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<< Evidence-Based Management Of Sickle Cell Disease In The Emergency Department

Special Circumstances: Other Complications Of Sickle Cell Disease

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

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.

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.

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 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.

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.

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.

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.

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

Noninvasive Ventilation
An open-label randomized trial of 71 episodes of acute chest syndrome found that early noninvasive ventilation was not associated with any improvement 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 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

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.

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 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.

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.

Sickle cell disease represents a state of immunocompromise due to increased bone marrow turnover, altered complement activation, and functional 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:

• 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

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.

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.

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, 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 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 vaso-occlusion after transfusion (stroke, pain, acute chest syndrome)

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).

Transient Red Cell Aplasia
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 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), with the 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 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.

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.

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)

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.

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 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.

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

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.



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