reports have associated the use of NSAIDs with renal failure in children with SCD52 and without SCD.53 Four studies have compared NSAIDs to placebo as adjunctive treatment for VOC. The largest and most rigorously designed study of 102 adults Table 4. Opiate Dosing Strategies For Patients > 50 kg With Vaso-Occlusive Crisis Initial Opiate Titration* IV hydromorphone 1-2 mg IV push every 15 min until pain score < 5 IV morphine 8-12 mg IV push every 15 min until pain score < 5 Intranasal diamorphine (children) 0.1 mg/kg Around-the-Clock Opiate Dosing After Initial Titration PCA analgesia with hydromorphone (1 mg/mL) Basal 0.1 mg/hr Demand 0.1-0.3 mg every 8 minutes PCA with morphine (4 mg/mL) Basal 0.7 mg/hr Demand 0.7-2 mg every 8 minutes Long-acting opioid agonist (controlled-release morphine or oxycodone or transdermal fentanyl) Base initial dosing on short-acting opioid requirements Rescue doses of 10% to 15% of the total 24-hour dose or 50% of the 4-hour dose should be the same opioid as the around-the-clock medication, available every 1-2 hours as needed Tapering opioids Wean dose by 10% to 20% every 8 hours as tolerated to keep pain score < 5. Once opioid dose is 25% to 30% of initial level, can switch to equianalgesic oral opioids and consider discharge *Place patient on monitor. Abbreviations: IV, intravenous; PCA, patient-controlled analgesia. August 2011 • ebmedicine.net 7 Emergency Medicine Practice © 2011 transfusion requirements.63 Supplemental oxygen is recommended only if the patient’s oxygen saturation is below 92%. with VOC found no differences with respect to pain scores, opiate requirements, or hospital length of stay with the addition of IV ketoprofen.37 Of the 3 smaller studies, 2 found no differences with respect to pain score, opiate dose, and length of stay.54,55 One study of 21 patients treated with meperidine found reductions in meperidine requirements with IV ketorolac.56 A Cochrane Review on this topic was unable to make definitive recommendations.57 Incentive Spirometry A randomized trial of 29 patients with VOC found that the addition of incentive spirometry during hospitalization for VOC was associated with a 37% decrease in the incidence of pulmonary infiltrates and atelectasis.64 Incentive spirometry should be included in the treatment protocol for all SCD patients admitted for VOC. Acute chest syndrome typically develops during inpatient admissions for VOC and pulmonary infiltrate is a clinical finding required for the diagnosis of acute chest syndrome. This low-risk intervention decreases the incidence of pulmonary infiltrates. Non-Steroidal Anti-Inflammatory Drugs – Recommendations And Commentary • Use acetaminophen and antihistamines as initial adjuvant therapy. • When using NSAIDs, only short courses (less than 72 hours) are indicated. • When discharging a patient with a prescription for NSAIDs, use short courses (preferably less than 72 hours). Controversies And Cutting Edge For Vaso-Occlusive Crisis It is likely that NSAIDs have small analgesic benefits for patients with SCD. The long-term effects of NSAIDs on patients with SCD have not been wellstudied; thus, they should be used judiciously. Steroids A placebo-controlled randomized controlled trial of 56 episodes of VOC found that high-dose methylprednisolone was associated with decreased length of hospital stay and severity of pain but was associated with increased frequency of readmission for recurrence of pain.65 Steroids are not recommended in the treatment of VOC. If the patient has a concurrent reason for the administration of steroids (eg, asthma exacerbation), steroids would not be contraindicated. Intravenous Fluid Choice – Available Evidence In vitro and in vivo studies have shown that lowering of serum osmolality with hypotonic fluid can reduce erythrocyte sickling.58,59 Excess IV fluids have been anecdotally associated with the development of atelectasis.60 A prospective observational cohort of 3751 patients with SCD identified atelectasis as a risk factor for the development of acute chest syndrome.61 Magnesium A single-arm study of 19 children with acute VOC compared hospital length of stay for patients admitted either with or without the administration of Intravenous Fluid Choice – Recommendations And Commentary • Use D5 ½ normal saline (NS) at a maintenance rate for the management of all complications related to SCD unless there is a specific indication to do otherwise. • Boluses of IV fluid should not be given unless patients are overtly hypovolemic (sepsis, diarrheal illness, vomiting). In these situations, resuscitate only to euvolemia with isotonic crystalloid. While it is thought that dehydration may precipitate VOC, overhydration — especially with isotonic crystalloid — does not cure crisis and may have detrimental effects. One additional undesirable effect of normal saline is that large amounts can cause hyperchloremic metabolic acidosis, and lowering the serum pH promotes sickling. Table 5. Non-Opiate Therapies For VasoOcclusive Crisis Recommended • Hypotonic fluids: D5 ½ NS at maintenance rate • Acetaminophen • Antihistamines (diphenhydramine, hydroxyzine) • Incentive spirometry Relatively contraindicated • Isotonic fluid (unless patient is overtly hypovolemic, eg, diarrhea or sepsis) • Supplemental oxygen (unless saturation is below 92%) • NSAIDs • Steroids (unless indicated for a concurrent illness) Supplemental Oxygen Administration of supplemental oxygen has been shown in real time to reduce circulating levels of erythropoietin in nonhypoxic individuals with SCD,62 and case reports have associated the administration of oxygen with marrow hypoplasia and Emergency Medicine Practice © 2011 Experimental • Intravenous magnesium (40mg/kg) • Low-dose ketamine infusion (0.06 mg/kg/h to 0.1 mg/kg/h) • Morphine and naloxone infusion Abbreviations: D5, dextrose 5%; NSAIDs, non-steroidal anti-inflammatory drugs; NS, normal saline. 8 ebmedicine.net • August 2011 Special Circumstances: Other Complications Of Sickle Cell Disease magnesium. The use of magnesium was associated with a decreased length of stay. A prospective randomized trial of magnesium for VOC is now underway. Until the results are available, current evidence is not sufficient to recommend its use in VOC. Acute Chest Syndrome Acute chest syndrome is a life-threatening clinical entity that occurs in individuals with SCD and is defined by a combination of at least 2 of the following signs or symptoms46: • Chest pain • Fever higher than 38.5°C (101.3°F) • Pulmonary infiltrate or focal abnormality on ventilation/perfusion scan • Respiratory symptoms • Hypoxemia Ketamine A retrospective case series of a subdissociative dose of ketamine for VOC suggested an improvement in pain control and a decrease in the need for opiate administration.66 A prospective trial to investigate the effects of ketamine is currently underway. Until further evidence is available, low-dose ketamine for VOC should be administered only after consultation with pain management experts. This constellation of findings is also consistent with the more widely known clinical entity, pneumonia. This overlap can be confusing to healthcare providers, but the two may be distinguished by how they respond to treatment. Pneumonia typically responds to antibiotics, whereas with acute chest syndrome, progressive hypoxemia, acute respiratory distress syndrome, and death will develop if exchange transfusion is not initiated. Acute chest syndrome is one of the most common causes of death in patients with SCD, and it should be considered whenever these patients present with respiratory signs or symptoms. Naloxone A pilot study of 18 children with VOC receiving continuous morphine infusion showed that concurrent infusion of naloxone was associated with a reduction in opiate side effects with no reduction in analgesic efficacy.67 Nitric Oxide Nitric oxide was recently evaluated in one of the largest trials of an acute intervention for VOC. In 150 patients at 11 centers, no differences were found with respect to duration of crisis, pain scores, or opiate consumption with the inhalation of nitric oxide.34 Etiology And Pathophysiology For Acute Chest Syndrome The best evidence regarding the etiology of acute chest syndrome comes from the Multicenter Acute Chest Syndrome Study (MACSS). Of 364 episodes of acute chest syndrome, 33% were due to infection, another 33% were found by exclusion to be due to pulmonary infarction, and 16% were due to pulmonary fat embolism.69 The most frequently isolated organisms are Chlamydophila (formerly Chlamydia) pneumoniae and Mycoplasma pneumoniae. The majority of acute chest syndrome cases will not present to the ED61; instead, they typically develop during an admission for VOC. Thus, the emergency clinician’s greatest role in acute chest syndrome is prevention with incentive