Critical Care Medicine

Respiratory Failure in Sickle cell anemia; Acute Chest Syndrome

Acute Chest Syndrome (ACS)

Synonyms

Sickle Cell Disease (SCD), Sickle Cell Anemia (SCA)

Related Conditions

Vaso-occlusive Crisis (VOC), Sickle Cell Crisis, Acute Lung Injury (ALI), Sickle Cell Chronic Lung Disease (SCCLD), Pulmonary Arterial Hypertension

1. Description of the problem

Pulmonary complications account for a significant proportion of morbidity and mortality in patients with sickle cell disease. There are several pulmonary manifestations of sickle cell disease: increased airway reactivity, nocturnal oxygen desaturation, thromboembolic disease, acute chest syndrome (ACS), sickle cell chronic lung disease (SCCLD), and pulmonary hypertension.

The clinician should be aware of ACS, a form of acute lung injury that is the most common form of acute pulmonary disease in SCD and occurs in almost half of these patients. ACS is a risk factor for early mortality and is the most frequently reported cause of death in SCD patients.

Nevertheless, median survival has improved with supportive care, and thus an increasing number of patients with sickle cell chronic lung disease (SCCLD) and pulmonary hypertension present acutely and will require special consideration in the intensive care setting.

Patients admitted with vaso-occlusive crises (VOC, sickle cell crisis or pain crisis) can often be considered as presenting with the prodrome of ACS. Severe VOCs may affect many organs and pulmonary involvement can lead to the development of ACS.

ACS is defined by the appearance of a new pulmonary infiltrate on CXR, associated with fever and respiratory symptoms such as tachypnea, wheezing, cough and pleuritic chest pain.

Underlying conditions predisposing to ACS include infection, embolic phenomena from bone marrow infarction or fat emboli and pulmonary infarction caused by in situ thrombosis. Hypoventilation and splinting due to local pain from rib and sternal infarction can cause atelectasis with hypoxemia and worsen intravascular sickling, increasing the risk of development of ACS.

Pulmonary edema resulting from pulmonary vascular permeability caused by excessive hydration, blood transfusions or opiate use may also precipitate ACS.

In practice, it may be difficult to distinguish between these conditions in the patient who presents with acute respiratory distress, and several abnormalities may be concurrent.

The most common presenting symptoms of ACS are fever, non-productive cough, tachypnea, chest pain and shortness of breath.

Arm and leg pain, abdominal pain and rib or sternal pain may also be present.

Wheezing is less common but may also be present, especially if the patient has underlying hyperreactive airway disease.

Physical exam of the chest may reveal local palpable tenderness of the ribs or sternum and auscultation findings consistent with pulmonary consolidation.

Lab findings include leukocytosis, thrombocytopenia or thrombocytosis, anemia, elevated LDH and elevated total and conjugated bilirubin levels.

One third of CXRs are normal at admission. Most patients develop lower lobe infiltrates, sometimes bilateral. Pleural effusions are also common, occurring in up to 35% of cases.

Worsening infiltrates and hypoxemia (paO2 < 70 mmHg) with widened A-a gradient may be present and suggest impending respiratory failure and possible multi-organ dysfunction.

Identify and treat all underlying factors precipitating acute illness.

Correct hypoxemia with supplemental oxygen: goal PaO2 > 70 mmHg.

Empiric antibiotics: Initiate broad-spectrum antibiotics to treat possible underlying infection

Transfusion therapy: Consider simple or exchange transfusion to lower sickled hemoglobin and improve blood oxygen content.

Consult hematologist for exchange transfusion therapy.

Pain control: Judicious use of opioid and non-narcotic analgesics

Bronchodilators: Consider their use in patients with history of asthma or hyperreactive airways. Standard therapy in patients requiring mechanical ventilation.

Supportive care: Mainstay of treatment for all patients. Continuous pulse oximetry, cautious hydration, incentive spirometry or aggressive pulmonary toilet for patients requiring mechanical ventilation.

2. Emergency Management

Emergency management of a patient with SCD in acute respiratory failure is no different than any other patient presenting with acute respiratory distress. Immediate concern should be the "ABCs."

Provide optimal oxygenation.

Establish IV access and institute continuous cardiac and pulse oximetry monitoring.

Determine need for emergent airway management and ventilatory support.

Search for any rapidly reversible causes (pneumothorax, cardiac tamponade, upper airway foreign body).

