MANAGEMENT OF SICKLE CELL DISEASE

NIH Publication No. 02-2117. Revised May28, 2002 (Forth Edition) National Institutes of Health, National Heart, Lung, and Blood Institute. Download the entire PDF  file for Adobe   Click Here to return to Contents

Chapter 16  

ACUTE CHEST SYNDROME AND OTHER PULMONARY COMPLICATIONS

The lung is a major target organ for acute and chronic complications of sickle cell disease (SCD). Acute chest syndrome (ACS) is a frequent cause of death in both children and adults (1-3) with SCD. Pulmonary problems not directly related to sickle cell vaso-occlusion, such as pneumonia or asthma, can worsen SCD because local or systemic hypoxia increases sickle hemoglobin (Hb S) polymerization. Multiorgan failure often is preceded or accompanied by pulmonary involvement, as observed with fat embolization in pain episodes. There is more frequent recognition of chronic pulmonary hypertension in adult patients, as this complication gives a poor prognosis, even though pulmonary artery pressures are not very high, compared to those in patients with primary pulmonary hypertension. 

Few of the management recommendations below are based on randomized clinical trials, since such trials are largely unavailable. The proposed guidelines are based on reviews of small case series in the literature, and on consensus among clinicians with experience in SCD treatment.

SUMMARY OF THE STATE OF KNOWLEDGE

ACS is an acute illness characterized by fever and respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest x ray. Because the appearance of radiographic changes may be delayed (3), the diagnosis may not be recognized immediately. A major risk factor for the development of ACS is the hemoglobin genotype: the highest incidence is seen in Hb SS genotype (12.8 events/100 person-years) and the lowest in Hb-S +-thalassemia genotype (3.9 events/100 personyears) (4). ACS is the second most common cause of hospitalization in sickle cell patients and the most common complication of surgery and anesthesia (5). 

Children have higher incidences of ACS (21 events/100 person-years, Hb SS genotype) but lower mortality (<2 percent) than adults (8.7 events /100 person-years and 4-9 percent mortality) (3,6). In SCD-SS persons, the incidence of ACS is related to low fetal hemoglobin (Hb F) levels and high steady-state hematocrits and white cell counts, but not to coexistent a-thalassemia (4). Children have seasonal variation in ACS incidence: lower in the summer, but higher in winter when respiratory infections are frequent (6). The seasonal pattern is less marked in adults. Even though the ACS usually is self-limited, it can present with or progress to respiratory failure, characterized by noncardiogenic pulmonary edema and severe hypoxemia. These critically ill patients need both respiratory support and emergency transfusions (see below).

The Multicenter Acute Chest Syndrome Study (MACSS) Group enrolled 538 patients with 671 ACS episodes in a comprehensive, standardized diagnostic and management protocol (3). The protocol included bacteriology, virology, and serologic studies, as well as examination of bronchoscopy-obtained secretions or deep sputum samples. In 108 of 364 episodes (30 percent) with complete diagnostic data, all results were negative, which led, by exclusion, to the diagnosis of pulmonary infarction. Fifty-nine of the 364 episodes (16.2 percent) had pulmonary fat embolization (PFE) defined by the finding of lipidladen macrophages in broncho-alveolar lavage specimens. About one-third of the PFE cases showed evidence of infection. Previous studies on mostly older patients had reported higher prevalences of PFE (44 to 77 percent) in ACS (7,8). Patients with PFE tend to be older and have lower oxygen saturations (3). An infectious agent was identified in 197 episodes (54 percent) but a wide variety of microorganisms was found, the most common of which were chlamydia (48 episodes, 13 percent), mycoplasma (44 episodes, 12 percent) and viruses (43 episodes, 12 percent). In 30 ACS episodes (8.2 percent), bacteria were isolated, which included Staphylococcus aureus, Streptococcus pneumoniae, and Hemophilus influenzae.

The MACSS reported findings from the first ACS episode in 128 adults and 419 children (82 percent with Hb SS genotype) (3). This study used strict criteria to define ACS: a pulmonary infiltrate consistent with consolidation, plus at least one of the following: chest pain, fever over 38.5°C, tachypnea, wheezing, or cough. An earlier series, the Cooperative Study of Sickle Cell Disease (CSSCD) enrolled 252 adults and 687 children (76 percent with SS genotype) who had a total of 1722 episodes of ACS (6) defined by the appearance of a new pulmonary infiltrate on the chest x ray. Table 1 summarizes findings from both of these prospective series.

Clearly, the MACSS enrolled more severely ill patients than did the CSSCD, as shown by more frequent use of red cell transfusions, longer hospital stays, and higher death rate, particularly in adult patients. In the MACSS, multilobe involvement, history of cardiac disease, and lower platelet counts independently predicted respiratory failure. Low platelet counts also were associated with neurologic complications.

Oxygen. Assessment of blood oxygenation requires determination of baseline arterial blood gases (ABG), and estimation of the alveolararterial (A-a) oxygen gradient and the PaO2/FiO2 ratio. Oxygen should be administered to moderately hypoxemic patients (PaO2 = 70-80 mm Hg, O2 saturation = 92-95 percent) nasally at a rate of 2 liters per min.