spirometry and avoidance of overhydration. All non-SCD-related causes of chest pain should be considered in the differential diagnosis prior to making the diagnosis of acute chest syndrome. Disposition For Vaso-Occlusive Crisis There are no rigid guidelines regarding which patients with simple VOC should be admitted. The standard practice in many EDs is to give the patient 3 doses of IV opiates followed by admission if additional analgesia is required. This practice of limiting the number of opiate doses a patient can receive without being admitted is often used to discourage patients from casually visiting the ED to receive IV opiates. There is indirect evidence that a more lenient approach may reduce hospital admissions and return visits to the ED. Between 1989 and 1993, the Bronx (New York) Comprehensive Sickle Cell Center at the Montefiore Medical Center operated an acutecare day hospital dedicated to treating SCD patients with simple VOC. Implementing a standardized, aggressive, opiate-based treatment protocol dramatically reduced hospital admissions and recidivism.68 Although certain features of the day hospital can never be replicated in the ED, a policy of aggressive pain control without reflexively admitting after 3 doses of IV opiates is possible and may lead to fewer admissions and return visits to the ED. The author recommends that the patient with VOC be involved in the decision to admit and only those patients whose pain is refractory to IV hydration and aggressive pain control should be admitted to the hospital. August 2011 • ebmedicine.net Emergency Department Evaluation For Acute Chest Syndrome In addition to laboratory studies, the evaluation of patients with SCD who have chest pain should include chest radiography. Cardiac enzyme and D-dimer levels should be ordered at the emergency clinician’s discretion. The use of arterial blood gas measurements is somewhat controversial. In one observational study of 44 patients with acute chest 9 Emergency Medicine Practice © 2011 Clinical Pathway For Management Of Pain In Sickle Cell Disease Patient presents with acute pain • • Perform history and physical examination Determine probable cause and precipitating factors for pain Related to SCD? NO Perform appropriate work-up and management YES Start D5 ½ normal saline at the maintenance rate (Class III) NO Currently on chronic opiate therapy? Administer IV dose of opiate (Class II) • Morphine 0.1-0.15 mg/kg • Hydromorphone 0.015 -0.02 mg/kg YES • • Administer IV equivalent of home oral opiate dose (Class III) Administer APAP and antihistamine (Class III) Assess degree of relief every 15-30 minutes (Class III) NO Moderate pain relief? Repeat IV opiate at half of initial dose YES Abbreviations: APAP, acetaminophen; IV, intravenous; PCA, patient-controlled analgesia; SCD, sickle cell disease. Begin around-the-clock dosing • Long-acting oral opiate • PCA • Opiate infusion (Class III) Disposition with short opiate prescription with hematology follow-up Class Of Evidence Definitions Each action in the clinical pathways section of Emergency Medicine Practice receives a score based on the following definitions. Class I • Always acceptable, safe • Definitely useful • Proven in both efficacy and effectiveness Level of Evidence: • One or more large prospective studies are present (with rare exceptions) • High-quality meta-analyses • Study results consistently positive and compelling Class II • Safe, acceptable • Probably useful Level of Evidence: • Generally higher levels of evidence • Non-randomized or retrospective studies: historic, cohort, or case control studies • Less robust RCTs • Results consistently positive Class III • May be acceptable • Possibly useful • Considered optional or alternative treatments Level of Evidence: • Generally lower or intermediate levels of evidence • Case series, animal studies, consensus panels • Occasionally positive results Indeterminate • Continuing area of research • No recommendations until further research Level of Evidence: • Evidence not available • Higher studies in progress • Results inconsistent, contradictory • Results not compelling Significantly modified from: The Emergency Cardiovascular Care Committees of the American Heart Association and represen- tatives from the resuscitation councils of ILCOR: How to Develop Evidence-Based Guidelines for Emergency Cardiac Care: Quality of Evidence and Classes of Recommendations; also: Anonymous. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Emergency Cardiac Care Committee and Subcommittees, American Heart Association. Part IX. Ensuring effectiveness of communitywide emergency cardiac care. JAMA. 1992;268(16):2289-2295. This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual needs. Failure to comply with this pathway does not represent a breach of the standard of care. Copyright © 2011 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine. Emergency Medicine Practice © 2011 10 ebmedicine.net • August 2011 syndrome, the alveolar-arterial gradient was the best predictor of clinical severity and the need for blood transfusion.70 Based on this evidence, the NIH guidelines recommend exchange transfusion for patients with Pa O2 below 70 mm Hg on room air. Contrary to the NIH guidelines, the decision to transfuse can usually be made clinically without the evaluation of arterial blood. Patients with pulmonary infiltrate and marked respiratory distress or pulse oximetry below 90% will almost always require transfusion, and measurements of arterial blood gases should not delay therapy. ment in clinical outcomes (transfusion, length of stay, pain scores) and was associated with significant patient discomfort. Noninvasive ventilation was associated with more rapid improvement in physiological indices of oxygenation. To date, evidence is not sufficient to recommend noninvasive ventilation for acute chest syndrome. Steroids Steroids are not recommended for the treatment of acute chest syndrome unless there is concurrent exacerbation of asthma. One randomized trial of 43 episodes of acute chest syndrome showed a decrease in length of stay, duration of pain, and opiate administration with administration of steroids. Steroids were also associated with increased rates of readmission within 72 hours.74 A retrospective review of 129 episodes of acute chest syndrome confirmed the association between steroids and readmisssions.75 Treatment For Acute Chest Syndrome Evidence for the various therapies is discussed below. Treatment of acute chest syndrome includes all the treatments for simple VOC including analgesia, maintenance fluids, and incentive spirometry, in addition to standard therapies including IV antibiotics and exchange transfusion. Emergent hematology consultation is indicated for all cases of acute chest syndrome. Disposition For Acute Chest Syndrome The NIH guidelines recommend that serial arterial blood gases be measured in patients with acute chest syndrome and that all patients with worsening alveolar-arterial gradients be managed in an intensive care setting.70 These recommendations are based on somewhat circular logic. In the study that led to these particular guidelines, patients were triaged to the intensive care unit (ICU) on the basis of clinical assessments, not blood gas data. Of all objective indicators, worsening of the alveolar-arterial gradient correlated most closely with the clinical decision to admit the patient to the ICU. This finding suggests that arterial blood gas evaluation can assist but should never supersede clinical judgment and that patients can be assigned to an appropriate level of care without the repeated use of this invasive test. Patients with confirmed or suspected acute chest syndrome should not be discharged from the ED. Oxygen There is no specific evidence regarding oxygen administration for patients with acute chest syndrome, thus the guidelines for VOC should be followed: administer supplemental oxygen to hypoxic patients only. Antibiotics The MACSS identified Chlamydia (now Chlamydophila) pneumoniae as the organism most commonly isolated from sputum in patients with acute chest syndrome,69 and the cooperative study of SCD identified Streptococcus pneumonia as the organism most frequently isolated from the blood.61 Antibiotics should cover both typical and atypical organisms. Transfusion In patients with worsening respiratory distress, hypoxemia, or arterial-alveolar gradient, exchange transfusion is recommended with a goal of increasing hemoglobin A levels above 70%. If exchange transfusion is not available, simple transfusion is recommended. In observational studies, transfusion (simple or exchange) has been associated with improvement of arterial blood gas indices of oxygenation69,71 and decreases in serum inflammatory mediators.72 One nonrandomized comparison of simple versus exchange