Consider alternative etiologies for acute respiratory failure: acute coronary syndrome, acute heart failure, arrythmia, cardiac tamponade, PE, etc.

Initiate appropriate treatment.

CBC with differential

Serum chemistry including BUN and creatinine

Reticulocyte count

Baseline CXR

ABG

Blood cultures

Sputum cultures

3. Diagnosis

ACS is a clinical diagnosis based on the presence of a new pulmonary infiltrate (not due to atelectasis and involving at least one complete lung segment), chest pain, fever, tachypnea, wheezing and cough in a patient with sickle cell disease. Patients with a previous history of ACS are at especially high risk of recurrent ACS.

No laboratory or radiographic findings differentiate ACS from other pulmonary manifestations of SCD, such as pneumonia or infarction. Positive blood cultures in the presence of radiographic infiltrate should be treated as an infectious pneumonia until proven otherwise.

Bronchoalveolar lavage (BAL) may be helpful when pulmonary fat embolism is suspected as etiology of ACS. A BAL finding of >5% lipid-laden alveolar macrophages is consistent with a diagnosis of pulmonary fat embolism.

Diagnosing pulmonary infarction due to thromboembolism in ACS is especially difficult. Typically, there is no evidence of DVT and ventilation-perfusion scans are abnormal at baseline. Furthermore, there is a high risk of promoting further sickling with the administration of IV contrast for more definitive diagnosis.

There are multiple etiologies of ACS and identifying a specific cause may be difficult. Vichinsky and colleagues of the National Acute Chest Syndrome Study Group identified the frequency of possible causes of ACS in 538 patients with 671 episodes of ACS across 30 centers (Table I).

Table I.

Etiology of ACS
Cause Frequency
Unknown 46% overall (30% in patients with complete data)
Pulmonary infarction 16%
Fat embolism - with or without infection 9%
Chlamydia pneumoniae infection 7%
Mycoplasma pneumoniae infection 7%
Viral infection - RSV, parvovirus, rhinovirus 6%
Mixed infections 4%
Other pathogens 1%

The differential diagnosis is narrow in a patient with SCD who presents with clinical signs and symptoms consistent with ACS. The diagnostic challenge is to identify a precipitating etiology for ACS, such as infection, infarction or thromboembolism.

There are no specific tests to confirm diagnosis of ACS. ACS is a clinical diagnosis based on the presence of a new pulmonary infiltrate (not due to atelectasis and involving at least one complete lung segment), chest pain, fever, tachypnea, wheezing and cough in a patient with sickle cell disease. Additional laboratory and radiographic findings listed above support the diagnosis.

4. Specific Treatment

Identify and treat all underlying factors precipitating acute illness.

Supplemental oxygen -- Correct hypoxemia to prevent further sickling. Obtain ABGs as needed: Goal paO2 > 70-100 mmHg. Pulse oximetry may correlate poorly with arterial oxygen tension due to peripheral vasoconstriction and sickling.

Empiric Antibiotics -- initiate broad-spectrum antibiotics (2nd- or 3rd-generation cephalosporin, add a macrolide) to treat possible underlying infection.

Bronchodilators -- May be used in patients with wheezing, severe respiratory compromise, clinical or radiographic evidence of hyperinflation or a prior history of asthma or obstructive airways disease. For patients requiring mechanical ventilation, hyperreactive airways may predispose to development of bronchospasm, autoPEEP and dynamic hyperinflation. Bronchodilators may be useful in this setting.

Transfusion Therapy - Simple and exchange transfusion may be required to lower fraction of sickled hemoglobin (Hb S < 30%) and to improve oxygen-carrying capacity of blood (goal Hg <10 g/dL and HCT 30). Simple transfusion is indicated in patients with single lobe involvement, mild hypoxemia responsive to low-flow oxygen, worsening anemia and moderate to severe ACS with Hg < 5 g/dL.

Exchange transfusion is indicated in patients with multi-lobar infiltrates, refractory hypoxemia, PaO2/FiO2 ratio < 300, rapidly progressive lung involvement or signs of multi-organ involvement including cardiac and neurologic abnormalities. Consult a hematologist if considering an exchange transfusion (a large-bore catheter will be required to perform exchange).