Chronically hypoxemic patients in whom the admission PaO2 is no lower than in their steady state may still benefit from oxygen because they may not tolerate additional hypoxemia due to ACS. Control of chest pain and incentive spirometry can prevent hypoventilation in most patients (9). The efficacy of these interventions should be checked with repeated ABGs as needed to monitor the A-a gradient, which appears to be the best predictor of clinical severity (10). Patients with worsening A-a gradients should be managed in an intensive care unit for adequate cardiorespiratory support.

Transfusions. Simple transfusions (or exchange transfusions) decrease the proportion of sickle red cells and are indicated for the treatment of ACS (3,11) (see chapter 25, Transfusion, Iron Overload, and Chelation). Transfusions will increase the oxygen affinity of blood in sickle cell patients (12). The main indication for transfusion therapy is poor respiratory function.

The goal is to prevent progression of ACS to acute respiratory failure. Two studies,though nonrandomized, demonstrate the effect of blood transfusion on oxygenation in ACS patients (table 2).

 From the data above, it would appear that transfusions or exchange transfusions should be initiated at the first sign of hypoxemia (PaO2 below 70 mmHg on room air). For patients with chronic hypoxemia, a drop in PaO2 of greater than 10 percent from baseline seems to be a reasonable transfusion trigger.

Transfusions may not be needed if the A-a oxygen gradient is due to splinting from pain, that is, if the gradient corrects with analgesia and incentive spirometry. Transfusion therapy should not be delayed, particularly in deteriorating patients. Altered mentation in such patients is often erroneously attributed to opioid excess, delaying the therapy of progressive acute chest syndrome.

Antibiotics. Intravenous broad-spectrum antibiotics should be given to febrile or severely ill ACS patients since it is difficult to exclude bacterial pneumonia or superinfection of a lung infarct. The MACSS used erythromycin and cephalosporin. A macrolide or quinolone antibiotic always should be included because atypical microorganisms are common (3).

Other measures. Optimal pain control and incentive spirometry are important to prevent chest splinting and atelectasis. A randomized controlled study showed that incentive spirometry reduced the risk of development of ACS by 88 percent in patients hospitalized with thoracic bone ischemia/infarction (9).

Airway hyperreactivity occurs in up to one fourth of ACS patients and is treated with bronchodilators. Fluid overload should be avoided by the use of 5 percent dextrose in water or 1/2- or 1/4-normal saline, and by limiting the infusion rate to 1.5 times maintenance requirements (3). More studies are needed to establish the safety and efficacy of the use of dexamethasone (13) and otherapproaches, such as nitric oxide inhalation (14), in the treatment of ACS.

The short-term prognosis of ACS with limited lung involvement and only mild hypoxemia is good. Some reports suggest an association between chronic pulmonary disease and frequent ACS episodes (15,16), but others did not find long-term lung damage in patients with recurrent ACS (17). In any case, frequent ACS episodes or painful events are associated with shorter lifespans (4). The frequency of ACS can be reduced by about 50 percent with hydroxyurea treatment (18). Nonrandomized observations suggest that transfusion regimens can prevent ACS. A preliminary report from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) showed that patients randomized to receive transfusions had significantly fewer ACS events (2.2/100 personyears), compared to patients in the nontransfused arm (15.7/100 person-years, p<0.001).

SYSTEMIC FAT EMBOLIZATION SYNDROME

Bone marrow infarction and necrosis is a known complication of SCD (19). When an infarct is massive, necrotic marrow and fat embolize to the pulmonary vasculature. Fat droplets can enter the systemic circulation, which results in systemic fat embolization (SFE) syndrome. Thus, in addition to respiratory insufficiency, patients can develop multiorgan failure from emboli in organs such as the brain and kidneys. SFE can affect patients with even the mildest forms of SCD. Few case reports are available (20,21), but risk factors for SFE appear to be a Hb SC genotype, pregnancy, and prior corticosteroid treatment. Clinical signs of SFE vary and depend on the organs involved and the degree of involvement.

Initially there may be a painful event, but patients can present with or develop a fever, hypoxemia, azotemia, liver damage, altered mental state, or coma. Hematologic signs include progressive anemia, normoblastemia, thrombocytopenia, and disseminated intravascular coagulation. A high index of suspicion for SFE should be maintained, even though this diagnosis is hard to prove. Fortunately, this problem is often preceded or accompanied by pulmonary involvement (severe chest syndrome, pulmonary fat embolism), so that transfusions given to hypoxemic ACS patients may prevent or inhibit the development of SFE.