transfusion did not show difference in outcomes, but this may be due to the fact that recipients of exchange transfusion were more critically ill.65 Stroke Stroke is one of the most devastating complications of SCD. Children with SCD have an approximately 300-fold increase in the rate of stroke as compared with children without SCD.76,77 Strokes occur most commonly in children before the age of 10 and are uncommon between 20 and 29 years of age, with a second peak after the age of 29.78 Because there are no prospective clinical data to help guide the acute evaluation or management of stroke in individuals with SCD, recommendations are based on indirect evidence and expert consensus. In contrast to conventional thrombotic or embolic stroke, the mechanism for ischemic stroke in children with SCD is thought to result from abnormal cell adhesion, intravascular sickling, and abnormal smooth muscle tone. In adults with SCD, the etiology of stroke is thought to be due to the Noninvasive Ventilation An open-label randomized trial of 71 episodes of acute chest syndrome found that early noninvasive ventilation was not associated with any improveAugust 2011 • ebmedicine.net 11 Emergency Medicine Practice © 2011 same thromboembolic mechanisms that cause stroke in the general population. For this reason, the recommendations for treatment of stroke are different for children and adults. For individuals with SCD, the evaluation of suspected stroke should include a careful history including potential precipitants of vaso-occlusion (especially infection), time of onset, and the nature of symptoms. Laboratory evaluation is the same as for VOC, except a type and screen should be included immediately because transfusion is highly likely. Emergent noncontrast or perfusion CT scan is indicated in children and adults with suspected acute stroke. asplenia that predisposes to infections with encapsulated organisms. For this reason, fever in the SCD patient must be approached with great caution. The NIH clinical guidelines for the management of fever are based mostly on expert consensus since clinical evidence in this area is lacking. In addition to sources of infection that are common in the general population, patients with SCD are at increased risk for bacteremia, meningitis, and osteomyelitis. The implementation of penicillin prophylaxis followed by pneumococcal vaccines has dramatically reduced the number of deaths due to bacterial sepsis in patients with SCD. Data reported in 2010 from the Dallas Newborn Cohort (the largest cohort of individuals followed for SCD) indicated that bacterial sepsis is no longer the most common cause of death in SCD.81 In cases of sepsis, the most common cause of bacterial infection in SCD is streptococcal pneumonia. Observational data in the post-pneumococcal vaccine era suggest that while serious bacterial infections with streptococcal pneumonia still occur, rates are much lower (44 infections in 4108 patient-years of data).82 The ED evaluation of a patient with SCD who has a fever should include a careful search for infectious causes. Always consider meningitis, septic arthritis, and osteomyelitis (specifically within the spine) in addition to standard infections. The NIH guidelines recommend the following studies in individuals with SCD and fever when the source is not clear46: • CBC • Blood culture • Urine culture • Throat culture • Chest radiograph • Urinalysis • Lumbar puncture (on toxic-appearing children) • Subperiosteal fluid aspiration and culture in patients with bone pain • Arthrocentesis for acute arthritis Treatment For Stroke Recommendations for the management of stroke in SCD are based almost entirely upon expert opinion. In children with SCD, thrombolysis is contraindicated, and the treatment for acute stroke is exchange transfusion. In one retrospective cohort, immediate exchange transfusion was associated with lower rates of recurrent stroke when compared to simple transfusion.79 In adults with SCD who present with stroke, it is recommended that patients receive conventional therapy as indicated. Tissue plasminogen activator (tPA) has never been studied in patients with SCD, so it is recommended that administration of tPA be in accordance with institutional guidelines and in consultation with a neurologist and hematologist. In children with transient ischemic attacks (TIAs), recommended treatment is early initiation of prophylactic exchange transfusion therapy. When TIA is suspected, the diagnosis will usually be unclear; thus, semiemergent magnetic resonance imaging (MRI) is indicated. Transfusion has been shown to prevent stroke in children with SCD who are at increased risk because of cerebrovascular disease.80 The presence or absence of anatomical/vascular risk factors on MRI will guide the hematologist’s decision to initiate secondary prevention by means of chronic transfusions. A single case report exists on the use of inhaled nitric oxide in a child in whom postoperative stroke occurred. Although the child made an excellent recovery, no conclusions can be drawn with respect to the efficacy of nitric oxide in acute stroke related to SCD. Beyond this case report, there has been essentially no clinical investigation with regard to the acute management of stroke in SCD. Several controversies exist with regard to the primary and secondary prevention of stroke, but these have limited relevance for the emergency clinician. The most controversial recommendation in this guideline involves aspirating from infected bone prior to administering antibiotics. This recommendation is based on the fact that radiographic appearance of noninfected bone and osteomyelitis may be similar in patients with SCD, and infection may be obscured by the administration of antibiotics prior to culture of the affected area. Although use of antibiotics prior to culture in SCD patients with bone pain may complicate later treatment decisions, this recommendation must be weighed against the possible consequences of delaying antimicrobial coverage in patients in whom the potential to deteriorate is significant, especially when a clinician skilled in bone aspiration is not immediately available. In clinically toxic patients, antibiotics should not be delayed to obtain subperiosteal cultures. Fever Sickle cell disease represents a state of immunocompromise due to increased bone marrow turnover, altered complement activation, and functional Emergency Medicine Practice © 2011 12 ebmedicine.net • August 2011 which can broadly be divided into 3 categories: bleeding (both internal and external), decreased RBC production, and increased RBC destruction. The key differentiating point for the emergency clinician is to determine whether the anemia is due to splenic sequestration, hemolysis, or transient red cell aplasia. (See Table 6.) Splenic sequestration and hemolysis will both cause elevated reticulocyte counts, with only hemolysis showing elevations in indirect bilirubin, ALT, and LDH. Transient red cell aplasia will be associated with low or zero reticulocyte counts. Key points in the history include identifying the baseline hemoglobin level, symptoms of anemia, prior history of splenic sequestration, prior history of transfusions, and possible precipitating events (eg, infection, stress). Physical examination may show the classic findings of anemia (pale conjunctiva and mucous membranes) in addition to a palpably enlarged spleen. Laboratory evaluation is the same as for VOC, with inclusion of type and crossmatch for 2 units of blood. Treatment For Fever For confirmed infections, standard treatment for the specific infection is indicated. When a serious source of infection cannot be identified in the ED, children who meet the following criteria can be given 1 dose of IV antibiotic that covers Haemophilus influenzae and Streptococcus pneumonia (eg, ceftriaxone 75 mg/ kg) and discharged with follow-up in 24 hours, provided: • They have remained clinically stable for 3 hours after the antibiotic dose; • Endemic S pneumoniae in the community is likely to be antibiotic-sensitive; • The parents have been appropriately trained, have a history of compliance with the prophylactic administration of penicillin, keep appointments reliably, and have emergency access to the hospital; • There is no infiltrate on chest radiograph or abnormal oxygen saturation levels; • The WBC count is not greater than 30,000/mcL or less than 5,000/mcL and the platelet count is less than 100,000/mcL; • Hemoglobin level is greater than 5 g/dL; and • The patient has no history of sepsis. Treatment For Splenic Sequestration All clinical trials relating to splenic sequestration in SCD focus on primary and secondary prevention measures; there are no studies regarding the acute management of splenic sequestration. The keys to management measures are as follows: • Immediate packed red cell transfusion once the condition is identified • Serial blood count measurements after transfusion to evaluate for overcorrection of anemia • Serial examinations to detect evidence of vasoocclusion after transfusion (stroke, pain, acute chest syndrome) Splenic Sequestration Splenic sequestration is a life-threatening cause of a rapid drop in hemoglobin in children with SCD.83 In a retrospective Jamaican cohort, mortality associated with this complication was 12%.84 Although splenic sequestration usually occurs in children (as young as 5 weeks85), it can be seen at any age. Adult cases usually involve patients with HbSC or HbS beta thalassemia.86-91 Estimates vary, but splenic sequestration accounts for 6.6% to 16.6% of deaths due to SCD.92,93 Splenic sequestration is caused by the trapping and removal of intrasplenic red cells from the systemic circulation. The risk is thought to be greatest in children because they produce sickled RBCs but have not yet undergone splenic auto-infarction. Massive amounts of blood can be sequestered in the spleen, and the condition can be fatal within a matter of hours. The disease can be thought of as occurring in 2 equally dangerous phases: pre-transfusion and post-transfusion. In the pre-transfusion phase, patients experience a rapid, life-threatening fall in hemoglobin level as blood is sequestered in the spleen. In the post-transfusion phase, red cells sequestered in the spleen are remobilized, thus producing increases in hemoglobin levels well beyond those expected with transfusion. In the post-transfusion phase, patients are at risk for vaso-occlusive phenomena including pain, stroke, and acute chest syndrome. The differential diagnosis of acute splenic sequestration includes other causes of acute anemia, August 2011 • ebmedicine.net Most of the controversy concerning management of splenic sequestration centers on optimal methods to prevent further attacks. Regimens include chronic transfusion, splenectomy, and partial splenectomy. All patients with acute splenic sequestration should be admitted to a monitored bed where CBCs and neurologic examinations can be performed frequently (at least every 4 hours). Table 6. Differentiating Common Causes Of Acute Anemia In Sickle Cell Disease 13 Condition Anemia Markers of Hemolysis Reticulocyte Count Splenic sequestration Severe Absent Elevated Hemolysis Severe Present Elevated Transient red cell aplasia Severe Absent Decreased Emergency Medicine Practice © 2011 Transient Red Cell Aplasia parvovirus infection is estimated to be 11.3 events per 100 patient-years, and 62% of these infections result in TRCA.94 The history should elicit any symptoms of anemia (pallor, fatigue, dyspnea on exertion, chest pain), and of recent infection (fever, cough, rash). The physical examination should focus on signs of anemia and splenic enlargement. In rare cases, splenic sequestration can occur simultaneously with TRCA, leading to catastrophic results if not recognized.95 Laboratory evaluation is the same as for VOC (see Diagnostic Studies section on page 6), with the Transient red cell aplasia (TRCA) is a common cause of acute anemia in patients with SCD. Evidence to guide therapy is based largely on anecdote, case report, and expert consensus. Most commonly caused by acute infection with parvovirus B19, TRCA infection results in a transient suppression of red cell production (approximately 5-7 days) via a direct cytotoxic effect on erythroid precursors. Because the lifespan of red cells in SCD is markedly reduced, this transient suppression can result in significant decreases in hemoglobin levels. The incidence of Risk Management Pitfalls For Sickle Cell Disease 1. “I thought it was just a pain crisis.” Always consider non-SCD-related conditions in your differential. For example, for right lower quadrant pain, consider appendicitis, kidney stone, and gynecological causes before presuming VOC. For chest pain, consider acute coronary syndromes, pulmonary embolism, or pneumothorax before presuming acute chest syndrome. complications after blunt eye trauma, even if hyphema is not apparent. 6. “I gave the patient a prescription for iron because she was anemic. I didn’t realize this would cause liver problems.” Never prescribe iron for patients with SCD. These patients are usually iron-overloaded. 7. “The creatinine was normal. How was I supposed to know the patient had kidney dysfunction?” Assume that all patients with SCD have some degree of renal dysfunction, even if the creatinine level is normal. Supranormal proximal tubule function creates falsely low creatinine in this patient population. Take this into consideration when prescribing NSAIDs and when ordering imaging studies with IV contrast. 2. “He’s had this back pain before, so it can’t be anything dangerous.” Consider epidural abscess and spinal osteomyelitis in the differential of midline back pain, even when fever is absent. 3. “The hemoglobin was low, so I gave blood. I didn’t think this would cause a stroke.” Never transfuse a patient simply because hemoglobin is low. Elevating the hemoglobin above baseline can cause hyperviscosity, pain, acute chest syndrome, and stroke. 8. “I didn’t know that a few liters of normal saline could be harmful.” Using bolus normal saline to treat sickle cell crisis presents several problems. Excess IV fluid can result in atelectasis, which may precipitate acute chest syndrome. Large amounts of normal saline can produce a hyperchloremic metabolic acidosis, which may promote sickling. 4. “I thought the patient had sickle cell trait, so I withheld pain medicines.” When it appears that a patient has sickle cell trait on hemoglobin electrophoresis, make sure the patient did not receive a transfusion within 90 days of having the test performed. Recent transfusion renders the electrophoresis useless for diagnostic purposes. 9. “I thought the patient was just faking because he had normal vital signs.” Most patients with VOC will not exhibit vital sign abnormalities. 5. “The patient doesn’t have SCD, so I never thought to check intraocular pressure for such minor eye trauma.” In cases of direct eye trauma, patients with SCD and sickle cell trait should be treated the same way. Many patients do not know that they carry the trait or will fail to mention it unless prompted. Both SCD and sickle cell trait increase the risk for catastrophic ophthalmologic Emergency Medicine Practice © 2011 10. “The patient wasn’t black, and I thought SCD only occurs in people of African descent.” Sickle cell disease has been described in all races and should no longer be considered exclusive to black persons. 14 ebmedicine.net • August 2011 inclusion of type and screen in the event the patient requires transfusion. The hallmark finding of TRCA is reticulocytopenia. Anemia and reticulocytopenia will typically develop 5-7 days after exposure to the virus. The decrease in hemoglobin will usually be less precipitous and less severe than splenic sequestration, although in one series mean nadir hemoglobin levels were 3.9 mg/dL.96 Treatment For Ophthalmologic Complications In 2002, a systematic review evaluated evidence to guide management of hyphema in patients with SCD or sickle cell trait. Recommendations are based mostly on physiologic data from rabbit models with few clinical trials having been performed.104 Treatment of traumatic hyphema, in addition to consultation with an ophthalmologist, should include the following: • Head-of-bed elevation to 30° • Topical timolol: In one series, timolol did not promote anterior chamber deoxygenation.105 • Topical brimonidine or apraclonidine as a second agent • Topical dorzolamide as a third agent The following treatments should be avoided because of their potential to promote sickling or exacerbate the physiologic alterations present in SCD: • Mannitol (increases serum osmolality) • Glycerin (increases serum osmolality) • Acetazolamide (increases serum osmolality and lowers serum pH) • Topical epinephrine (thought to promote anterior chamber deoxygenation) Treatment For Transient Red Cell Aplasia There are no experimental trials to guide management of TRCA. Management includes IV immune globulin (IVIG) administration, red cell transfusion, and isolation from pregnant patients and pregnant healthcare workers. Unlike splenic sequestration, for which transfusion should be immediate, NIH guidelines recommend transfusion in TRCA only if symptomatic anemia develops. Data to support the use of IVIG come from a case report of a patient with leukemia97,98 and a case series of patients with HIV infection, all of whom had chronic parvovirus infection.99 In all patients, complete resolution of anemia and viremia occurred after IVIG treatment. Because maternal infection with parvovirus is associated with a 10% rate of fetal hydrops,100 all