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By Mark T. Gladwin, MD
A 24-year-old african-american man immigrated to the United States from Ghana 15 months before presentation. His past medical history was significant for a diagnosis of sickle cell anemia, complicated by frequent painful crises (vaso-occlusive crisis) and priapism, as well as a distant history of malaria. One week before this admission, he presented with severe leg and lower back pain and his hematocrit was found to have dropped from 21% to 16%. He was transfused to a hematocrit of 25% and discharged home on acetaminophen and oxycodone. He subsequently developed recurrent lower back, leg, and abdominal pain, along with wheezing, dyspnea, cough, and fever. On this admission his hematocrit was 18% and his temperature was 38.7°C. Oxygen saturation by pulse oximetry was 85% while breathing room air, and his chest radiograph revealed bibasilar opacities with small effusions. His oxygen requirement increased and he was endotracheally intubated. His white blood cell count was 12,000 per mm3 and his hematocrit was 16%. The patient received a red blood cell transfusion, antibiotics, and hydration. On pressure-controlled ventilation with an FIO2 of 1.0 and positive end-expiratory pressure (PEEP) of 15 cm H2O, his PaO2 was 65 mmHg. The chest radiograph demonstrated diffuse bilateral parenchymal opacities. He became progressively more confused. All cultures were negative. After 36 hours of mechanical ventilation, the arterial saturation dropped to 50%, and cardiopulmonary arrest followed. At postmortem examination, the lung weight was twice normal, and microscopic examination revealed small 2-3 mm occlusive thrombi composed of sickled red cells, fibrin, fat, and infarcted bone marrow. All organs contained sickled red cells and there was extensive avascular necrosis of the right femoral head.
Sickle Cell Anemia and the Acute Chest Syndrome
This case illustrates severe manifestations of the acute chest syndrome of sickle cell anemia. An intensivist’s exposure to sickle cell disease is often limited to this type of presentation. The sudden severe desaturation prior to the patient’s demise likely represented massive diffuse bone marrow fat embolization from infarcted vertebrae, femurs, and, in this case, the femoral head.
Sickle cell anemia is the most common genetic disease affecting African-Americans, with 0.15% of African-American children homozygous for the sickle cell gene and 8% having the sickle cell trait (heterozygous condition). This autosomal recessive disorder is characterized by a single amino acid substitution (glutamic acid to valine) in each of the beta subunits of hemoglobin. Upon deoxygenation, hemoglobin S undergoes conformational changes that expose a hydrophobic region surrounding the valine moiety in the beta subunit. Polymerization with other hemoglobin tetramers occurs, with the formation of long polymer chains that ultimately distort the erythrocyte membrane.1 The rigid polymer-containing erythrocytes occlude the microvasculature, resulting in acute and chronic ischemic injury to the lungs, kidneys, liver, spleen, skeleton, skin, and central nervous system. Sickle cell disease is characterized by periods of stability, punctuated by episodes of severe pain involving the back, chest, abdomen, and joints. This syndrome is referred to as the acute painful crisis or vaso-occlusive crisis (VOC).
Pulmonary disease, manifested as the acute chest syndrome (ACS), is a common complication of sickle cell anemia. Half of individuals with sickle cell anemia develop this syndrome at least once. It is the second most common cause of hospitalization, and it accounts for 25% of premature deaths.2 ACS occurs more commonly in sickle cell individuals with higher steady-state leukocyte counts, higher hemoglobin concentrations, and lower hemoglobin F levels.3 ACS can be thought of as a specific form of acute lung injury that can progress to the acute respiratory distress syndrome (ARDS). This injury is caused by multiple insults superimposed upon the genetically based pathophysiology of sickle cell disease. These multiple insults include vascular obstruction due to sickling and adherence of erythrocytes in the pulmonary microvasculature, with infarction of the pulmonary parenchyma, bone marrow fatty embolization from infarcted bone, and, to a lesser extent, macrovascular pulmonary embolism and infection.4 The figure illustrates the pathogenesis of ACS schematically.
Patients with ACS present with fever (80%), cough (74%), chest pain (57%), dyspnea (28%), productive cough (24%), hypoxema (mean PaO2 of 71 mmHg), leukocytosis, and infiltrates on chest radiographs. The illness often progresses to multilobar pulmonary disease indistinguishable from ARDS in other settings.5 There are some differences between adults and children with ACS. Fifty percent of adults experience a vaso-occlusive crisis prior to developing ACS, while only 11% of children have an antecedent crisis. Adults present with lower lobe disease and more frequently develop multilobe involvement (36% vs 24% of children) and pleural effusion (21% vs 3%) and receive more frequent transfusions (39% vs 22%), are hospitalized longer (9 vs 5.4 days), and suffer a higher mortality (4.3% vs 1.1%).4,5 Compared to adults, children are more frequently bacteremic with Streptococcus pneumoniae.
