Pediatrics

Acute chest syndrome in sickle cell disease

Are you sure your patient has acute chest syndrome? What are the typical findings for this disease?

Acute chest syndrome (ACS) is the second most common reason for hospitalization of children with sickle cell disease (SCD) and is a leading cause of mortality. ACS is defined as a new pulmonary infiltrate on chest radiograph in the presence of lower respiratory tract disease (e.g., cough, shortness of breath, retractions, rales, etc.).

The peak occurrence is in children 2-4 years of age although it may occur at any age. ACS is most common with homozygous sickle cell anemia compared to those with sickle beta zero thalassemia, hemoglobin SC or sickle beta plus thalassemia. ACS occurs more frequently in winter and is the leading cause of death in children with SCD. Recurrent ACS is a risk factor for premature mortality.

What causes this syndrome to develop?

Risk factors for ACS are an elevated white blood cell count, higher hemoglobin and lower percent fetal hemoglobin at baseline. Also, asthma/reactive airway disease increases the risk by 2-4 fold. Atopy is associated with an increased risk. Other risk factors include hypoventilation and pulmonary edema. Nocturnal hypoxemia and chronic exposure to tobacco smoke are also risk factors. Approximately one-half of ACS develop in the hospital, usually in association with a vaso-occlusive crisis.

What are the most common etiologies?

In the majority of cases of ACS, an etiology is not identified. The most common identified etiology is infection, but ACS may result from pulmonary vaso-occlusion or embolus, pulmonary infarction or fat embolism. The primary infectious agents implicated in ACS include Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae, and viruses.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Complete blood count with differential: Elevated white blood cell count with a left shift is suggestive of a bacterial infection (The white blood count may be elevated at baseline so results must be interpreted in that context). Leukopenia is suggestive of parvovirus infection, but it can also be a sign of severe sepsis. A decrease in hemoglobin concentration is often seen at the onset of ACS.

  • Secretory phospholipase A2 is an enzyme that cleaves fatty acids from triglycerides and in one multi-center study a rise was 80% predictive of onset of ACS. It must be followed serially and is not generally available.

  • Type and cross match for minor-antigen-matched, sickle-negative, leukocyte-depleted red blood cells should be considered if the child is severely ill or if the hemoglobin is greater than 1 g/dL below baseline.

  • Blood cultures to look for bacterial pathogens.

  • Arterial blood gas per clinical discretion.

  • Renal (BUN, creatinine) and liver (fractionated bilirubin, ALT) function tests for severe illness or if multi-organ failure is suspected.

  • Viral polymerase chain reaction because pneumonia can be the cause and a positive result, especially for influenza, may prompt addition of anti-viral therapy.

Would imaging studies be helpful? If so, which ones?

Chest radiography should be performed in patients with fever, shortness of breath, tachypnea, cough, rales or chest pain and of a white blood cell count of at least 18,750 or history of ACS. These signs, symptoms and laboratory findings are reported to identify 98% of children with ACS. In one study, 61% of children presenting with a fever were found to have an unsuspected pulmonary infiltrate.

Computed tomography of the chest is important to identify progressive disease. Spiral computed tomography can be considered when pulmonary embolism is suspected, but may be difficult to interpret due to preexisting ventilation-perfusion mismatch.

What procedures may be considered?

Bronchoalveolar lavage (BAL) to obtain bacterial cultures, viral polymerase chain reaction and cytopathologic analysis can help identify the etiology of the ACS. The presence of large numbers of lipid-laden macrophages is suggestive of fat embolism. BAL is reserved for patients with severe or progressive disease.

What general treatment should be initiated?

Treatment is provided in the hospital and aims to prevent red blood cell sickling by supporting oxygen delivery and treating potential infection. Treatment should be started immediately.

  • Daily weights to assess fluid status.

  • Record intake and output strictly to assess fluid status. The goal is to maintain "euvolemia" (IV + P.O. = 1 x maintenance). More fluid is appropriate only if the patient is dehydrated or if insensible losses are increased (e.g., with persistent fever). IV fluid should be D5 1/4 NS to avoid exacerbating the sickling process.

  • Antipyretics such as acetaminophen, 15 mg/kg PO q4h, should be given as needed for a temperature greater than or equal to 38.3°C (maximum daily dose 75 mg/kg/day or 4,000 mg/day) after blood cultures have been obtained.