patients with TRCA should be isolated and contact with pregnant healthcare workers prohibited. All patients with TRCA should be admitted for serial CBC and reticulocyte counts, and they can be discharged when reticulocytosis has resumed and there are no significant symptoms of anemia. A 2011 Cochrane Review found that the antifibrinolytic agent epsilon-aminocaproic acid is associated with decreased incidence of secondary hemorrhage after traumatic hyphema.106 Although this agent has not been specifically tested in SCD and sickle cell trait, experts speculate that it may be beneficial since patients with SCD have increased rates of fibrinolysis. The threshold for admitting patients with SCD (or sickle cell trait) and traumatic hyphema should be extremely low. In the absence of clear evidence, the author recommends ophthalmologic consultation, followed by admission for medical therapy and serial intraocular pressure measurements. Ophthalmologic Complications Traumatic hyphema is an ophthalmologic emergency in patients with SCD. It is also an emergency in patients with sickle cell trait. Because the rheologic properties of blood are altered in patients with SCD, traumatic hyphema has been associated with the development of acute narrow-angle glaucoma, frequent rebleeding into the hyphema, and delayed complications such as optic nerve atrophy and central retinal artery occlusion.101 Glaucoma is thought to result from RBC vaso-occlusion in the trabecular meshwork, and rebleeding is thought to result from the increased steady-state thrombolysis in SCD.102 Evaluation of any eye trauma in the patient with SCD or sickle cell trait should include a careful history (to determine the mechanism and detect foreign bodies), visual-acuity and visual-field testing, a slit-lamp examination, and intraocular pressure measurements. The presence of hyphema warrants emergent ophthalmologic consultation. Some advocate for consultation in all cases of direct trauma to the eye, since elevated intraocular pressures have been reported in the absence of hyphema.103 Standard laboratory studies are indicated for SCD patients with eye trauma, since many will be admitted for serial intraocular pressure measurements. August 2011 • ebmedicine.net Priapism Priapism, defined as sustained, undesired penile erection, is a common complication for men with SCD. According to a questionnaire in one study, the cumulative incidence of priapism by the age of 20 was 89%.107 Recurrent episodes, even if properly treated, can result in fibrosis and impotence. The etiology of priapism in SCD is vaso-occlusion. As such, treatments that are effective for pain and acute chest syndrome are likely to be effective for priapism. Unfortunately, clinical trial data are lacking. The history and physical examination focuses on potential triggers, including infection, stress, dehydration, and ingestion of certain medications (trazodone or phosphodiesterase inhibitors such as sildenafil). Onset and duration directs treatment. The physical examination specifically looks 15 Emergency Medicine Practice © 2011 Summary for signs of local tissue ischemia. Recommended laboratory studies include CBC, reticulocyte count, basic metabolic panel, liver function tests, type and screen, and lactate dehydrogenase. Serum lactate is a marker for tissue ischemia but is optional in evaluating these patients. Sickle cell disease is a complex disease with manifestations that involve every organ system. Although high-quality evidence is lacking, several recommendations have been made that will likely improve the care of individuals with SCD who present to the ED. Treatment For Priapism Treatment is based on the duration of priapism • Less than 2 hours: Analgesics, IV fluids • More than 2 hours: First-line therapy: • Local intracavernosal aspiration and injection with 1:1,000,000 solution of epinephrine in saline. In a prospective single arm study of 39 cases of priapism treated with epinephrine injection, detumescence was achieved in 37 of 39 patients. The procedure was unsuccessful in 2 patients who presented with priapism of greater than 24 hours duration. Second-line therapies: • Exchange transfusion: Successful detumescence with exchange transfusion has been reported several times in the literature.108-111 However, since the use of this therapy has been associated with adverse neurologic events,112-114 it should be employed only after conventional therapies have failed. • Epidural anesthesia: There are 2 reports in the literature of successful treatment of priapism with epidural anesthesia.115,116 Case Conclusions You returned to the bedside of the young man with SCD who presented with the complaint of sickle cell crisis. After reviewing the literature, you now have answers to the clinical questions that were raised: • Can this patient be having a crisis without a drop in hemoglobin? Yes. Painful crises are not associated with drops in hemoglobin; furthermore, high hemoglobin (10 mg/dL is very high for individuals with SCD) is associated with increased viscosity, which may predispose to pain. • Is there a blood test I can do to confirm that he is truly having a crisis? No. Performing a peripheral smear to look for sickled cells will not yield any information about whether the patient is in crisis, nor will any other readily available laboratory test. The patient had normal vital signs and looked comfortable, which initially made you skeptical about his 10/10 pain, but you realized that vital sign abnormalities are uncommon with VOC. The patient told you he has regular follow-up in a hematology clinic and access to dilaudid prescriptions through his hematolo gist. He assured you that he would not come to the ED unless the pain was intractable. • Is the patient addicted to opiates or drug-seeking? It is unlikely, but you realized that the ED is not the time or the place to evaluate for addiction. You treated the patient’s pain aggressively and relayed any concerns to the hematologist who will be following the patient. Once priapism has been present for more than 2 hours, intracavernosal epinephrine injection should be initiated immediately. If this fails, consider exchange transfusion or epidural anesthesia in consultation with urology and hematology. Time- And Cost-Effective Strategies For Patients With Sickle Cell Disease 1. Limit the use of oxygen. Oxygen may be detrimental because of the potential for myelosuppression and has never been shown to improve outcomes. Administer supplemental oxygen only for hypoxic patients. 3. Limit laboratory testing. In patients presenting with simple pain without other symptoms – especially if discharge is likely – laboratory tests are not necessary. Liver function tests and markers of hemolysis are not indicated unless patients have worsening icterus or significant decreases in hemoglobin from baseline. 2. Consider oral rehydration and oral opiates, especially in children. Oral opiates are associated with shorter timeto-opiates. Consider oral opiates and hydration especially when pain is perceived to be mild with potential for discharge. Emergency Medicine Practice © 2011 4. Order an incentive spirometer for all admitted patients. This simple intervention may decrease the incidence of inpatient acute chest syndrome, which is a high-cost, high-mortality event. 16 ebmedicine.net • August 2011 • What fluids should I administer? You instructed the nurse to stop the 1-L bolus of NS, and start an infusion of D5 ½ NS at the maintenance rate. • What kind of opiates should I give this patient? You administered 2 doses of 2-mg IV hydromorphone 15 minutes apart, and the patient reported his pain score was down to 6/10. You started the patient on a hydromorphone PCA with a basal rate of 0.1 mg/hr and demand doses of 0.2 mg every 8 minutes. • Should I administer supplemental oxygen? No. The patient is not hypoxic, so you stopped all supplemental oxygen. • Should I give him IV ketorolac? Are there any other medications that might help? No. The patient’s creatinine level came back at 0.9. Because patients with SCD have supranormal proximal tubule function, you know that his renal function may be significantly decreased even though his creatinine is normal. You elected not to give NSAIDs. You gave the patient acetaminophen, diphenhydramine, and an incentive spirometer. You decided not to give magne sium or ketamine. 8. 9. 10. 11. 12. 13. 14. After 3 hours in the ED, you reassessed the patient. His pain was well controlled, but he did not think he would be able to go home. You contacted the inpatient service and admitted him to the hospital. Five days later, he was transitioned to oral analgesics and discharged from the hospital. 15. 16. References 17. Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report. The most informative references cited in this paper, as determined by the author, are noted by an asterisk (*) next to the number of the reference. 