IV Fluids - Volume depletion may contribute to and worsen intravascular sickling. Hydration is standard therapy in the management of VOC and ACS; however, aggressive hydration with hypotonic fluids in combination with opioid analgesics may predispose to pulmonary edema. Frequent re-assessment of volume status is required with the goal of achieving a euvolemic state. Maintain euvolemia with D5W or D51/4NS.

Pain Control - Judicious use of narcotic analgesics is required to avoid respiratory depression. NSAIDs and acetaminophen should be used to supplement analgesia and as opioid-sparing agents when possible.

Supportive Care - Close pulmonary monitoring with continuous pulse oximetry and incentive spirometry are suggested. For patients requiring mechanical ventilation, adequate pulmonary toilet with aggressive suctioning, HOB >30 degrees and chest PT as needed.

Hydroxyurea - Reduces sickling by increasing fetal hemoglobin and decreasing relative concentration of Hb S in erythrocytes. Significantly reduces the incidence of ACS, hospitalizations and need for transfusions. This is a well tolerated medication with minimal side effects and has a proven mortality benefit in patients with SCD. There is no evidence supporting its use in the acute setting and this medication should already be part of the outpatient medical regimen, especially in those with severe disease or previous history of ACS.

Analgesics

(Use of narcotic and non-narcotic, i.e., opioid-sparing agent, is suggested to promote comfort, pulmonary toilet, incentive spirometry and sedation).

Codeine 15-60 mg PO/IV/IM/SC q 4-6 hours (do not exceed 120 mg/d)

Aspirin 325-600 mg PO q4 hours

Acetaminophen 325-650mg PO q4-6 hours (do not exceed 4 gm/day)

Ibuprofen 200-800mg PO qday

Oxycodone and acetaminophen (Percocet, Roxicet) 1 tablet PO q4-6 hrs as needed

Morphine 2-5 mg IV q 10-30 minutes titrated to pain control

Morphine 30 PO q8-12 hours

Antibiotics

(Cover S. pneumoniae, H. influenzae, Mycoplasma pneumoniae and Chlamydia pneumoniae. A second- or third-generation cephalosporin in combination with macrolide is suggested.)

Ceftriaxone 1-2 gm IV/IM qday

Cefuroxime 250-500 mg po q12 hours or 750-1500 mg IV/IM q8 hours

Azithromycin 500 mg PO day

Exchange Transfusion

Simple transfusion of leukocyte-depleted red cells that are negative for sickle cells has been shown to improve oxygenation and decrease new red cell antibody formation. However, simple transfusion may excessively increase hematocrit and blood viscosity, exacerbating vaso-occlusion. Do not raise Hg above 10 g/dL.

Consider exchange transfusion in the setting of progressive infiltrates and hypoxemia. Reduction of HbS level to <30% and HCT ~25-30 leads to improvement in majority of cases. Consult hematologist when exchange transfusion is required.

Bronchoscopy

Consider in patients not responding to initial therapy. May be used as diagnostic test or therapeutic intervention to clear airway secretions.

Corticosteroids

In pediatric patients, a short course of corticosteroids may reduce the need for blood transfusion and the hospital LOS. However, corticosteriod therapy during VOC is associated with increased rebound attacks. Considered experimental therapy in the management of ACS in refractory cases; no data support routine use in adult patients.

Inhaled Nitric Oxide

May act in part by decreasing sickle cell adhesion to pulmonary endothelium, an effect that may be mediated by down-regulation of VCAM-1 expression in pulmonary endothelial cells exposed to hypoxia. In anecdotal reports, inhaled NO has been effective in patients with severe ACS and clinical trials are ongoing.

Inhaled NO is approved for the treatment of neonatal pulmonary hypertension only. Currently not standard of care for management of severe ACS in adults. Should only be considered in the setting of a clinical trial.

5. Disease monitoring, follow-up and disposition

Among patients with SCD, fat embolism and infection, especially community-acquired pneumonia, commonly precipitates ACS. Older (non-pediatric) patients and those presenting with neurologic signs and symptoms often progress to respiratory failure. With transfusion and bronchodilator therapy, oxygenation improves and with aggressive treatment, most patients with respiratory failure are expected to recover.

Other diagnoses to consider when treating acutely ill patients with SCD include pneumonia, fat and bone marrow embolism and venous thromboembolism.