Treatment of the Acute Chest Syndrome
At this time, preventive and treatment options for ACS are based on a number of standard therapies, such as cautious hydration, oxygen therapy, pain control, antibiotics, simple and exchange transfusion, and incentive spirometry (see Table 1). While there are no hard data that hydration, oxygen therapy, and narcotic analgesia prevent or treat ACS, experience suggests that these interventions are helpful. Pain control should be sufficient to offer relief of suffering and prevent splinting during breathing, while avoiding excessive sedation that could lead to hypoventilation. Incentive spirometry (10 maximum inspirations every two hours while awake) has been demonstrated to reduce pulmonary infiltrates or atelectasis in patients admitted to the hospital with a VOC and should be considered standard of care.6
Although infection occurs in less than 20% of cases of ACS, empiric antibiotic coverage is indicated and should include coverage for Chlamydia pneumoniae and Mycoplasma pneumoniae. Cultures should include nasal washings for viral pathogens (influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, cytomegalovirus, and parvovirus). Up to 70% of patients with sickle cell anemia have evidence of reactive airways disease on pulmonary function testing, and this fact should be considered when managing these patients on the ventilator. Efforts to detect auto-PEEP and prevent dynamic hyperinflation and its sequellae (e.g., hypotension, barotrauma, and increased work of breathing) are indicated.
|Table 1-Therapy of the Acute Chest Syndrome of Sickle Cell Anemia|
|• 1-1.5 times daily requirement; fluid restriction may be indicated in patients with severe ACS and capillary leak|
|• Indicated to maintain adequate oxygenation; does not offer benefit for vaso-occlusive crisis in the absence of hypoxemia|
|• Codeine, acetaminophen, ibuprofen|
|Moderate to severe pain|
|• Medication can be administered on a fixed time schedule with interval analgesics to obtain adequate pain control|
|• Morphine is drug of choice; meperidine use has been associated with an increased incidence of seizures and should be avoided in patients with renal insufficiency or neurologic disease; hydromorphone and fentenyl are acceptable|
|• Consider patient-controlled analgesia|
|ف. Loading dose 0.05 mg morphine/kg|
|ق. Basal infusion 2-4 mg/h|
|ك. Bolus q 15 min with 1-2 mg/dose|
|Prevention of Atelectasis|
|• Incentive spirometry: 10 maximum inspirations every two hours while awake|
|• Include macrolide or quinolone for coverage of atypical pathogens Chlamydia pneumoniae and Mycoplasma pneumoniae|
|• Cultures should include nasal washings for viral pathogens (influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, cytomegalovirus, and parvovirus)|
|Diagnosis and Treatment of Reactive Airways Disease|
|• Consider occult auto-PEEP and its complications|
|Consider Exchange Transfusion or Simple Transfusion|
|• See Table 2|
|Inhaled Nitric Oxide|
|• May prove efficacious but cannot be recommended at this time|
|Table 2-Exchange Transfusion in Sickle Cell Disease|
|• Patients with pulmonary infiltrates (especially multilobar)|
|• Rapidly progressive disease|
|• Signs of respiratory distress|
|• A PaO2 less than 60 mmHg in an adult breathing supplemental oxygen (70% for children) or a drop of more than 25% from baseline in a patient with known hypoxemia|
|• Patient requiring ICU admission|
|• Increase the hematocrit to 30% (hemoglobin should not exceed 10-12 g/dL to avoid hyperviscosity)|
|• Maintaining the percentage of hemoglobin S to less than 30%|
|Methods of Exchange Transfusion|
|• Exchange transfusion is performed if there is concern about volume overload, the initial hematocrit is greater than 25-30%, or a significant rapid reduction in hemoglobin S is required (which is usually the case)|
|• Remove 500 cc of whole blood by phlebotomy from one arm while transfusing one unit of whole blood into the other.|
|• Alternatively, remove 500 cc of blood then infuse 500 cc of normal saline. Then remove a second 500 cc of blood and transfuse two units of packed red cells. Repeat until the goals are met.|
|• Automated apheresis devices can also be used. A typical adult will require 6-8 units of blood for apheresis exchange.|
|*Note: I believe that exchange transfusion should be initiated earlier, at first sign of pulmonary infiltrate, dyspnea, or any significant drop in PaO2 from baseline.|
Blood transfusion and exchange transfusion are likely to significantly affect the course of ACS by replacing hemoglobin S with hemoglobin-A-containing erythrocytes and correcting anemia. Virtually all patients presenting with ACS are anemic (mean hemoglobin is 7.8 g/dL, range 2.7-10.9 g/dL), and more than half continue to hemolyze, with mean reported hemoglobin decreases of 1.6 g/dL during their acute illness.7 Reports of several case series suggest that transfusion rapidly improves oxygenation and the clinical course of ACS.8-10 Emre and colleagues8 measured arterial PaO2 following transfusion in 27 patients with ACS. The mean pretransfusion oxygen tension was 65 ± 15 mmHg and 12-24 hours after transfusion increased to 86 ± 19 mmHg.