1. 2. 3. 4. 5. 6. 7. 18. 19. 20.* 21.* 22.* Therrell BL, Hannon WH. National evaluation of US newborn screening system components. Ment Retard Dev Disabil Res Rev. 2006;12:236-245. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38:S512-S521. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Archives of Internal Medicine. 6 (5):517–521. doi:10.1001/archinte.1910. http:// archinte.ama-assn.org/cgi/content/summary/VI/5/517. Vekilov PG. Sickle-cell haemoglobin polymerization: is it the primary pathogenic event of sickle-cell anaemia? Br J Haematol. 2007;139:173-184. Villagra J, Shiva S, Hunter LA, et al. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood. 2007;110:2166-72. Sugihara K, Sugihara T, Mohandas N, et al. Thrombospondin mediates adherence of CD36+ sickle reticulocytes to endothelial cells. Blood.1992;80:2634-2642. Belcher JD, Mahaseth H, Welch TE, et al. Critical role of August 2011 • ebmedicine.net 23.* 24. 25. 26. 27. 17 endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. Am J Physiol Heart Circ Physiol. 2005;288:H2715-H2725. Belcher JD, Marker PH, Weber JP, et al. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood. 2000;96:24512459. Blann AD, Marwah S, Serjeant G, et al. Platelet activation and endothelial cell dysfunction in sickle cell disease is unrelated to reduced antioxidant capacity. Blood. 2003;14:255-259. Canalli AA, Franco-Penteado CF, Saad ST, et al. Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation. Haematologica. 2008;93:605-609. Graido-Gonzalez E, Doherty JC, Bergreen EW, et al. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood.1998;92:2551-2555. Brun M, Bourdoulous S, Couraud PO, et al. Hydroxyurea downregulates endothelin-1 gene expression and upregulates ICAM-1 gene expression in cultured human endothelial cells. Pharmacogenomics J. 2003;3:215-226. Conran N, Fattori A, Saad ST, et al.. Increased levels of soluble ICAM-1 in the plasma of sickle cell patients are reversed by hydroxyurea. Am J Hematol. 2004;76:343-347. Duits AJ, Pieters RC, Saleh AW, et al. Enhanced levels of soluble VCAM-1 in sickle cell patients and their specific increment during vasoocclusive crisis. Clin Immunol Immunopathol.1996;81:96-98. Duits AJ, Rojer RA, van Endt T, et al. Erythropoiesis and serum sVCAM-1 levels in adults with sickle cell disease. Ann Hematol. 2003;82:171-174. Glassberg J, Spivey JF, Strunk R, et al. Painful episodes in children with sickle cell disease and asthma are temporally associated with respiratory symptoms. J Pediatr Hematol Oncol. 2006;28:481-485. Boyd JH, Macklin EA, Strunk RC, et al. Asthma is associated with increased mortality in individuals with sickle cell anemia. Haematologica. 2007;92:1115-1118. Boyd JH, Macklin EA, Strunk RC, et al. Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Blood. 2006;108:2923-2927. Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med. 2008;359:2254-2265. 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;330:1639-1644. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148:94-101. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325:1116. McClish DK, Smith WR, Dahman BA, et al. Pain site frequency and location in sickle cell disease: the PiSCES project. Pain. 2009;145:246-251. Jacob E, Mueller BU. Pain experience of children with sickle cell disease who had prolonged hospitalizations for acute painful episodes. Pain Med. 2008;9:13-21. Sidman JD, Fry TL. Exacerbation of sickle cell disease by obstructive sleep apnea. Arch Otolaryngol Head Neck Surg. 1988;114:916-917. Jones S, Duncan ER, Thomas N, et al. Windy weather and low humidity are associated with an increased number of hospital admissions for acute pain and sickle cell disease in an urban environment with a maritime temperate climate. Br J Haematol. 2005;131:530-533. Vichinsky, E. Overview of the clinical manifestations of sickle cell disease. Available online at www.utdol.com. Accessed 6/28/2011. Emergency Medicine Practice © 2011 28. Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Acad Emerg Med. 2003;10:390392. 29. Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med. 2001;38:633-638. 30. Garra G, Singer AJ, Taira BR, et al. Validation of the WongBaker FACES Pain Rating Scale in pediatric emergency department patients. Acad Emerg Med. 2010;17:50-54. 31. Solomon LR. Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void. Blood. 2008;111:997-1003. 32. Elander J, Lusher J, Bevan D, et al. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci Med. 2003;57:1683-1696. 33.* Aisiku IP, Smith WR, McClish DK, et al. Comparisons of high versus low emergency department utilizers in sickle cell disease. Ann Emerg Med. 2009;53:5875-5893. 34.* Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011;305:893-902. 35.* Bartolucci P, El Murr T, Roudot-Thoraval F, et al. A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults. Blood. 2009;114:37423747. 36. Ernst AA, Weiss SJ, Johnson WD, et al. Blood pressure in acute vaso-occlusive crises of sickle cell disease. South Med J. 2000;93:590-592. 37. Britto MC, Freire EF, Bezerra PG, et al. Low income as a protective factor against asthma in children and adolescents treated via the Brazilian Unified Health System. J Bras Pneumol. 2008;34:251-255. 38. Chapman JI, El-Shammaa EN, Bonsu BK. The utility of screening laboratory studies in pediatric patients with sickle cell pain episodes. Am J Emerg Med. 2004;22:258-263. 39. Ballas SK, Files B, Luchtman-Jones L, et al. Safety of purified poloxamer 188 in sickle cell disease: phase I study of a nonionic surfactant in the management of acute chest syndrome. Hemoglobin. 2004;28:85-102. 40. Bouchair N, Manigne P, Kanfer A, et al. Prevention of sickle cell crises with multiple phlebotomies. Arch Pediatr. 2000;7:249-255. 41. Serjeant GR, Petch MC, Serjeant BE. The in vivo sickle phenomenon: a reappraisal. J Lab Clin Med. 1973;81:850-856. 42. Embury SH. The not-so-simple process of sickle cell vasoocclusion. Microcirculation. 2004;11:101-113. 43. Mohammed FA, Mahdi N, Sater MA, et al. The relation of Creactive protein to vasoocclusive crisis in children with sickle cell disease. Blood Cells Mol Dis. 2010;45:293-296. 44. Standards for the care of adults with sickle cell disease in the UK. 2008. available online http://www.nhlbi.nih.gov/ guidelines/scd/index.htm. Accessed 6/28/2011. 45. Benjamin L, Dampier CD, Jacox AK, et al. Guideline for the management of acute and chronic pain in sickle cell disease. Glenview, IL: American Pain Society. 1999. 46. National Institutes of Health. The Management of Sickle Cell Disease. 4th ed. Bethesda, MD: National Heart, Lung, and Blood Institute; 2002:59-74. NIH Publication 02-2117. 47. Robieux IC, Kellner JD, Coppes MJ, et al. Analgesia in children with sickle cell crisis: comparison of intermittent opioids vs. continuous intravenous infusion of morphine and placebo-controlled study of oxygen inhalation. Pediatr Hematol Oncol.1992;9:317-326. 48. Telfer P, Criddle J, Sandell J, et al. Intranasal diamorphine for acute sickle cell pain. Arch Dis Child. 2009;94:979-980. 49.* van Beers EJ, van Tuijn CF, Nieuwkerk PT, et al. Patientcontrolled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial. Am J Hematol. 2007;82:955-960. Emergency Medicine Practice © 2011 50.* Gonzalez ER, Bahal N, Hansen LA, et al. Intermittent injection vs patient-controlled analgesia for sickle cell crisis pain. Comparison in patients in the emergency department. Arch Intern Med. 1991;151:1373-1378. 51. Jacobson SJ, Kopecky EA, Joshi P, et al. Randomised trial of oral morphine for painful episodes of sickle-cell disease in children. Lancet. 1997;350:1358-1361. 52. Simckes AM, Chen SS, Osorio AV, et al. Ketorolac-induced irreversible renal failure in sickle cell disease: a case report. Pediatr Nephrol. 1999;13:63-67. 53. Schaller S, Kaplan BS. Acute nonoliguric renal failure in children associated with nonsteroidal antiinflammatory agents. Pediatr Emerg Care. 1998;14:416-418. 54.* Hardwick WE, Jr., Givens TG, Monroe KW, et al. Effect of ketorolac in pediatric sickle cell vaso-occlusive pain crisis. Pediatr Emerg Care. 1999;15:179-182. 55.* Wright SW, Norris RL, Mitchell TR. Ketorolac for sickle cell vaso-occlusive crisis pain in the emergency department: lack of a narcotic-sparing effect. Ann Emerg Med. 1992;21:925-928. 56.* Perlin E, Finke H, Castro O, et al. Enhancement of pain control with ketorolac tromethamine in patients with sickle cell vaso-occlusive crisis. Am J Hematol. 1994;46:43-47. 57.* Dunlop R, Bennett KCLB. Pain management for sickle cell disease in children and adults. Cochrane Database of Systematic Reviews. 2006;2:Art. No. CD003350. DOI: 10.1002/1465 1858, pub 2. 58. Guy RB, Gavrilis PK, Rothenberg SP. In vitro and in vivo effect of hypotonic saline on the sickling phenomenon. Am J Med Sci. 1973;266:267-277. 