Pneumonia

Difficult to differentiate isolated infectious pneumonia from ACS since blood and sputum cultures may often be nondiagnostic. Patients with SCD are predisposed to develop pneumonia due to impaired host defense, loss of antibody protection in the setting of auto-splenectomy, altered phagocytic function and defective opsonization. Thus, infection with encapsulated organisms, such as Strep pneumococcus, H. influenzae, Mycoplasma pneumoniae and Chlamydia pneumoniae, are frequently associated with development of ACS.

Fat and bone marrow embolism

Bone marrow infarction resulting from microvascular occlusion leads to fat and bone marrow embolism in patients with SCD. Patients frequently have mental status changes, thrombocytopenia, declining HCT and severe hypoxemia. Bronchoscopy with BAL may be helpful to assess fat content in pulmonary macrophages, although it is not diagnostic and is rarely performed. Management generally involves exchange transfusion.

Venous thromboembolism

Pulmonary infarction in patients with SCD is likely due to microvascular occlusion and subsequent in-situ thrombosis. Patients with HbSC have increased incidence of thrombosis compared with those with HbSS due to increased blood viscosity and hematocrit. Evaluation of potential venous thromboembolism in patients with SCD is similar to evaluation in patients without SCD; however, baseline abnormalities render interpretation of V/Q scans difficult.

Administration of hypertonic contrast during pulmonary angiography may also precipitate intravascular sickling. Newer contrast media and high index of suspicion is required to evaluate patients for VTE. Prophylactic anticoagulation is not recommended because of the increased risk of renal and intracranial hemorrhage in patients with HbSS and should only be used when VTE is documented.

All patients with SCD and history of ACS should be followed closely by a hematologist in the outpatient setting. Chronic management is aimed at preventing recurrent episodes in patients with history of ACS. Recurrent episodes increase the risk of developing sickle cell chronic lung disease.

Pathophysiology

Sickle cell disease includes a group of hemoglobinopathies resulting from a single amino acid substitution in the beta globin chain. Substitution of valine for glutamic acid at the sixth position in the beta globin chain results in Hb S. A hemoglobin tetramer forms with the folding of two alpha and two beta globin chains; however, it is poorly soluble when deoxygenated. Deoxygenated tetramers polymerize into long sheets of fibers that distort the shape of the red cell and significantly decrease the native deformability of red cells.

Vaso-occlusive crises and hemolysis are the clinical hallmarks of HbSS. The polymerization of deoxygenated Hb S is the primary pathophysiologic event causing vaso-occlusive complications. In addition, changes in red cell membrane structure and function, deregulated control of intracellular volume, increased "stickiness" or adherence to vascular endothelium are other mechanisms for vaso-occlusion.

The pathogenesis of parenchymal lung infiltrates in ACS is not well understood but can be viewed as a specific form of acute lung injury that progresses to the acute respiratory distress syndrome.

Pulmonary infiltrates likely result from multiple processes including atelectasis, infection, fat embolism, thromboembolism and, most commonly, infarction from in situ thrombosis due to intravascular sickling and microvascular occlusion.

In addition to Hb S polymerization and red cell sickling, increased expression of adhesion molecules on sickled red cells and pulmonary endothelium, release of inflammatory mediators, interaction of sickled red cells with leukocytes, microvascular thrombosis and endothelial damage may all contribute to microvascular occlusion and tissue infarction.

Hypoxia-induced adhesion of sickled red cells to the pulmonary endothelium is mediated by several inflammatory factors (endothelial cell vascular cell adhesion molecule 1, endothelin-1, cell-free hemoglobin and nitric oxide metabolites). In addition, free radical byproducts (F2 isoprostanes) from lipid peroxidation and catabolism have been found in ACS, suggesting that increased oxidative stress may also have a pathogenetic role in the development of ACS.

An overview of the presumed pathophysiology of sickle acute lung injury is shown in Figure 1.

Figure 1.

Pathophysiology of Sickle Acute Lung Injury.

Epidemiology

One in every 650 African Americans is born with SCD and approximately 8% are heterozygous for the sickle cell gene. With an official US Census Bureau estimate of over 35.5 million African Americans in the year 2000, this represents approximately 50,000 patients living with sickle cell anemia. There is an increasing number of adult patients with sickle cell disease, and approximately 35% of the African American population is between the ages of 30 and 54 years.

In addition to population growth, however, mortality rates for children with sickle cell anemia have declined markedly due to penicillin prophylaxis, H. influenzae and S. pneumoniae vaccination, improved screening programs for early detection and parental education. The median age of death is now estimated at 42 years for men and 48 years for women.