  • Analgesia may be needed. Consider ketorolac 0.5 mg/kg (maximum 15 mg/dose) IV q6h, but limit to 48 hour maximum duration. Then start ibuprofen 10 mg/kg (maximum 800 mg/dose) PO q6-8hr (not PRN) if no contraindication is present (i.e. gastritis, ulcer, coagulopathy, renal impairment). If pain does not respond to anti-inflammatory medications, consider oral or intravenous opiates. Beware that opiates may depress the respiratory drive.

What antibiotics should be prescribed?

  • Ceftriaxone or cefotaxime intravenously for 7-10 days. Prophylactic penicillin should be discontinued while the child is receiving broad-spectrum antibiotics.

  • Azithromycin or other macrolide antibiotic for a total 5-day course.

  • Strongly consider adding vancomycin for severe illness, or if large infiltrate with pleural effusion present and S. aureus is suspected. If vancomycin is added monitor renal function (i.e. creatinine, BUN, urine output at baseline and minimum twice weekly thereafter).

When is transfusion indicated?

Consider a simple blood transfusion (10 mL/kg red blood cells) to improve oxygen carrying capacity for children with symptomatic ACS whose hemoglobin concentration is > 1 g/dL below their baseline; hemoglobin should not rise to more than 10 g/dl. If baseline hemoglobin is 9 g/dL or higher, consider red cell exchange transfusion. Do not transfuse acutely to hemoglobin greater than 10 g/dL if the percent sickle hemoglobin is or is presumed to be greater than 30% since that is associated with increased pain and stroke.

Urgent red blood cell exchange is indicated for rapid progression of ACs as manifested by oxygen saturation <90% with supplemental oxygen, increasing respiratory distress, worsening pulmonary infiltrates and or decline in hemoglobin with transfusions.

What is the respiratory management?

  • Monitor with pulse oximetry but consider arterial blood gas.

  • Oxygen therapy should be administered to maintain O2 saturation at least 95%. Oxygen should be administered by nasal cannula or face mask for mild to moderate hypoxemia.

  • Incentive spirometry 10 breaths every 2 hours while awake (at least 6 times/day) should be used to minimize atelectasis.

  • If clinical features suggestive of asthma or acute bronchospasm or history of asthma, try an albuterol inhaler or l 2.5 mg nebulized Q4 and PRN.

  • Consider oscillatory positive expiratory pressure, These devices (e.g., flutter and acapella devices) promote the mobilization of mucus plugs and the overall clearance of airway secretions.

  • Positive pressure ventilation (CPAP and bipap) should be considered for pain-induced hypoventilation and respiratory insufficiency as well as for progressive hypoxemia.

  • Intubation and mechanical ventilation are necessary in cases of progressive hypoxemia and/or hypercapnia refractory to noninvasive positive pressure ventilation.

  • Consider consulting pulmonology.

What drug is controversial?

The risk/benefit ratio of corticosteroids in the management of ACS is controversial.

Corticosteroids (1-2 mg/kg/day—maximum, 40-60 mg/day) may be considered in severe ACS, especially in patients with a history and/or symptoms of underlying or concurrent asthma.

Slow weaning (over 2 weeks or longer) may minimize "rebound" vaso-occlusive crises that have been described in some patients who received high doses of corticosteroids and/or short courses.

What can be done to prevent ACS?

Hydroxyurea has been shown to decrease the frequency of ACS. Hydroxyurea increases fetal hemoglobin, thereby decreasing the level of sickle hemoglobin and the rate of sickling. It also decreases the white blood cell count and platelet count. Close monitoring is essential because of potential bone marrow suppression.

Chronic blood transfusion either short or long-term has been given for prevention of recurrent ACS.

What are the adverse effects associated with each treatment option?

  • Red blood cell transfusion risks include transfusion incompatibility, infection, iron overload and alloimmunization.

  • Nonsteroidal anti-inflammatory drugs in large doses or prolonged use may cause renal toxicity and gastrointestinal bleeding.

  • Opiates cause respiratory depression that leads to hypoventilation and atelectasis. They also decrease gastrointestinal motility resulting in constipation.

  • Oxygen may suppress erythropoietin stimulated production of red blood cells.

  • Mechanical ventilation is associated with barotrauma.

  • Hydroxyurea may cause neutropenia, thrombocytopenia, or anemia. Male fertility may be reduced during administration.

What are the possible outcomes of acute chest syndrome?

During an ACS, there is an increased risk of posterior reversible encephalopathy. The risk for silent infarct of the brain is increased. The risk for overt stroke is increased in the two weeks following discharge for ACS. Early onset ACS (<4 years of age) contributes to the development of chronic lung disease.

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