59.* Clark MR, Guatelli JC, Mohandas N, et al. Influence of red cell water content on the morphology of sickling. Blood. 1980;55:823-830. 60.* Jenkins MT, Jones RF, Wilson B, et al. Congestive atelectasis; a complication of the intravenous infusion of fluids. Trans Meet Am Surg Assoc Am Surg Assoc. 1950;68:7-27. 61.* Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease. Blood. 1997;89:1787-1792. 62. Embury SH, Garcia JF, Mohandas N, et al. Effects of oxygen inhalation on endogenous erythropoietin kinetics, erythropoiesis, and properties of blood cells in sickle-cell anemia. N Engl J Med.1984;311:291-295. 63.* Lane PK, Embury SH, Toy PT. Oxygen-induced marrow red cell hypoplasia leading to transfusion in sickle painful crisis. Am J Hematol.1988;27:67-68. 64.* Bellet PS, Kalinyak KA, Shukla R, et al. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. N Engl J Med.1995;333:699-703 65. Bryant-Stephens T, Kurian C, Guo R, et al. Impact of a household environmental intervention delivered by lay health workers on asthma symptom control in urban, disadvantaged children with asthma. Am J Public Health. 2009;99 Suppl 3:S657-S665.6 66. Zempsky WT, Loiselle KA, Corsi JM, et al. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010;26:163167. 67. Koch J, Manworren R, Clark L, et al. Pilot study of continuous co-infusion of morphine and naloxone in children with sickle cell pain crisis. Am J Hematol. 2008;83:728-731. 68.* Benjamin LJ, Swinson GI, Nagel RL. Sickle cell anemia day hospital: an approach for the management of uncomplicated painful crises. Blood. 2000;95:1130-1136. 69.* 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;342:1855-1865. 70. Emre U, Miller ST, Rao SP, et al. Alveolar-arterial oxygen gradient in acute chest syndrome of sickle cell disease. J Pediatr. 18 ebmedicine.net • August 2011 1993;123:272-275. 71. Emre U, Miller ST, Gutierez M, et al. Effect of transfusion in acute chest syndrome of sickle cell disease. J Pediatr. 1995;127:901-904. 72. Liem RI, O’Gorman MR, Brown DL. Effect of red cell exchange transfusion on plasma levels of inflammatory mediators in sickle cell patients with acute chest syndrome. Am J Hematol. 2004;76:19-25. 73. Turner JM, Kaplan JB, Cohen HW, et al. Exchange versus simple transfusion for acute chest syndrome in sickle cell anemia adults. Transfusion. 2009;49:863-868. 74.* Bernini JC, Rogers ZR, Sandler ES, et al. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood.1998;92:3082-3089. 75. Strouse JJ, Takemoto CM, Keefer JR, et al. Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatr Blood Cancer. 2008;50:1006-1012. 76. Leikin SL, Gallagher D, Kinney TR, et al. Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics. 1989;84:500-508. 77. Fullerton HJ, Wu YW, Zhao S, et al. Risk of stroke in children: ethnic and gender disparities. Neurology. 2003;61:189194. 78. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91:288-294. 79. Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. J Pediatr. 2006;149:710-712. 80. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5-11. 81. Quinn CT, Rogers ZR, McCavit TL, et al. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115:3447-3452. 82. Hord J, Byrd R, Stowe L, et al. Streptococcus pneumoniae sepsis and meningitis during the penicillin prophylaxis era in children with sickle cell disease. J Pediatr Hematol Oncol. 2002;24:470-472. 83. Neonato MG, Guilloud-Bataille M, Beauvais P, et al. Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur J Haematol. 2000;65:155-164. 84. Emond AM, Collis R, Darvill D, Higgs DR, Maude GH, Serjeant GR. Acute splenic sequestration in homozygous sickle cell disease: natural history and management. J Pediatr.1985;107:201-206. 85. Airede AI. Acute splenic sequestration in a five-week-old infant with sickle cell disease. J Pediatr. 1992;120:160. 86. Aslam AF, Aslam AK, Dipillo F. Fatal splenic sequestration crisis with multiorgan failure in an adult woman with sickle cell-beta+ thalassemia. Am J Med Sci. 2005;329:141-143. 87. Hutchins KD, Ballas SK, Phatak D, et al. Sudden unexpected death in a patient with splenic sequestration and sickle cellbeta+-thalassemia syndrome. J Forensic Sci. 2001;46:412-414. 88. Koduri PR. Acute splenic sequestration crisis in adults with sickle cell anemia. Am J Hematol. 2007;82:174-5. 89. Koduri PR, Agbemadzo B, Nathan S. Hemoglobin S-C disease revisited: clinical study of 106 adults. Am J Hematol. 2001;68:298-300. 90. Koduri PR, Kovarik P. 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Management of 19 Emergency Medicine Practice © 2011 6. In patients admitted for VOC, which treatment is indicated to prevent the development of acute chest syndrome? a. IV fluids b. Patient-controlled analgesia c. Incentive spirometry d. Supplemental oxygen e. Exchange transfusion priapism in a child with sickle cell anemia; successful outcome using epidural analgesia. Can J Anaesth. 2007;54:642645. 116. Labat F, Dubousset AM, Baujard C, et al. Epidural analgesia in a child with sickle cell disease complicated by acute abdominal pain and priapism. Br J Anaesth. 2001;87:935-936 CME Questions Take This Test Online! 7. Which treatment is indicated for patients with pulmonary infiltrate and worsening dyspnea or hypoxemia? a. Steroids b. Hydroxyurea c. Thrombolysis d. Exchange transfusion Current subscribers receive CME credit absolutely free by completing the following test. Monthly on line testing is now available for current and archived issues. Visit http://www.ebmedicine.net/CME Take This Test Online! today to receive your free CME credits. Each issue includes 4 AMA PRA Category 1 CreditsTM, 4 ACEP Category 1 credits, 4 AAFP Prescribed credits, and 4 AOA Category 2A or 2B credits. 8. 1. In patients with SCD, painful crises are associated with a drop in hemoglobin. a. True b. False The treatment for transient red cell aplasia is: a. Supplemental oxygen b. Hydroxyurea c. IVIG d. Exchange transfusion 9. Patients with sickle cell trait are at risk for: a. Ophthalmologic complications after minor eye trauma b. Pulmonary hypertension c. Painful episodes d. Stroke 2. The genotype of SCD associated with the highest risk for avascular necrosis is a. HbSS b. HbSC c. HbS beta thalassemia0 d. Alpha thalassemia 10. In adults with SCD who present with acute stroke, tPA is contraindicated. a. True b. False 3. The laboratory test that can be used to objectively determine if a patient with SCD is truly having a painful episode is: a. Hemoglobin b. WBC c. Peripheral smear with sickled cells d. Troponin e. There is no reliable laboratory test to identify painful episodes 11. After initial treatment with fluids and analgesics, first-line therapy for priapism in patients with SCD is a. Intracavernosal drainage and epinephrine injection b. Exchange transfusion c. Epidural anesthesia d. Phlebotomy 4. Most SCD patients with true VOC will be hypertensive. a. True b. False 5. Which treatment is indicated in the management of every VOC? a. Normal saline b. Supplemental oxygen c. Opiates d. NSAIDs Emergency Medicine Practice © 2011 20 ebmedicine.net • August 2011 Board-Certified Emergency Physicians: Are you prepared for the ABEM LLSA Exam? Physician CME Information Date of Original Release: August 1, 2011. Date of most recent review: July 10, 2011. Termination date: August 1, 2014. Accreditation: EB Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: EB Medicine designates this enduring material for a maximum of 4 AMA PRA Category I Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. ACEP Accreditation: Emergency Medicine Practice is approved by the American College of Emergency Physicians for 48 hours of ACEP Category I credit per annual subscription. AAFP Accreditation: This Medical Journal activity, Emergency Medicine Practice, has been reviewed and is acceptable for up to 48 Prescribed credits per year by the American Academy of Family Physicians. AAFP Accreditation begins July 31, 2011. Term of approval is for 1 year from this date. Each issue is approved for 4 Prescribed credits. Credits may be claimed for 1 year from the date of each issue. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AOA Accreditation: Emergency Medicine Practice is eligible for up to 48 American Osteopathic Association Category 2A or 2B credit hours per year. Needs Assessment: The need for this educational activity was determined by a survey of medical staff, including the editorial board of this publication; review of morbidity and mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for emergency physicians. Target Audience: This enduring material is designed for emergency medicine physicians, physician assistants, nurse practitioners, and residents. Goals: Upon completion of this article, you should be able to: (1) demonstrate medical decision-making based on the strongest clinical evidence; (2) costeffectively diagnose and treat the most critical ED presentations; and (3) describe the most common medicolegal pitfalls for each topic covered. Discussion of Investigational Information: As part of the newsletter, faculty may be presenting investigational information about pharmaceutical products that is outside Food and Drug Administration-approved labeling. Information presented as part of this activity is intended solely as continuing medical education and is not intended to promote off-label use of any pharmaceutical product. Faculty Disclosure: It is the policy of EB Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CMEsponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. In compliance with all ACCME Essentials, Standards, and Guidelines, all faculty for this CME activity were asked to complete a full disclosure statement. 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August 2011 • ebmedicine.net 21 Emergency Medicine Practice © 2011 In This Month’s Pediatric Emergency Medicine Practice Evidence-Based Emergent Management of Bleeding Disorders Authors: Katherine Fullerton, MD Department of Emergency Medicine, Inova Fairfax Hospital for Children, Falls Church, VA; Assistant Professor, Virginia Commonwealth University School of Medicine, Richmond, VA Rick Place, MD Pediatric Medical Director, Department of Emergency Medicine, Inova Fairfax Hospital for Children, Falls Church, VA Children with both congenital (eg, hemophilia or von Willebrand disease) and acquired (eg, immune thrombocytopenia [ITP]) bleeding disorders frequently present to the emergency department with a wide variety of bleedingrelated problems ranging from petechiae to intracranial hemorrhage. In many instances, such as hemophilia or von Willebrand disease, the bleeding disorder has been previously diagnosed because of an abnormal family history or bleeding in infancy. However, in other instances, a patient may present with abnormal bleeding symptoms (such as a patient with ITP), and it is the role of the emergency clinician to facilitate the diagnosis and initiate therapy. This issue of Pediatric Emergency Medicine Practice provides up-todate guidelines and an evidence-based review of the most common bleeding disorders and management of specific bleeding emergencies in the ED. Do You See Pediatric Patients? If your answer is yes, it’s time you subscribe to Pediatric Emergency Medicine Practice. “Pediatric Emergency Medicine Practice provides the most up-to-date information on managing the most frequent and high-risk conditions all of us are called upon to treat in children. Each issue uses an organized, evidencebased approach to explain what we know and don’t know, the cutting edge and controversies, and the essentials of caring for children in emergency medicine.” — Joseph Toscano, MD, San Ramon, CA Pediatric Emergency Medicine Practice subscribers: Access this article at no charge at www.ebmedicine.net/pemp Non-subscribers: Purchase this article with CME at www.ebmedicine.net/pediatricbleedingdisorders or subscribe with a $100 savings at www.ebmedicine.net/subscribe using Promotion Code NP11M Emergency Medicine Practice © 2011 Visit www.ebmedicine.net/subscribe and use Promotion Code NP11M to save $100 off the regular price of $299, or call 1-800-249-5770 within 30 days. Your subscription includes monthly evidencebased print issues, full online access to searchable evidence-based archives, and over 150 CME credits. 22 ebmedicine.net • August 2011 In This Month’s EM Critical Care For the intensivist inside every emergency physician... Noninvasive Ventilation: Update On Uses For The Critically Ill Patient Authors: Jose Dionisio Torres, Jr., MD Clinical Instructor in Emergency Medicine, New York Hospital Queens, Flushing, NY Michael S. Radeos, MD, MPH Research Director, Department of Emergency Medicine, Flushing, NY; Assistant Professor of Emergency Medicine, Weill Cornell Medical College, New York, NY Noninvasive ventilation (NIV) is a method of delivering oxygen by positive pressure mask that allows the clinician to postpone or prevent invasive tracheal intubation in patients who present to the emergency department (ED) with acute respiratory failure (ARF). There are 2 primary modalities of NIV: continuous positive airway pressure (CPAP) and bi-level positive pressure ventilation (BPAP) where the inspiratory positive airway pressure (IPAP) is higher than the expiratory positive airway pressure (EPAP). Continuous positive airway pressure appears to be more effective in reducing the need for tracheal intubation and possibly mortality in patients presenting with acute cardiogenic pulmonary edema (ACPE). Bi-level positive pressure ventilation appears to be more effective in reducing mortality and the need for tracheal intubation in patients with an acute decompensation of chronic obstructive pulmonary disease (COPD). Proper patient selection is critical in the use of NIV for ED patients. They must be able to cooperate with the respiratory therapist and tolerate the often uncomfortable nasal or face mask. The emergency clinician must be vigilant for signs of clinical deterioration in these patients as they may need an emergent definitive airway placed. This issue of EMCC examines the evidence supporting the use of NIV in various causes of ARF and reviews potential complications. EB Medicine is pleased to announce the launch of the only publication dedicated to helping emergency clinicians enhance their critically ill patients’ care. “EM Critical Care (EMCC) is the first-ever peer-reviewed publication that provides succinct content designed to resonate with the intensivist that dwells inside every emergency physician. Providing evidence-based reviews on topics that define the emergency medicinecritical care interface, EMCC will be invaluable to clinicians seeking to enrich their care and understanding of the sickest, most complex patients in their ED.” — Robert Arntfield, MD, Editor-in-Chief EMCC subscribers: Access this article at no charge at www.ebmedicine.net/EMCC Visit www.ebmedicine.net/EMCCinfo (or call 1-800-249-5770) today for more information and an exclusive, limited-time discount. Non-subscribers: Purchase this article with CME at www.ebmedicine.net/NIV or subscribe with a $120 savings a www.ebmedicine.net/EMCCinfo August 2011 • ebmedicine.net 23 Emergency Medicine Practice © 2011 ACEP Conference Attendees: Take advantage of an exclusive discount to begin receiving all these benefits of an Emergency Medicine Practice subscription: RESIDENTS: Did you know you can receive Emergency Medicine Practice absolutely free? Evidence-Based Print & Online Issues Each month, you receive in-depth, peer-reviewed evidence-based content designed to help you improve your quality of patient care. Print issues are delivered directly to your door, and our complete archives are available online - that’s over 120 additional evidencebased issues. Simply visit www.ebmedicine.net/EMRA today to activate your free account — it’s easy and takes less than a minute! Free CME Your subscription includes FREE CME: up to 48 AMA PRA Category 1 CreditsTM, 48 ACEP Category 1 credits, 48 AAFP Prescribed credits, and 48 AOA Category 2A or 2B CME credits per year from current issues, plus an additional 144 credits online. SEMPA Members: Did you know you can subscribe to Emergency Medicine Practice for just $149? Your subscription includes 12 monthly evidence-based print issues, over 150 CME credits, and full online access to our complete evidence-based archives and additional CME. Free CME Tracking All of your CME credits are stored permanently on our website and can be viewed and printed at any time. Plus, you can add CME received from other sources, so you can easily keep track of all of your CME. A Free Subscription to EM Practice Guidelines Update: EM Practice Guidelines Update provides quick, easy-to-reference summaries of Clinical Policies relevant to your emergency practice. This monthly online resource provides you with practice-improving, evidence-based recommendations in just a few quick clicks. This free resource also includes 24 AMA PRA Category 1 CreditsTM per year. To subscribe, complete the order form below or visit www.ebmedicine.net/subscribe and enter Promotion Code NBEAT in your cart. Simply complete the form below to receive an exclusive ACEP Conference discount. Or, call 1-800249-5770 or visit www.ebmedicine.net/subscribe and use Promotion Code NBEAS Exclusive ACEP Conference Attendee Discount Special introductory rate for ACEP Conference Attendees: Just $249 ($199 for PAs/NPs & $149 for SEMPA members) for a full year (12 print issues) of Emergency Medicine Practice. Plus, you receive over 150 free CME credits and full online access to evidence-based archives. 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