Because SFE is life-threatening but difficult to recognize, a proposal for management includes the following:

- A high index of suspicion for SFE should be maintained, and all cases of ACS are considered to be at risk. Treatment of SFE should not await proof of diagnosis, since only two premortem findings prove SFE in sickle cell or trauma patients: detection of fat droplets within retinal vessels and a biopsy of petechiae (22) that shows microvascular fat. Urine fat stains are unreliable. Indirect evidence of SFE in sickle cell patients includes positive fat stain in bronchial macrophages, lung microvascular cells, or venous blood buffy coat (23) and multiple areas of necrosis on bone marrow scans. The descriptions of these signs are anecdotal in SCD-related SFE (and in non-SCD patients with fat emboli due to trauma).

- As in cases of severe ACS, support in a critical care setting is essential to manage respiratory insufficiency and multiorgan  failure. Case reports suggest that prompt transfusion or exchange transfusion may prevent some deaths from SFE (20). Since fat embolism causes severe hypoxemia which promotes Hb S polymerization, it seems likely that transfused normal blood will dilute the patient’s sickle cells and improve pulmonary and systemic microvascular circulation. Survival in sickle cell patients with SFE has been reported only in those treated with transfusions.

Airway hyperreactivity (asthma) is not a classical feature of SCD, but transgenic mouse models of SCD have airway obstruction that is responsive to albuterol. Cold air challenge induced hyperresponsiveness in 83 percent of asymptomatic children with SCD who had a history of reactive airways (24). Also, two large prospective studies of ACS described above reported wheezing in 11 percent (6) and 26 percent (3) of patients on admission. In the latter group, the mean predicted forced expiratory volume was 53 percent, and 61 percent of patients were treated with bronchodilators.

Twenty percent of ACS patients improved with bronchodilators and had a 15 percent increase in predicted forced expiratory volume (3). Like nonhemoglobinopathy subjects, asthmatic sickle cell patients are treated with inhaled bronchodilators, with or without inhaled steroids. Steroids can be added systemically to manage acute asthma, but sickle cell patients should be monitored for the development of vaso-occlusive events.

Pulmonary hypertension (PHT), defined as a mean pulmonary artery pressure above 25 mmHg, can be secondary to SCD (20), but its prevalence is not known. In sickle cell patients the frequency of chronic lung disease with cor pulmonale is reported at 4.3 percent. PHT is probably more frequent in adult patients (20), although it was not listed as an underlying condition in 209 adult CSSCD patients who died during that study (25).

The mechanisms for PHT in SCD are not known. One or more of the following factors could be responsible: sickle cell-related vasculopathy, chronic oxygen desaturation or sleep hypoventilation (26), pulmonary damage from recurrent chest syndrome (15), repeated episodes of thromboembolism (27), or high pulmonary blood flow due to anemia. The last reason, combined with decreased lung vasculature, also was given as a cause of PHT in thalassemia intermedia (28). Regardless of the exact mechanism, the development of PHT raises the risk for cor pulmonale, recurrent pulmonary thrombosis, and worsened hypoxemia, all of which increase the frequency and severity of vaso-occlusive episodes (pain events, ACS) in SCD (15).

The diagnosis of PHT should be considered in sickle cell patients with (a) increased intensity of the second heart sound, (b) right ventricular enlargement on chest x ray, EKG, or echocardiogram, or (c) unexplained oxygen desaturation.

As PHT worsens, patients complain of chest pain and dyspnea, and have hypoxemiaat rest. Additional problems are rightsided heart failure, syncope, and a risk of sudden death from pulmonary thromboembolism, systemic hypotension, or cardiac arrhythmia. Unless an echocardiogram shows tricuspid regurgitation with increased pulmonary artery pressure, the diagnosis of PHT requires rightsided cardiac catheterization. In a few patients whose catheterization results were published, the pulmonary pressures were lower and cardiac outputs (measured by thermodilution) were higher than in primary PHT (20).

There is no proven treatment for sickle cellrelated PHT. Therefore, recommendations are tentative and based mostly on what is known about the treatment of primary PHT. During cardiac catheterization, vasodilators or oxygen may be given to see if they reduce pulmonary pressure acutely in order to predict the benefit of long-term administration. Continuous infusion of prostacyclin, a vasodilator and inhibitor of platelet aggregation, improves pulmonary artery pressure and survival in primary PHT (29), and also may be effective in secondary PHT (30). This drug also causes some patients with SCD-related PHT to respond during cardiac catheterization (31), but there are no published data on long-term use. Other agents used to treat primary PHT are the calciumchannel blockers nifedipine and diltiazem (32), and these or similar medications could be tried in responsive sickle cell patients.

Long-term anticoagulation with warfarin [to an international normalized ratio (INR) of 2-3] is used in primary PHT because of the risk of thromboembolism (29) and also may be useful for SCD-related PHT (27).

Continuous or nocturnal oxygen therapy decreases pulmonary artery pressure in patients who are hypoxemic from various lung disorders. It should be used in SCD-related PHT if it lowers pulmonary pressure at cardiac catheterization, and in chronically hypoxemic patients (PaO2 <60 mmHg, O2 saturation <90 percent). A red cell transfusion program would help to reduce the incidence of vasoocclusive events, ACS, lung scarring, and PHT in some patients. Hydroxyurea would be expected to have the same effect, but it does not seem to prevent the development of PHT in SCD.

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