Homozygous variant sickle cell anemia (HbSS) is the most frequently occurring form of sickle cell disease associated with clinical hallmarks of vaso-occlusion and hemolysis. Heterozygous sickle cell trait (HbSC) and sickle hemoglobin-beta thalassemia occur less frequently and are associated with less severe clinical manifestations. Organ dysfunction, including ACS and pulmonary infarction, and sudden death are rare in patients with sickle cell trait except in cases associated with severe dehydration.

Pulmonary complications account for a large proportion of illness and death among adults with sickle cell anemia. HbSS genotype carries the highest likelihood for the development of ACS, with an overall incidence of 12.83 patients per 100 patient years. ACS is the second most common cause of hospitalization in patients with SCD and accounts for up to 25% of deaths.

In the Cooperative Study of Sickle Cell Disease, 29% of 3,751 patients experienced at least one episode of ACS. Recurrent episodes of ACS are common in patients with at least one prior episode of ACS and are associated with a higher likelihood of developing chronic lung disease and early death.

Prognosis

The National Acute Chest Syndrome Study Group identified 538 patients with 671 episodes of ACS. The following outcomes were observed:

Nearly half of the patients were initially admitted for another reason, usually pain crisis.

When ACS was diagnosed, patients had hypoxia, anemia and progressive multi-lobar pneumonia.

The mean length of hospital stay was 10.5 days.

  • 13% of patients required mechanical ventilation.

  • Patients 20 years of age or older had more severe courses than their pediatric counterparts.

  • Neurologic events occurred in 11% of patients and nearly half of these patients experienced respiratory failure.

Phenotypically matched blood transfusion improved oxygenation, with a 1% rate of alloimmunization.

  • 20% of patients treated with bronchodilators demonstrated clinical improvement.

  • 81% of patients requiring mechanical ventilation recovered.

  • 3% of patients died, and the most common cause of death was pulmonary emboli or infectious bronchopneumonia.

Infection was a contributing factor in 56% of all deaths.

A specific cause of ACS was identified in 38% of all episodes and 70% of episodes with complete data. Pulmonary fat embolism and 27 different infections were found among the specific causes.

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Vichinsky, E. P., Styles, L. A., Colangelo, L. H., Wright, E. C., Castro, O., Nickerson, B. "Acute chest syndrome in sickle cell disease: Clinical presentation and course. cooperative study of sickle cell disease". Blood. vol. 89. 1997. pp. 1787-1792.

(Largest prospective study following the clinical presentation and natural course of disease.)

Manci, E. A., Culberson, D. E., Yang, Y. M., Gardner, T. M., Powell, R., Haynes, J., Shah, A. K., Mankad, V. N.. "Causes of death in sickle cell disease: An autopsy study". British Journal of Haematology. vol. 123. 2003. pp. 359-365.

(Largest autopsy study identifying causes of death in sickle cell disease.)

Melton, C. W., Haynes, J.. "Sickle acute lung injury: Role of prevention and early aggressive intervention strategies on outcome". Clinics in Chest Medicine. vol. 27. 2006. pp. 487-502.

Siddiqui, A. K., Ahmed, S. "Pulmonary manifestations of sickle cell disease". Postgraduate Medical Journal. vol. 79. 2003. pp. 384-390.

(Comprehensive clinical and pathophysiologic review of acute chest syndrome.)

Minter, K. R., Gladwin, M. T.. "Pulmonary complications of sickle cell anemia. A need for increased recognition, treatment, and research". American Journal of Respiratory and Critical Care Medicine. vol. 164. 2001. pp. 2016-2019.

(Concise overview of acute and chronic aspects of sickle cell anemia.)

Stuart, M. J., Setty, B. N. "Sickle cell acute chest syndrome: Pathogenesis and rationale for treatment". Blood. vol. 94. 1999. pp. 1555-1560.

(Excellent overview and discussion of clinical presentation, pathophysiology and intervention in acute sickle cell lung injury.)

Vichinsky, E. P., Neumayr, L. D., Earles, A. N., Williams, R., Lennette, E. T., Dean, D., Nickerson, B., Orringer, E., McKie, V., Bellevue, R., Daeschner, C., Manci, E. A. "Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group". New England Journal of Medicine. vol. 342. 2000. pp. 1855-1865.

(Frequently cited landmark multi-center study identifying the epidemiology of causes, outcomes and responses to therapy.)
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