Although there are no data to establish an appropriate transfusion threshold, it has been recommended that transfusion be considered in patients with pulmonary infiltrates (especially multilobar), rapidly progressive disease, signs of respiratory distress, a PaO2 less than 60 mmHg in an adult breathing supplemental oxygen (70% for children), or a drop of more than 25% from baseline in a patient with known hypoxemia.11 I believe that these recommendations are conservative and that exchange transfusion should be initiated earlier, at first sign of pulmonary infiltrate, dyspnea, or any significant drop in PaO2 from baseline. This view is based on the idea that pulmonary infiltrates, especially when caused by bone marrow fat embolization, are a late complication of significant bone marrow infarction and therefore early transfusion may abrogate this process. It would be reasonable to initiate exchange transfusion in any sickle cell anemia patient sufficiently ill to warrant ICU admission.
The goal of simple transfusion is to increase the hematocrit to 30%, although the hemoglobin level should not exceed 10-12 g/dL in order to avoid hyperviscosity; the percentage of hemoglobin S should be maintained less than 30% (see Table 2). Exchange transfusion is performed if there is concern about volume overload, if the initial hematocrit is greater than 25-30%, or if a rapid reduction in hemoglobin S is required. This can be accomplished by removing 500 mL of whole blood by phlebotomy from one arm while transfusing one unit of whole blood into the other. Alternatively, 500 mL of blood is removed followed by infusion of 500 mL of normal saline. Then, a second 500 mL of blood is removed, followed by transfusion of two units of packed red cells. This process is usually repeated until the goals are met. Automated apheresis devices can be used for exchange transfusion as well. A typical adult will require six to eight units of blood for apheresis exchange.
Inhaled Nitric Oxide and the Acute Chest Syndrome
While inhaled nitric oxide (NO) has recently been considered as a possible therapy for ACS, there are virtually no data on the effects of inhaled NO on the clinical course of ACS. Atz and Wessel11 described the effects of inhaled NO on the clinical course of two mechanically ventilated pediatric patients with ACS. Following 15 minutes of 80 ppm inhaled NO, the two patients’ PaO2 values increased from 69 mmHg and 107 mm Hg to 176 mmHg and 185 mmHg, respectively. This was accompanied by decreases in right ventricular systolic and pulmonary artery pressures. While there was a clear initial improvement in oxygenation and a decrease in pulmonary artery pressures, it is not known whether the sustained improvement that followed was the result of the NO therapy or of the aggressive hydration, exchange transfusions, and oxygen therapy that both patients received.
Recent clinical studies of inhaled NO in patients with ARDS demonstrate an increase in PaO2/FiO2 ratio as compared to controls that only last for one to two days, with no effect on the duration of mechanical ventilation or mortality. However, in sickle cell indivduals, even transient improvements in ventilation-perfusion matching would potentially improve hemoglobin saturation and reduce erythrocyte sickling, both in the pulmonary vasculature and in distal organs. The ACS of sickle cell anemia may represent a unique pulmonary disorder in which brief improvements in oxygenation may have profound effects on outcome. However, at this time the use of inhaled NO remains experimental and cannot be recommended until clinical trials provide supporting data.
1. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762-769.
2. Platt OS, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death [see comments]. N Engl J Med 1994;330:1639-1644.
3. Castro O, et al. The acute chest syndrome in sickle cell disease: Incidence and risk factors. The cooperative study of sickle cell disease. Blood 1994;84:643-649.
4. Gladwin MT, et al. The acute chest syndrome in sickle cell disease. Possible role of nitric oxide in its pathophysiology and treatment. Am J Respir Crit Care Med 1999;159:1368-1376.
5. Vichinsky EP, et al. Acute chest syndrome in sickle cell disease: Clinical presentation and course. Cooperative study of sickle cell disease. Blood 1997;89: 1787-1792.
6. Bellet PS, et al. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases [see comments]. N Engl J Med 1995;333:699-703.
7. van Agtmael MA, et al. Acute chest syndrome in adult Afro-Caribbean patients with sickle cell disease. Analysis of 81 episodes among 53 patients. Arch Intern Med 1994;154:557-561.
8. Emre U, et al. Effect of transfusion in acute chest syndrome of sickle cell disease. J Pediatr 1995;127: 901-904.
9. Wayne AS, et al. Transfusion management of sickle cell disease. Blood 1993;81:1109-1123.
10. Mallouh AA, Asha M. Beneficial effect of blood transfusion in children with sickle cell chest syndrome. Am J Dis Child 1988;142:178-182.
11. Reid CD, et al (eds). Management and Therapy of Sickle Cell Disease. 3rd ed. Washington, DC: National Institutes of Health, National Heart, Lung, and Blood Institute; 1995.
12. Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology 1997;87:988-990.
a. patients with multilobar pulmonary infiltrates.
b. rapidly progressive disease or signs of respiratory distress.
c. a PaO2 less than 60 mmHg in an adult breathing supplemental oxygen.
d. uncomplicated pregnancy.